bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3138: SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: A multi-cohort analysis
Authors: LIU LIANG , Ahmed Tamjeed , Petty Willam Jeffrey , Grant Stefan , Ruiz Jimmy , Lycan Thomas W. , Topaloglu Umit , Chou Ping-Chieh , Miller Lance D. , Hawkins Gregory A. , Alexander-Miller Martha A. , O’Neill Stacey S. , Powell Bayard L. , D’Agostino Ralph B. , Munden Reginald F. , Pasche Boris , Zhang Wei 
Published: August 2019

Abstract
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 was co-mutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in 4 independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received non-immunotherapy treatment from 1) The Cancer Genome Atlas (TCGA) and 2) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from 3) the MSK-IMPACT (MSK-IO) and 4) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving non-immunotherapy treatment, in the TCGA cohort (n=155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome (P=6e-04 for disease-free survival (DFS) and .031 for overall survival (OS), respectively), compared to KRAS-TP53 co-mutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n=314), KS patients also exhibited shorter OS than KP (P=.03) or K (P=.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P=.0091) in the MSK-IO (n=77), and the shortest PFS (P=.0026) and OS (P=0.0014) in the WFBCCC (n=18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor that lead to adverse clinical outcome in lung adenocarcinoma treated by either non-immunotherapy or immunotherapy.
Citation Format: LIANG LIU, Tamjeed Ahmed, Willam Jeffrey Petty, Stefan Grant, Jimmy Ruiz, Thomas W. Lycan, Umit Topaloglu, Ping-Chieh Chou, Lance D. Miller, Gregory A. Hawkins, Martha A. Alexander-Miller, Stacey S. O’Neill, Bayard L. Powell, Ralph B. D’Agostino, Reginald F. Munden, Boris Pasche, Wei Zhang. SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: A multi-cohort analysis [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 3138.
Abstract 3319: Rare cell isolation by enhanced microfluidic filter using wing-shaped micro posts
Authors: Kasani Nanda , Yeriswamy Manjunath , Li Guangfu , Kaifi Jussuf , Kwon Jae W 
Published: August 2019

Abstract
Purpose: Study of effective isolation of rare cells using specially designed microfluidic filter.
Design: A novel microfluidic filter chip is proposed to enhance the isolation efficiency on rare cells, and has been successfully tested with micro beads and A549 cell lines using our unique designs of micro-posts. While most of the other filtration techniques have serious issues of channel clogging and prolonged processing, we have successfully accomplished outstanding improvements from such problems by utilizing inertial displacement through curved structures, built-in bypassing routes, and dedicated trapping zones. A solution containing polystyrene micro beads of 9.9 μm in diameter was successfully separated at the isolation efficiency of 96% with a high flow rate of 1ml/min. Additional experiments were also carried out, with A549 cell-lines in a PBS solution to see the filtration feasibility on bio-particles. Our device may offer an effective and reliable label free separation technique without channel blockage issues. By far, we have studied two design configurations called Model I and Model II. (Model II is an improved version of Model I).
Results: Capture efficiency of 96% was recorded from Model II for microbeads at the flowrate of 1ml/min. The capture efficiency of 85% was marked from Model I for microbeads at the flowrate of 1 ml/min. The relationship between the flowrate and capture efficiency has also been studied as shown in Table.1
Conclusion: Our studies demonstrate the excellence of our microfluidic devices with a capture efficiency of 96% and exhibits potential capabilities of isolating circulating tumor cells from peripheral blood of cancer patients.
Table 1: Flow rate vs Filtering efficiency of microbeads and A549 cells
Flow rate (ml/min)Model - I Filtering efficiency % (Standard Error Mean)Model II Filtering efficiency % (Standard Error Mean)MicrobeadsA549 cellsMicro beadsA549 cells185 (±4.5%)78 (±4.0%)96 (±3.4%)92 (±4.0%)1.580 (±4.0%)71 (±3.5%)90 (±3.1%)85 (±3.4%)273 (±3.5%)65 (±3.1%)84 (±2.8%)80 (±3.0%)2.556 (±2.6%)48 (±2.5%)80 (±2.3%)73 (±2.2%)345 (±2.2%)38 (±1.8%)70 (±2.0%)65 (±1.5%)
Citation Format: Nanda Kasani, Manjunath Yeriswamy, Guangfu Li, Jussuf Kaifi, Jae W Kwon. Rare cell isolation by enhanced microfluidic filter using wing-shaped micro posts [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 3319.
Abstract 4812: 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines
Authors: Kuroki Hiroo , Anraku Tsutomu , Bilim Vladimir , Tasaki Masayuki , Schmitt Daniel , Mazer Andrew , Giles Francis J. , Ugolkov Andrey , Tomita Yoshihiko 
Published: August 2019

Abstract
Glycogen synthase kinase-3beta (GSK-3β) is a serine/threonine protein kinase that has been established as a therapeutic target in a broad spectrum of human malignancies. We have previously identified aberrant GSK-3β nuclear expression in bladder cancer (BC), and demonstrated that GSK-3β positively regulated BC cell survival and proliferation. Our objective was to evaluate the antitumor effects of the clinically viable agent 9-ING-41, a maleimide-based ATP-competitive GSK-3 inhibitor, which has broad spectrum antitumor activity and marked activity in reversing chemoresistance in a variety of pre-clinical models of human cancers. We used flow cytometry, Western immunoblotting, quantitative RT-PCR, BrDU incorporation and MTS assays to examine antitumor activity of 9-ING-41 in BC (T24, HT1376, RT4 cell lines). Additionally, we studied combination therapy of 9-ING-41 with gemcitabine and cisplatin, standard agents used for the treatment of patients with advanced BC, with cabozantinib, a multi kinase inhibitor, and with chloroquine, an autophagy inhibitor. A dose-dependent decrease in cancer cell proliferation was observed by MTS assay and BrdU incorporation assay with GI50 0.7μM (T24), 4.7 μM(HT1376), 2.2μM(RT4). Treatment with 9-ING-41 induced prominent cell cycle arrest (predominantly G2 arrest) in BC cells. Expression of cell cycle related proteins, including Cyclin D, and anti-apoptotic proteins, such as XIAP and Bcl-2, were significantly decreased as detected by Western immunoblotting and real time RT-PCR. Treatment with 9-ING-41 significantly potentiated the growth inhibitory effect of cisplatin and gemcitabine in cultured cells. In addition, combination therapy with 9-ING-41 and cabozantinib or chloroquine, significantly potentiated the effect of either single agent. Our data proved that a single treatment using 9-ING-41 is effective in BC cells. Combination treatment of 9-ING-41 with standard chemotherapeutic drugs or novel agents may provide a new therapeutic approaches in BC. These data provide a rational for the inclusion of patients with advanced BC in clinical studies of 9-ING-41.
Citation Format: Hiroo Kuroki, Tsutomu Anraku, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew Mazer, Francis J. Giles, Andrey Ugolkov, Yoshihiko Tomita. 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines [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 4812.
Abstract 5201: Using Taqman assays to verify eQTL links arising from GWAS studies
Authors: Jackson Stephen M. , Veereshlingham Harita , Varma Kamini 
Published: August 2019

Abstract
Tremendous progress has been made using genome-wide association studies (GWAS) to link genetic variation with phenotypes and pathologies. In spite of these success, it has been estimated that as many as 90% of SNPs identified in GWAS studies map to non-coding regions, complicating the mechanistic interpretation of the results. It is thought that these non-coding SNPs fall into regulatory regions and influence the expression of a gene or genes. The study of expression quantitative trait loci (eQTLs) provides a method for understanding the link between genetic variants and altered gene expression, and could potentially provide new insights connecting GWAS results to molecular mechanisms. To illustrate how eQTLs can be found and verified, we generated transcriptomic information from various tumor samples using Applied Biosystems’ Clariom D microarrays. We also generated SNP genotyping data from the same samples using Applied Biosystems’ Axiom UK Biobank microarrays. To find putative eQTLs, we compared the SNPs genotypes and the gene expression levels in these samples to the GTEx database. Potential eQTLs in this set of samples were verified using Applied Biosystems’ Taqman SNP Genotyping and Taqman Gene Expression assays. We therefore illustrate a workflow where candidate eQTLs can be confirmed and screened in larger cohorts using the more economical qPCR reagents available from Applied Biosystems.
Citation Format: Stephen M. Jackson, Harita Veereshlingham, Kamini Varma. Using Taqman assays to verify eQTL links arising from GWAS studies [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 5201.
Abstract 649: Alpha -Santalol, a component of sandalwood oil inhibits migration of breast cancer cells by targeting beta-catenin pathway
Authors: Bommareddy Ajay , Knapp Kacey , Nemeth Abigail , Dwivedi Chandradhar 
Published: August 2019

Abstract
Alpha-santalol, a terpenoid found in sandalwood oil has been shown to inhibit breast cancer cell growth in vitro by inducing apoptosis but the mechanisms underlying the growth inhibitory effects of alpha-santalol are not fully understood. In this study, we demonstrate that alpha-santalol treatment targets Wnt/beta-catenin pathway to inhibit migration of cultured breast cancer cells. Exposure of MDA-MB 231 and MCF-7 cells to alpha-santalol resulted in a significant reduction in their migratory potential and wound healing ability. In addition alpha-santalol affected the localization of beta-catenin from cytosol to nucleus in MDA-MB 231 cells. In conclusion, the present study indicates that alpha-santalol inhibited migration of breast cancer cells may be mediated in part by targeting Wnt//β-catenin pathway, and that beta-catenin represents an important target of alpha-santalol’s response for future pre-clinical studies.
Citation Format: Ajay Bommareddy, Kacey Knapp, Abigail Nemeth, Chandradhar Dwivedi. Alpha -Santalol, a component of sandalwood oil inhibits migration of breast cancer cells by targeting beta-catenin pathway [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 649.
Abstract 670: Molecular basis of the idling state uncovers vulnerabilities suitable to sequential targeting in melanoma
Authors: Hayford Corey E. , Paudel Bishal B. , Harris Leonard A. , Hardeman Keisha N. , Tyson Darren R. , Quaranta Vito 
Published: August 2019

Abstract
Recent published work from the lab identified a novel “idling” population state in the response of BRAF-mutant melanoma cancer cell lines to BRAF inhibition. The idling state is marked by a long-term net-zero proliferation rate in drug treatment, resulting from a balance of division and death events within isogenic clonal populations. We hypothesize that the idling state is equivalent to stable disease in patients that experience short-term tumor reduction on targeted therapy (e.g. tumor stops growing or shrinking but is still capable of rebound). Specifically, the idling state may be a prelude to resistance as a reservoir for genetic modifications that lead to tumor rebound. It is therefore critical to understand the molecular mechanisms underlying the idling state, since they may point to exploitable treatment vulnerabilities. Here, we have characterized the idling state in several isogenic clonal lineages isolated from the melanoma SK-MEL-5 cell line across several biological scales, including genomics, transcriptomics, metabolism, and cell morphology. Consistently across these measurements, these lineages converge to a molecularly homogeneous phenotype, which we consider to be an idling state molecular signature. Prominent in this signature are genes involved in metabolism redox balance and neuronal cell differentiation. This convergence appears to be a property of many cell lineages in the SK-MEL-5 parental population, since they were observed in barcoded lineages at approximately the same abundance pre- and post-treatment. When treating cells in the idling state with drugs that target the convergent molecular signature, we observe remarkable cell death and a significant drug effect compared to untreated cells. Together, we propose that these data reflect a non-selective convergence mechanism to tolerate drug treatment. We expect idling state drug vulnerabilities may inform sequential drug treatment strategies that exploit convergence mechanisms and reduce the number of cells that could acquire genetic resistance modifications. It may also shed light on the mechanism to achieve complete remission for melanoma patients in the clinic.
Citation Format: Corey E. Hayford, Bishal B. Paudel, Leonard A. Harris, Keisha N. Hardeman, Darren R. Tyson, Vito Quaranta. Molecular basis of the idling state uncovers vulnerabilities suitable to sequential targeting in 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 670.
Abstract 935: Genetic modification potentiates the antitumor activity of human placental CD34+ cells-derived NK cells
Authors: Li James , Guo Xuan , Rana Hemlata , DiFiglia Andrea , Gleason Joseph , Herzberg Uri , Hariri Robert , Zhang Xiaokui 
Published: August 2019

Abstract
Celularity is currently developing a proprietary allogeneic NK cells (PNK) derived from human placental CD34+ progenitors for treatment of a broad spectrum of blood disorders and malignant diseases. To augment the anti-tumor function of CD34-derived PNK-cells, a study was conducted to simultaneous knock-out (KO) CBLB (negative regulator of NK cytotoxicity) and TGFβ receptor II TGFBR2 (tumor microenvironment) genes in PNK-cells using CRISPR/Cas9. In DKCT (Double Knockout CBLB TGFBR2) cells, high efficiency of editing (&gt;80%) was achieved for both genes and did not affect expansion and differentiation of CD34 cells into DKCT PNK-cells. The results showed that knocking-out CBLB (CBLB-KO) in PNK-cells led to an increase (2–4 fold) of cytotoxicity and cytokine secretion against a range of hematological and solid cancer cell lines as well as primary tumor cells. However, these enhanced functions from CBLB-KO PNK-cells were still found to be sensitive to TGFβ-mediated suppression. TGFBR2-KO rendered PNK-cells the ability to maintain high-level expression of NK activating receptors and resist inhibition of cytotoxicity after TGFβ exposure. The improved cytolytic function of DKCT cells in vitro was confirmed using xCELLigence platform. Furthermore, DKCT PNK-cells were insensitive to exogenous TGFβ and exhibited improved (2–4 fold) cytotoxicity. Subsequently, we compared the anti-tumor activity of DKCT to controls in an in vivo model of AML, where conditioned NSG mice were engrafted with HL60-GFP-luc cells 3 days prior to PNK-cell infusion. All four PNK-cell groups exhibited increased survival compared to vehicle. In CBLB-KO and DKCT groups, the tumor burden was similar but significantly reduced compared to Cas9 control or TGFBR2-KO. Future studies will address the benefit of DKCT PNK-cells in TGFβ secreting tumor-bearing animal models to pave the way for genetically modified NK cell therapy.
Citation Format: James Li, Xuan Guo, Hemlata Rana, Andrea DiFiglia, Joseph Gleason, Uri Herzberg, Robert Hariri, Xiaokui Zhang. Genetic modification potentiates the antitumor activity of human placental CD34+ cells-derived NK cells [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 935.
Abstract LB-117: Increased peripheral glucose levels restores chemotherapeutic efficacy in a mouse model of pancreatic cancer
Authors: Vaziri-Gohar Ali , Khokhar Imran , Titomihelakis George , Brody Jonathan R. , Winter Jordan M. 
Published: August 2019

Abstract
Pancreatic cancer is the third leading cause of cancer-related death in the United States. The 5-year survival rate is less than 10% and less than 5% for patients with metastatic disease due to the lack of effective therapy. Therefore, searching for novel therapies or strategies to improve existing therapies is a high priority in the field. The pancreatic cancer microenvironment comprises the majority of the tumor mass, and is characterized by a dense, fibrotic stroma, high interstitial fluid pressure and diminished vascularity. This creates a large nutrient gradient, such that pancreatic cancers must adapt to severely austere conditions to survive. We previously demonstrated that the harsh, nutrient-deprived conditions directly resulted in aggressive pancreatic cancer biology and chemotherapy resistance, in part due to activation of a stress response protein, HuR (ELAVL1). It also followed that higher blood glucose levels (e.g., diabetics) correlated with longer disease-free survival in pancreatic cancer patients who received gemcitabine after tumor resection. Herein, we extend this line of investigation in an in vivo mouse model of pancreatic cancer. First, we induced moderate hyperglycemia using a single dose of streptozotocin (120 mg/kg), which destroys beta islets in the pancreas. Blood glucose levels were titrated to a “non-toxic” level (~300 mg/dL) through daily injections of long-acting insulin, glargine. In a second independent model, we induced mild hyperglycemia by adding dextrose to the drinking water (30% dextrose). In both models, blood glucose levels and body weights were measured weekly, and mice were examined for the signs of distress. Interestingly, low-dose gemcitabine treatment, 50 mg/kg twice per week, significantly inhibited PDA xenograft growth under moderate and mild hyperglycemia. However, gemcitabine had no benefit in euglycemic mice with especially low levels of glucose in the xenograft microenvironment. These results demonstrate that chemotherapeutic efficacy may be potentially enhanced through forced induction of hyperglycemia in patients receiving chemotherapy.
Citation Format: Ali Vaziri-Gohar, Imran Khokhar, George Titomihelakis, Jonathan R. Brody, Jordan M. Winter. Increased peripheral glucose levels restores chemotherapeutic efficacy in a mouse model of pancreatic 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 LB-117.
Abstract LB-246: Apoptotic mechanisms of Vernonia amydalina delile in the prevention of prostate cancer
Authors: Yedjou Clement G. , Tchounwou Solange S. , Johnson William K. , Njiki Sylvianne , Tchounwou Paul B. 
Published: August 2019

Abstract
Prostate cancer is one of the common cancers in males and its incidence keeps increasing globally. Approximately 81% of prostate cancer is diagnosed during the early stage of the disease. The treatment options for prostate care include surgery, radiotherapy, and chemotherapy, but these treatments often have side effects that may result in a poor quality of life such as impotence or decreased bowel function. Our central goal is to test the apoptotic mechanisms of Vernonia amydalina Delile (an edible medicinal plant that is relatively inexpensive, non-toxic, and virtually without side effects) for the prevention of prostate cancer using human adenocarcinoma (PC-3) cells as a test model. To address our specific goal, PC-3 cells were treated with Vernonia amydalina Delile (VAD). Cell viability was determined by the MTT assay and cell morphology was analyzed by acridine orange and propidium iodide (AO/PI) dye using the fluorescent microscope. Cell cycle arrest and cell apoptosis were evaluated by Flow Cytometry assessment. Nucleosomal DNA fragmentation was detected by DNA laddering. Data obtained from the AO/PI dye assessment indicated that VAD significantly reduced the number of live cells in a dose-dependent manner, showing a gradual increase in the loss of viability in VAD-treated cells. A similar result was obtained by the MTT assay. We observed a significant increase in DNA damage in VAD-treated cells compared to the control group. Flow cytometry data demonstrated that VAD induced apoptosis in treated cells compared to the control cells. These results suggest that induction of cell death, cell cycle arrest, and cell apoptosis are involved in the therapeutic efficacy of VAD as anticancer candidate towards the prevention and/or treatment of prostate cancer.
Citation Format: Clement G. Yedjou, Solange S. Tchounwou, William K. Johnson, Sylvianne Njiki, Paul B. Tchounwou. Apoptotic mechanisms of Vernonia amydalina delile in the prevention of prostate 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 LB-246.