tbuckley/cabot-search huggingface dataset:
Abstract 16: 3,3'-diindolylmethane induces cytoglobin expression and synergizes with poly ADP ribose polymerase inhibitor PJ34 to inhibit triple negative breast cancer cell growth
Authors: Jonathan V. Wooten, Nicole Mavingire, Leah Rowland, Jason Matthews, Eileen Brantley
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC), characterized by tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), carries a poor prognosis. While recently approved poly ADP ribose polymerase (PARP) inhibitor olaparib shows favorable activity in patients with TNBC harboring tumors deficient in DNA repair enzyme BRCA1, patients with TNBC possessing BRCA1-proficient tumors are largely unresponsive to olaparib. Emerging evidence suggests that small molecules that activate aryl hydrocarbon receptor (AhR) signaling have the capacity to confer anticancer actions. 3,3′-diindolylmethane (DIM), an AhR ligand, is the major metabolite of indole-3-carbinol (I3C) found in cruciferous vegetables such as broccoli. Patients often consume natural product-derived AhR ligands while undergoing chemotherapy. It is therefore crucial to enhance our understanding of nutraceutical-pharmaceutical interactions. We previously demonstrated the ability of synthetic AhR ligands to induce the expression of putative tumor suppressor cytoglobin (CYGB) and inhibit Akt signaling in breast cancer cells. Since PARP inhibitor PJ34 has been shown to synergize with Akt inhibitors we hypothesize that DIM induces CYGB expression and synergizes with PJ34 to inhibit TNBC cell growth. Using the Alamar Blue assay, we found that DIM substantially enhanced the sensitivity of TNBC BRCA1 proficient cells to PJ34, though knockdown of CYGB did not significantly influence the responsiveness of cells to DIM. Chromatin immunoprecipitation followed by next-generation sequencing data revealed that DIM promoted the binding of AhR to the CYGB promoter in breast cancer cells. Finally, DIM induced CYGB gene expression in TNBC cells as determined by quantitative PCR. Taken together, our data suggest that DIM upregulates CYGB in TNBC cells and synergizes with PJ34 to confer anticancer actions in TNBC. Our data provide a rationale for incorporating the use of natural product-derived AhR ligands as a strategy to enhance PARP inhibitor efficacy in patients with TNBC that have BRCA1-proficient tumors. Citation Format: Jonathan V. Wooten, Nicole Mavingire, Leah Rowland, Jason Matthews, Eileen Brantley. 3,3'-diindolylmethane induces cytoglobin expression and synergizes with poly ADP ribose polymerase inhibitor PJ34 to inhibit triple negative breast cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 16.
Abstract 4244: Novel expressed long non-coding RNAs in uveal melanoma
Authors: Daniel A. Rodriguez, Jeffim N. Kuznetsov, Margaret I. Sanchez, Stefan Kurtenbach, J. William Harbour
Journal: Cancer Research (2019)

Abstract Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UMs can be divided into two prognostic groups based on their gene expression profile (GEP). The class 1 GEP is associated with low metastatic risk and the class 2 GEP with high metastatic risk. Class 1 tumors are associated with EIF1AX or SF3B1 mutations while Class 2 tumors are associated with inactivating mutations in the tumor suppressor BAP1. Class 1 and Class 2 UMs have been shown to differ in their expression of numerous known micro-RNAs and long non-coding RNAs (lncRNA). Here, we sought to identify novel differentially expressed lncRNAs using a publicly available RNA-Seq database. Raw RNA-Seq fastq files from 80 TCGA UM samples were obtained from the Cancer Genomics Hub (CGHub), quality controlled using FastQC (v0.11.3), and trimmed using trim-galor (v0.4.1). Sequences were aligned to the human genome (GRCh38) and accompanying general transfer format file (gtf) (Gencode v28) using STAR (v2.5). Transcript discovery was performed using Cufflinks (v2.2.1). Protein coding probability was calculated using CPC (v2.0), and transcripts predicted to be non-coding with transcript length &amp;gt;200bps were retained. 1671 novel transcripts were added to the gtf file, and fastq files were realigned with the new annotation. Estimated counts for all known and novel transcripts were generated using RSEM (v1.3.0) after STAR alignment. A cutoff of RPKM &amp;gt; 1 in at least 35% of tumors was used as a threshold for transcripts of interest, resulting in 61 novel transcripts, 32 of which were differentially expressed at FDR &amp;lt; 0.05 between Class 1 and Class 2 tumors, including 7 upregulated and 25 downregulated in Class 2 tumors. Further work is underway to elucidate the function of these novel transcripts in UM pathogenesis. Citation Format: Daniel A. Rodriguez, Jeffim N. Kuznetsov, Margaret I. Sanchez, Stefan Kurtenbach, J. William Harbour. Novel expressed long non-coding RNAs in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4244.
Abstract 185: Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line
Authors: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Ali Alaseem, Sivanesan Dhandayuthapani, Appu Rathinavelu
Journal: Cancer Research (2019)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive and lethal types of brain cancers with low 5-year survival rate. Therefore, search for better drugs and effective treatment strategies for GBM to improve patient outcomes is continuing. Since GBM is one of the most highly vascularized solid tumors and its growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors seems to be one of the promising approaches. In this context, intensive pre-clinical evaluation of our patented anti-angiogenic compound, code-named F16, has exhibited potent anti-angiogenic and anti-tumor activities via selectively antagonizing VEGFR-2 in both in vitro and in vivo models. More importantly, assessment of biochemical parameters that are reflecting the safety of F16 in the in vivo system showed no alterations in the toxicological parameters of heart, liver, kidney, and pancreas, after 30 days of treatment, at the dose of 100 mg/kg body weight. Hence, we tested the direct effects of F16 for inhibiting the growth, angiogenesis and the migratory abilities of the U87MG glioblastoma cells, which are known to express high levels of VEGFR. Our in vitro studies have confirmed potent inhibitory effects of F16 towards the migration and invasion of U87MG cells, and also revealed potent cytotoxic effects (IC50 26 µM) against U87MG cells in comparison to Temozolomide (IC50 430 µM) treatment. In addition, F16 inhibited the phosphorylation of VEGFR-2 through competitive binding and also induced cell cycle arrest and apoptosis by activating p53 pathway in U87MG cells. Furthermore, our in vivo results with ectopically implanted xenograft model confirm the fact that F16 can significantly inhibit tumor growth in the mice implanted with U87MG glioblastoma cell line. Based on our preliminary results, we are proposing that F16 could be a potential candidate for treating GBM, either in monotherapy or in combination with a cytoreductive drug. (This research was supported by the generous funds provided by the Community Foundation of Broward, Florida and also by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida) Citation Format: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Ali Alaseem, Sivanesan Dhandayuthapani, Appu Rathinavelu. Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 185.
Abstract 2493: Disulfide bond disproportionation agents activates the death receptor 5 pathway to kill highly resistant breast cancer
Authors: Mengxiong Wang
Journal: Cancer Research (2019)

Abstract There are significant unmet medical needs among patients who have HER2+ breast cancers that have acquired resistance to targeted agents, and patients with Triple-Negative Breast Cancers (TNBCs) that lack therapeutic targets. Novel treatment strategies are needed to target these cancers. Disulfide bond Disproportionation Agents (DDAs) represent a new chemical class of anticancer drugs and show prominent anti-cancer activities both in vitro and in animal model. Blockade of breast tumor growth by DDAs is associated with downregulation of EGFR/HER2/HER3 in parallel, induction of AKT dephosphorylation, and activation of ER stress. However, it is not known how DDAs trigger cancer cell death without affecting non-transformed cells. This study aims to investigate the death pathways involved in the anti-cancer activities of DDAs, and to develop strategies that target drug resistant breast cancer and cancer metastasis. This study demonstrates that DDAs induce breast cancer cell death by activating the Death Receptor 5 (DR5) pathway. DDAs are the first compounds identified that upregulate DR5 via both transcriptional and post-transcriptional mechanisms and uniquely cause DR5 accumulation and oligomerization by altering DR5 disulfide bond pattern. This study also shows that the combination of DDAs and Tumor Necrosis Family-Related Apoptosis-Inducing Ligand (TRAIL), a natural ligand of DR5, significantly overcomes TRAIL resistance that has been encountered in clinical trials with this ligand. Furthermore, DDAs and TRAIL synergistically kill Lapatinib-resistant breast cancer and cancer metastatic cells, and that this anti-cancer effect is amplified by the overexpression of EGFR/HER2/MYC. Together, this study highlights a promising novel pharmacological approach against drug resistant cancer and cancer metastasis. Citation Format: Mengxiong Wang. Disulfide bond disproportionation agents activates the death receptor 5 pathway to kill highly resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2493.
Abstract 2829: Pancreatic tumor microbiome and associated immune responses determine clinical outcomes
Authors: Erick M. Riquelme, Yu Zhang, Liangliang Zhang, Montiel Maria, Zoltan Michelle, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Nadim Ajami, Joseph Petrosino, Christine B. Peterson, Deborah Nejman, Michael P. Kim, Cynthia L. Sears, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo, Florencia McAllister
Journal: Cancer Research (2019)

Abstract Most patients diagnosed with pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a very small subset of patients survive longer. The factors that determine the long-term survivorship remain elusive. Recently, studies have shown that bacteria can be found in PDAC which may influence therapy responses. In this study, we aimed to determine if the tumor microbiome, and its associated immune responses, can guide long-term survivorship in resected PDAC patients. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition and immunoprofile in PDAC patients who survived less than 5 years (short term survivors, STS) versus those who survived more than 5 years (long term survivors, LTS) in two independent cohorts of patients from two institutions (MD Anderson Cancer Center and Johns Hopkins University). We found higher alpha-diversity in the tumor microbiome from LTS compared to STS PDAC patients. Additionally, we found greater densities of immune cells in the LTS compared to STS, with significant correlation with alpha-diversity. Taken together, our study demonstrates that the PDAC microbiome composition may influence the host immune response and the natural history of the disease. E.R. and Y.Z. contributed equally to this work. Citation Format: Erick M. Riquelme, Yu Zhang, Liangliang Zhang, Montiel Maria, Zoltan Michelle, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Nadim Ajami, Joseph Petrosino, Christine B. Peterson, Deborah Nejman, Michael P. Kim, Cynthia L. Sears, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo, Florencia McAllister. Pancreatic tumor microbiome and associated immune responses determine clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2829.
Abstract 1937: pH-responsive tumor-targeted mesoporous silica nanoparticle for the identification of pancreatic cancer using optoacoustic tomography
Authors: William MacCuaig, Abhilash Samykutty, Molly McNally, Kylie Nairon, Surya Banks, William Grizzle, Lacey R. McNally
Journal: Cancer Research (2019)

Abstract Purpose: Due to inadequate early detection and inability to operate at advanced stages, pancreatic ductal adenocarcinoma (PDAC) has remained one of the most difficult types of cancer to treat. A small range of non-specific symptoms coupled with quick metastasis rate result in a poor 5-year survival rate; 14% for those diagnosed within stage IA, and as low as 1% for those diagnosed during stage IV. Nanoparticles have recently emerged as a potential delivery agent for diagnostic and therapeutic agents, and although clinical success has not been ample due to targeting accuracy issues. This work shows a nanoparticle that has been functionalized with a pancreatic cancer-specific targeting ligand and exhibits specific particle release in pancreatic malignant environment (pH 6.6) as compared to non-malignant environments (pH 7.4). Methods: Wormhole-pored mesoporous silica nanoparticles were formed at 80°C using Tetrapropyl orthosilicate (TPOS) and a scaffold of hexadecyltrimethyl-ammonium bromide (CTAB). Acetic acid and ethanol were used in dialysis procedures to remove the CTAB scaffold and create worm-like pores. Chitosan was added to coat the silica particles and serve as a gatekeeper. IR-780 was added before the solution was acidified to load the dye into the worm-hole particles created. Shortly after, the solution pH was raised back to physiological levels (pH=7.4) to trap the dye within the particle. The particle surfaces were functionalized to attach a targeting ligand pH-low insertion peptide (V7) to conjugate the dye-loaded nanoparticles. Pancreatic adenocarcinoma cells (S2VP10 line) were plated in pH-7.4,6.8, and 6.6 PBS solutions with the loaded particles to assess uptake via near-infrared fluorescence and multispectral optoacoustic imaging. Results: Zeta potential and dynamic light scattering were used to ensure the 63nm size nanoparticle and proper coating. Near-infrared fluorescence imaging showed ~10X increased signal at pH 6.6 as compared to pH=7.4. MSOT imaging ~5X increased signal in the malignant microenvironment environment that is acidic as compared to the non-malignant environment at pH 7.4. Conclusion: The functionalized wormhole mesoporous silica nanoparticles coated with chitosan demonstrated pH-sensitivity in terms of cellular uptake via NIR fluorescence and MSOT imaging. Citation Format: William MacCuaig, Abhilash Samykutty, Molly McNally, Kylie Nairon, Surya Banks, William Grizzle, Lacey R. McNally. pH-responsive tumor-targeted mesoporous silica nanoparticle for the identification of pancreatic cancer using optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1937.
Abstract 20769: Sudden Cardiac Death Risk After Hospitalization for Heart Failure: Insights From EVEREST
Authors: Muthiah Vaduganathan, Robert J Mentz, Haris Subacius, Ravi B Patel, Neal A Chatterjee, Stephen J Greene, Andrew P Ambrosy, Aldo P Maggioni, James E Udelson, Karl Swedberg, Marvin A Konstam, Christopher M O'Connor, Javed Butler, Mihai Gheorghiade, Faiez Zannad
Journal: Circulation (2017)

Introduction: Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device-based therapies that target sudden cardiac death (SCD). However, uncertainty...
Abstract 4687: Gastric cancer stem cell-related marker LINGO2 is associated with cancer phenotype and poor patient survival
Authors: Soo Been Park, Jung Hyun Jo, Chanyang Kim, Hee Seung Lee, Dawoon E. Jung, Si Young Song
Journal: Cancer Research (2019)

Abstract The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2), has been reported in Parkinson’s disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, and tumorigenicity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility and tumorigenicity while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced AKT/MEK/ERK phosphorylation and decreased EMT-associated markers - N-cadherin and Vimentin and stemness-associated markers - OCT4 and IHH. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment. Citation Format: Soo Been Park, Jung Hyun Jo, Chanyang Kim, Hee Seung Lee, Dawoon E. Jung, Si Young Song. Gastric cancer stem cell-related marker LINGO2 is associated with cancer phenotype and poor patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4687.
Endoscopic resection of a large adenocarcinoma involving the appendix using a full-thickness resection device
Authors: Gianluca Andrisani, Francesco Di Matteo
Journal: Endoscopy (2019)

The endoscopic treatment of adenomas involving the appendiceal orifice with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is a big challenge, even for experienced endoscopists, because of the high risks of incomplete resection and perforation [1] [2] [3]. To date, these lesions have usually required surgical therapy, for example ileocecal resection. Endoscopic full-thickness resection (EFTR) using a full-thickness resection device (FTRD; Ovesco, Tübingen, Germany) was introduced in 2011. Since 2014, the device has had a Conformité Européene (CE) mark and been commercially available in Europe. The device has been well investigated in several studies [4] [5] and one indication for its use is lesions involving the appendix [4] [5].
Abstract 986: High content analysis of 2D and 3D oncology models for target and phenotypic drug discovery
Authors: Servane Lachize, Rhea van de Bospoort, Marta da Silva da Silva, Niki van der Steentraten, Ian Gowers, Roger Clark, Jeroen DeGroot, Ian Waddell, Hajo Schiewe, Shushant Jain
Journal: Cancer Research (2019)

Abstract Charles River (CR) has developed many disease-relevant cellular models to screen small molecules and genetic modifiers for target and phenotypic based drug discovery. Our expertise and portfolio in bespoke oncology model development (e.g. patient derived xenografts) covers a wide variety of target classes such as inhibitors of cell cycle, cellular motility and migration and transcription factor translocation. Complex cellular models derived from primary cells, patient derived embryonic stem cells and induced pluripotent stem cells have been adapted for phenotypic screening. Models have been further developed to produce physiologically relevant multicellular structure co-cultures. Combining complex biological systems with multiparametric high content analysis provides detailed single cell quantification of cellular and subcellular biology. Such validated High Content assays can be applied to both target and phenotypic based drug-discovery platforms to support preclinical drug discovery and improve translation of targets and compounds to the clinic. Citation Format: Servane Lachize, Rhea van de Bospoort, Marta da Silva da Silva, Niki van der Steentraten, Ian Gowers, Roger Clark, Jeroen DeGroot, Ian Waddell, Hajo Schiewe, Shushant Jain. High content analysis of 2D and 3D oncology models for target and phenotypic drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 986.
Abstract 1718: Down-regulation of p16INK4a by hYSK1 promotes cancer cell migration under hypoxic conditions
Authors: Mee-Hyun Lee, Jung-Hyun Shim, Zigang Dong, Young-Joon Surh, Bu Young Choi
Journal: Cancer Research (2019)

Abstract The alteration expression of p16INK4a, a well-known cyclin-dependent kinase inhibitor involved in cancer cell cycle control, is unclear, especially under hypoxic conditions. To evaluate p16INK4a regulation, we performed a protein microarray analysis. Among 1,800 proteins, we identified hYSK1 as a novel protein that interacts with the tumor suppressor p16INK4a. hYSK1, a member of the Ste20 family of serine/threonine protein kinases, promotes cell migration &amp; tumorigenesis and is activated by oxidative stress. However, the molecular mechanisms underlying the oncogenic potential of hYSK1 remain elusive. Here, we report here that hYSK1 interacts with p16INK4a under hypoxic conditions like tumors, where it negatively regulates p16INK4a, enhancing cancer cell migration. Hypoxic stimulation of hYSK1 reduces p16INK4a accumulation through p16 promoter regulation to interact with unphosporylated SP-1 &amp; increases matrix metalloproteinase-2 (MMP-2) expression by activating the MMP-2 promoter associated with cell migration and proliferation.Conversely, knocking down hYSK1 expression activated p16INK4a expression &amp; suppressed MMP-2 expression.Thus, hYSK1 is necessary as a trigger for inactivating p16INK4a &amp; activating MMP-2 during tumor migration, suggesting that hYSK1 is a specific negative regulator of the tumor suppressor p16INK4a may represent a novel molecular target for reactivation of tumor suppressor genes in humans. Citation Format: Mee-Hyun Lee, Jung-Hyun Shim, Zigang Dong, Young-Joon Surh, Bu Young Choi. Down-regulation of p16INK4a by hYSK1 promotes cancer cell migration under hypoxic conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1718.