bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1001: Functional and mechanistic interrogation of androgen receptor degraders for the treatment of metastatic castration resistant prostate cancer
Authors: Kregel Steven , Wang Chao , Fernandez-Salas Ester , Wilder-Romans Kari , Han Xin , Qin Chong , Xiang Weiguo , Tien Jean , Cao Xuhong , Speers Corey , Wang Shaomeng , Chinnaiyan Arul M.
Published: August 2019

The clinical development of second-generation androgen receptor (AR) antagonists, including enzalutamide, has confirmed that the AR remains a key oncogene in castration-resistant prostate cancer (CRPC). However, response to enzalutamide is temporary and incremental, and prostate cancer (PCa) cells usually maintain AR expression and signaling upon resistance to AR-targeted therapies. One novel strategy for targeting the AR axis in CRPC is to target proteins through proteasomal degradation, which improves the efficacy and specificity of standard inhibitors. We have developed compounds that bind to AR and engage the proteasomal degradation machinery to specifically degrade the AR protein. Based on this, we hypothesized that the pharmacologic degradation of AR represents an important advance in CRPC treatment, and may provide a novel therapeutic strategy for advanced prostate cancer. These compounds affect AR-positive prostate cancer cells by decreasing AR protein levels as well as disrupting oncogenic AR signaling and enzalutamide resistance. Nanomolar concentrations of AR degraders ultimately lead to decreases in PCa cell growth in vitro and in vivo. In conclusion, we developed highly potent small molecules that induced proteasomal degradation of AR proteins, thus demonstrating degrader compounds to be a potential therapeutic strategy for patients with CRPC.

Citation Format: Steven Kregel, Chao Wang, Ester Fernandez-Salas, Kari Wilder-Romans, Xin Han, Chong Qin, Weiguo Xiang, Jean Tien, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan. Functional and mechanistic interrogation of androgen receptor degraders for the treatment of metastatic castration resistant 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 1001.
Abstract 1195: Stochastic co-evolution of the adaptive immune system and an evading cancer population
Authors: George Jason Thomas , Molldrem Jeffrey J. , Levine Herbert
Published: August 2019

Recent advances in immunotherapy have revolutionized modern cancer treatment. While encouraging, robust therapies that lead to durable remission outcomes still remain a challenge in curing many malignancies as cancer cells may acquire clones that effectively evade the immune system. Cancer immunotherapeutic treatment strategies are quite complex. In extreme cases, hematopoietic stem cell recipients enlist an entire allogeneic T-cell repertoire to fight against a growing malignancy. Perhaps most importantly, the adaptive nature of the immune system uniquely enables this treatment approach to co-evolve alongside an evasive threat. However, this process is poorly quantified and thus merits further study in order to maximally benefit cancer patients. Here, we develop a theoretical framework to quantify the dynamics between a growing collection of cancer cells capable of acquiring multiple evasive clones and a T-cell repertoire that may eventually recognize the evading populations. We create the first mathematical model of stochastic tumor-immune co-evolution by applying principles of stochastic process theory. We demonstrate that our model agrees with experimental time-course data in solid and liquid cancers and relate differences in branched vs. clonal evolution to the stringency of immunosurveillance present during early cancer progression. We argue that the clonal dynamics observed in leukemia patients treated with T-cell transplant therapy likely arise from the selection of pre-existent immune-evasive clones. In conclusion, our co-evolutionary model recapitulates empirical observations and offers a framework for quantifiable predictions to further improve cancer immunotherapy.

Citation Format: Jason Thomas George, Jeffrey J. Molldrem, Herbert Levine. Stochastic co-evolution of the adaptive immune system and an evading cancer population [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 1195.
Abstract 164: MALAT1 regulates the transcriptional and translational levels of proto-oncogene RUNX2 and promotes colorectal cancer metastasis
Authors: Ji Qing , Cai Guoxiang , Liu Xuan , Zhang Yi , Wang Yan , Zhou Lihong , Sui Hua , Li Qi
Published: August 2019

Ectopic expression of lncRNA-MALAT1 has been discovered in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients, however, its biological mechanism remained un-elucidated. Our study firstly revealed the novel mechanisms of MALAT1 in promoting CRC metastasis through at least the following two mechanisms: First of all, MALAT1 binds miR-15 family members, to “de-inhibit” their effect on LRP6 expression, enhances beta-catenin signaling, leading to elevated transcriptional levels of downstream target genes RUNX2. Secondly, MALAT1 binds SFPQ, dissociate SFPQ/PTBP2 dimer to release free PTBP2, which elevates translational levels of RUNX2, through interacting with IRES domain in the 5’UTR of the corresponding RUNX2 mRNAs. Moreover, elevated RUNX2 expression levels were detected in recurrent CRC tumors, which were closely associated with TMN stages and CRC patients’ survival. Our data demonstrated that, MALAT1 and RUNX2 may serve as two biomarkers for predicting the recurrence of CRC patients.

Note: This abstract was not presented at the meeting.

Citation Format: Qing Ji, Guoxiang Cai, Xuan Liu, Yi Zhang, Yan Wang, Lihong Zhou, Hua Sui, Qi Li. MALAT1 regulates the transcriptional and translational levels of proto-oncogene RUNX2 and promotes colorectal cancer metastasis [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 164.
Abstract 1736: Targeting Hsp90-Cdc37 complex overcomes drug resistance in glioma cells harboring FGFR3-TACC3 fusion gene
Authors: Li Tao , Mehraein-Ghomi Farideh , Namjoshi Sanjeev V. , Phillips Lynette M. , Ballard Elizabeth A. , Forbes Mary E. , Chou ping-Chieh , Yang Xuejun , Zhang Wei
Published: August 2019

Glioblastoma is one of the most lethal malignancies with the poorest prognosis among tumors of the central nervous system. Fusion genes are common chromosomal aberrations in many cancers that may give rise to an in-frame fusion protein with oncogenic function. These fusion genes can be used as prognostic markers as well as drug targets in clinical practice. The FGFR3-TACC3 (F3T3) fusion gene was discovered in glioblastoma, with an occurrence rate of up to 8.3% and leading to uncontrolled proliferation and chromosomal instability. Our studies have shown that glioblastoma cells harboring the F3T3 are resistant to the frontline glioblastoma drug Temozolomide (TMZ). Using the Comet assay, we show that TMZ-mediated DNA damage is repaired more rapidly in cells harboring the F3T3 compared to control. Our studies on the mechanism of this drug resistance show that the F3T3 confers an aberrant activation of FGFR and ERK pathways when treated with TMZ. To further explore druggable target(s) to overcome resistance caused by F3T3, we immunoprecipitated (IP) the proteins that interact with F3T3 in U251 glioblastoma cells overexpressing the F3T3 or wildtype FGFR3, followed by LC-MS/MS analyses. Our quantitative proteomic analysis revealed interactions of the F3T3 fusion protein with Hsp90α and Cdc37 proteins. These interactions were further validated by reciprocal IPs followed by Western blotting. Activation of many kinases, such as FGFRs, depends on their interaction with the Hsp90 molecular chaperone system. Hsp90 recruitment is mediated by the co-chaperone adaptor protein Cdc37, which simultaneously binds to both the kinase and Hsp90. To test inhibition of F3T3 association with the Hsp90-Cdc37 complex, we treated U251 cells constitutively expressing F3T3 with the Hsp90 inhibitor Onalespib. We show that Onalespib treatment at 26 nM significantly suppresses the proliferation of F3T3 expressing U251 cells in comparison to micromolar levels of the pan-FGFR inhibitor BGJ398 and PD173074. Our results provide evidence that the F3T3 fusion gene contributes to drug resistance via multiple chemo-resistance pathways. Importantly, our findings establish that F3T3 is an Hsp90 client that shows strong addiction to the Hsp90-Cdc37 complex for cell growth and suggests a novel strategy for targeting F3T3 fusion gene in glioma.

Citation Format: Tao Li, Farideh Mehraein-Ghomi, Sanjeev V. Namjoshi, Lynette M. Phillips, Elizabeth A. Ballard, Mary E. Forbes, ping-Chieh Chou, Xuejun Yang, Wei Zhang. Targeting Hsp90-Cdc37 complex overcomes drug resistance in glioma cells harboring FGFR3-TACC3 fusion gene [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 1736.
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

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

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

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

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

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

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

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 (>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

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

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.
Remission Patterns of Food Protein-Induced Enterocolitis Syndrome in a Greek Pediatric Population
Authors: Xepapadaki Paraskevi , Kitsioulis Nikolaos Aggelis , Manousakis Emmanouil , Manolaraki Ioanna , Douladiris Nikolaos , Papadopoulos Nikolaos G.
Published: August 2019

Background: Data on the prevalence and clinical course of food protein-induced enterocolitis syndrome (FPIES) vary between populations and according to the culprit food. Objective: To evaluate the incidence, clinical characteristics, and remission patterns of FPIES among children in a Greek pediatric allergy referral center. Methods: We retrospectively studied children with acute FPIES. Data on age, sex, type of reaction, the implicated food, and oral food challenge (OFC) outcomes at baseline and upon reevaluation were analyzed. Results: Between October 2010 and March 2017, 72 (38 males) out of 15,114 subjects who had been referred to our department due to any reported allergic symptoms were diagnosed with acute FPIES. The most commonly implicated foods were cow’s milk (CM) (45.8%), fish (34.7%), rice (9.7%), egg (6.9%), and chicken (2.8%). The mean age at diagnosis was 7.1/19.3/9.1/18.7/8.7 months for those with CM/fish/rice/egg/chicken FPIES, respectively. Sixty-nine OFCs were performed, of which 8 were diagnostic and 61 for tolerance evaluation. The type of culprit food was significantly associated with the outcome of the tolerance OFCs. OFCs to fish resulted positive at a significantly higher rate (12/22; 54.5%) than OFCs to CM (4/29; 13.7%), rice (1/5; 20%), egg (0/3; 0%), and chicken (0/2; 0%) (p = 0.01). The time period between diagnosis and tolerance acquisition was prolonged in the fish FPIES cases (74.8 months; 95% CI: 57.9–91.6) compared to that with other foods such as CM (20.7 months; 95% CI: 17.3–24.1), rice (31.8 months; 95% CI: 21.9–41.7), and egg (24.3 months; 95% CI: 10.7–37.9), as shown in a Kaplan-Meier analysis (log-rank, p < 0.001). When the fish FPIES children were assessed for tolerance, OFCs were significantly more often positive than in CM FPIES children (52 vs. 18.1%; p = 0.03), despite the fact that the children were challenged at an older age (fish: 70.4 months, 95% CI: 58.3–82.5, vs. CM: 26.57 months, 95% CI: 21.1–32, p < 0.001). Conclusions: Acute FPIES had a low incidence in our population. CM and fish were the two most frequent elicitors. Significantly delayed presentation and prolonged remission was noted for FPIES caused by fish.
Adaptation of the Modified Mini-Mental State Examination (3MS) and Determination of Its Normative Values in Turkey
Authors: Karadag Caman Ozge , Karahan Sevilay , Ünal Ferhat , Bilir Nazmi , Saka Esen , Barışkın Elif , Ayhan Yavuz
Published: August 2019

Background/Aims: This study aimed to adapt the Modified Mini-Mental State Examination (3MS) and determine its normative values in Turkey. Methods: After translation and cultural adaptation processes, a population-based study was conducted between February and June 2016 in Ankara with individuals over the age of 55 years. Subjects with a previous diagnosis of dementia along with neuropsychiatric disorders that might affect cognition were excluded. Data analyses were performed to assess the association of sociodemographic variables with 3MS scores. Results: Two versions of the Turkish 3MS (for educated and minimally educated individuals) were developed. A total of 2,235 participants were included in the field study. After exclusion, the data on the final sample of 1,909 individuals were analyzed, where age, gender, and education accounted for variance in 3MS scores. Younger age and higher educational attainment were associated with better 3MS performance. Conclusions: A widely applicable dementia screening test was adapted to Turkish and its normative values were determined. The test will make it possible to evaluate the cognitive performance of both educated and minimally educated elderly individuals based on their age, gender, and educational level.
Exposure to Cypress Pollens and Subsequent Symptoms: A Panel Study
Authors: Rakotozandry Thierry , Cassagne Etienne , Martin Sylvie , Alauzet Pierre , Navarro Ingrid , Delcroux Clémentine , Caillaud Denis , Besancenot Jean-Pierre , Thibaudon Michel , Charpin Denis
Published: August 2019

Objective: The objective of this panel study was to document the relationship between exposure to cypress pollen and allergic symptoms. Methods: The study group included 47 patients with allergy to cypress pollen who completed a daily diary and a weekly evaluation of quality of life (QoL) during the cypress pollen season. Different patients were included in three consecutive pollen seasons: 2014–2015, 2015–2016, and 2016–2017. Daily cypress pollen counts were obtained from the National Aerobiological Network. Air pollution and meteorological data were recorded on a daily basis. The pollen-symptoms relationship was quantified by calculating odds ratios for an increase of 1 log of grains of pollen/m3, taking into account potential confounding factors. The QoL score was expressed with a beta coefficient that increased with 1 grain of pollen/m3. Results: There was a marked increase in rhinitis and ocular symptoms during the pollen season, with a plateau effect at high levels of exposure, but no relationship with bronchial symptoms. The QoL score had a linear and significant relationship with the cypress pollen count. We did not detect any threshold level. Conclusion: This panel study demonstrated a significant association between exposure to cypress pollens and allergic symptoms, with a plateau effect for high exposures.
Congenital Hypothyroidism: 8-Year Experience Using 2 Newborn Screens in Alabama
Authors: Pitts Leslie , McCormick Winston , Mick Gail J.
Published: August 2019

Background/Aims: Newborn screening protocols for congenital hypothyroidism (CH) vary as to whether a TSH or T4 algorithm or some combination is performed. We aimed to determine the 3-year clinical outcome of infants diagnosed with CH and screen-positive for CH using a 2-screen protocol that measures both T4 and TSH on all specimens. Methods: Retrospective analysis of patients with CH who were detected by first (NBS1) or second (NBS2) newborn screen in Alabama (2009–2016) and followed at our university-based practice. Clinical follow-up established the final diagnoses in 146 patients, including a subset of 72 patients with eutopic glands. Results: 168 patients were studied: 139 (83%) were detected by NBS1 and 29 (17%) by NBS2. Screening T4 concentrations were 45% reduced in NBS2 compared to NBS1 (p= 0.0002). Thyroid dysgenesis was present in 55% of NBS1 patients while all in NBS2 were eutopic. Follow-up of 146 patients confirmed permanent CH in 92 patients in NBS1 (75%) and 5 in NBS2 (20%). Hispanic infants were only detected by NBS1, and 93% had permanent CH. Transient CH was associated with congenital heart disease. In patients with eutopic, permanent CH, dyshormonogenesis was confirmed in 23% of NBS1 patients and 40% of NBS2. One case of central CH was detected by each screen. Conclusions: This 8-year, retrospective study buttresses the importance of a 2-screen approach for CH by identifying 5 infants with clinically significant permanent thyroid dysfunction including dyshormonogenesis and central hypothyroidism. It is the first 2-screen study to incorporate thyroid ultrasound. Disconcertingly, 4 of 5 second-screen infants with permanent CH had no risk factors for CH, and these infants would otherwise not have been detected.
Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials
Authors: Kim Hawk , Lee Kyoo-Hyung , Sohn Sang Kyun , Kim Inho , Kim Sung-Hyun , Park Yong , Choi Jung Hye , Kwak Jae-Yong , Kim Min Kyoung , Bae Sung Hwa , Shin Ho-Jin , Won Jong Ho , Lee Won Sik , Choi Yunsuk ,   on behalf of the Korean Society of Blood and Marrow Transplantation
Published: August 2019

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.
Recognition and Treatment of Adrenal Insufficiency Secondary to Abiraterone: A Case Report and Literature Review
Authors: Baloch Harris M. , Grice-Patil Zachary Joseph , Selig Daniel Jaaron , Hoang Thanh D. , Mai Vinh Q. , Shakir Mohamed K.
Published: August 2019

Objective: Abiraterone is a relatively noncytotoxic drug approved by the US Food and Drug Administration in 2011 for the treatment of metastatic prostate cancer (MPC). As an inhibitor of 17α-hydroxylase and C17,20-lyase (CYP17), abiraterone blocks androgen synthesis and glucocorticoid production. Decreased cortisol levels result in an increased ACTH release, which can lead to increased mineralocorticoid levels. While coadministration of abiraterone and glucocorticoids has been effective in reducing an apparent mineralocorticoid excess, adequate replacement of physiologic glucocorticoids, especially in times of acute stress, remains less well-defined. Methods: A literature search was conducted using the PubMed and Google Scholar databases for abiraterone and adrenal insufficiency. Publications were selected based on the quality of the data and clinical relevance. We reviewed the landmark trials leading to FDA approval and establishment of the standard glucocorticoid replacement dosing. Results: We present 2 patients with MPC on abiraterone therapy. These 2 patients required modification of the glucocorticoid therapy because of adverse effects. Conclusions: We found that a standard dose of prednisone of 5 mg/day as recommended previously may be inadequate to achieve physiologic glucocorticoid replacement in some patients with prostate cancer while on abiraterone treatment and as a result adrenal insufficiency due to inadequate dosing might be more common than initially thought. Additionally 10 mg of prednisone daily may cause adverse effects in some patients. Thus clinicians should be aware of the potential for development of adrenal insufficiency or symptoms of glucocorticoid excess in these patients receiving prednisone so that appropriate modifications in glucocorticoid dosing can be instituted without any delay. Prednisone dosing may need to be individualized in each patient receiving abiraterone therapy.
Social Life in the Schizophrenia Spectrum: A Phenomenological Study of Five Patients
Authors: Nilsson Lars Siersbæk , Urfer Parnas Annick , Nordgaard Julie
Published: August 2019

Background: Social difficulties are a hallmark of schizophrenia spectrum conditions, yet their background and exact nature remain contested. Previous pivotal studies on chronically ill patients have suggested that a position of “positive withdrawal” is associated with a decreased tendency to rehospitalization. This concept designates an essentially withdrawn but not negatively experienced position balanced by elements relating the individual to the social world. Objectives: To explore a less ill subgroup of schizophrenia spectrum patients’ ways of navigating the social world and examine potential links to anomalous self-experiences by applying key insights from phenomenology and anthropology. Method: The present study was part of a 5-year follow-up on a group of first-admission schizophrenia spectrum patients. From this sample of 48 patients, 5 were selected for qualitative evaluation following the principles of thematic analysis. Results: A “positively withdrawn” position characterizes a wider group of patients than originally reported. Further, we identified a preference for partaking in social activities in particular circumstances with clearly circumscribed goals or social roles and rules. This alleviated social discomfort and helped patients stay embedded in a social milieu. All patients experienced high levels of self-disorders. Conclusions: We suggest that certain aspects of social impairment may, in fact, reflect meaningful compensatory mechanisms, and argue that this conceptualization of social difficulties is relevant to various psychotherapeutic interventions.
Plant‐Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All‐Cause Mortality in a General Population of Middle‐Aged Adults
Authors: Kim Hyunju , Caulfield Laura E. , Garcia‐Larsen Vanessa , Steffen Lyn M. , Coresh Josef , Rebholz Casey M.
Published: August 2019

Background

Previous studies have documented the cardiometabolic health benefits of plant‐based diets; however, these studies were conducted in selected study populations that had narrow generalizability.

Methods and Results

We used data from a community‐based cohort of middle‐aged adults (n=12 168) in the ARIC (Atherosclerosis Risk in Communities) study who were followed up from 1987 through 2016. Participants’ diet was classified using 4 diet indexes. In the overall plant‐based diet index and provegetarian diet index, higher intakes of all or selected plant foods received higher scores; in the healthy plant‐based diet index, higher intakes of only the healthy plant foods received higher scores; in the less healthy plant‐based diet index, higher intakes of only the less healthy plant foods received higher scores. In all indexes, higher intakes of animal foods received lower scores. Results from Cox proportional hazards models showed that participants in the highest versus lowest quintile for adherence to overall plant‐based diet index or provegetarian diet had a 16%, 31% to 32%, and 18% to 25% lower risk of cardiovascular disease, cardiovascular disease mortality, and all‐cause mortality, respectively, after adjusting for important confounders (all
P
<0.05 for trend). Higher adherence to a healthy plant‐based diet index was associated with a 19% and 11% lower risk of cardiovascular disease mortality and all‐cause mortality, respectively, but not incident cardiovascular disease (
P
<0.05 for trend). No associations were observed between the less healthy plant‐based diet index and the outcomes.

Conclusions

Diets higher in plant foods and lower in animal foods were associated with a lower risk of cardiovascular morbidity and mortality in a general population.