bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-178: Oxidation markers in relation to prostate cancer and BPH and progression of prostate cancer
Authors: Wu Tianying , Bracken Bruce , Kasper Susan 
Published: August 2018

Abstract
Prostate cancer (PCa) is the leading cancer affecting men of all races in the U.S. Benign prostatic hyperplasia (BPH) is prostate enlargement and is not malignant. BPH and PCa have similar symptoms and both have elevated PSA levels. A biomarker which can distinguish PCa from BPH will help the diagnosis of PCa and avoid unnecessary biopsies. Further, many PCa patients after prostatectomy can have recurrence. Currently, PSA is the only monitoring marker for recurrence; however, the underlying mechanism for recurrence is unknown. A mechanistic marker that can predict the progression and recurrence this will allow us to design prevention strategies. Many animal studies have linked oxidative stress with PCa progression and recurrence. The aim of this study is to compare the levels of several oxidation markers between PCa and BPH, and compare the levels of oxidation marker in different stages of PCa and determine their associations with PSA velocities after prostatectomy. We have measured multiple oxidation markers including lipid, protein, DNA, carbohydrate and global oxidation markers. We have collected blood samples among 15 BPH and 22 prostate cancer patients who have prostatectomy. We have found that levels of advanced glycation end products (AGEs), a marker of glucose oxidation, formed under nonenzymatic glycation of lipids and proteins, are higher in PCa patients than BPH. However, among PCa patients, AGEs levels are lower among those with Gleason score higher than 7 than those with Gleason score less than 7. Finally, we have found F2-isoprostanes, a well-established lipid oxidation marker, are associated with PSA velocities among PCa patients who had prostatectomy. Our results suggest that AGEs can help distinguish BPH and PCa but are associated with lower grade PCa. Measurement of F2-isoprostanes, a marker of lipid oxidation can predict PCa progression among men with prostatectomy.
Citation Format: Tianying Wu, Bruce Bracken, Susan Kasper. Oxidation markers in relation to prostate cancer and BPH and progression of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-178.
Abstract LB-183: Investigating the role of polarity protein, SCRIB, in hematopoiesis
Authors: Novita Novita , Dew Alysha , Johnson Chad , Walkley Carl R. , Purton Louise E. , Humbert Patrick O. , Darcy Phillip K. , Ellis Sarah L. 
Published: August 2018

Abstract
Acting as both a polarity regulator and a scaffolding protein, Scribble (SCRIB), coordinates intracellular signalling pathways that regulate cell proliferation, migration and apoptosis. Deregulation of SCRIB has been linked to multiple epithelial cancers but the role of SCRIB in hematopoiesis and hematopoietic malignancies remains relatively unexplored. Using different approaches, we show that SCRIB is expressed in hematopoietic stem and progenitor cells and in their differentiated progenies, implying a role for SCRIB in blood production. We investigated the effect of SCRIB loss in hematopoiesis using two conditional knockout mouse models in conjunction with an extensive phenotypic labelling regime and multi-color flow cytometry. We reveal a role for SCRIB in T cell development although subtle differences between the two mouse models were noted. Compensatory mechanisms often mask the effects of single protein deletion during steady-state so stress hematopoiesis was induced through a transplant assay to minimise these effects. Lethally irradiated recipient mice receiving a transplant of SCRIB knockout bone marrow revealed a more striking phenotype with significantly altered populations of granulocyte, macrophage, erythroid, T and B cell progenitors, and mature macrophage fractions compared to controls. Collectively, our data shows SCRIB is required for the development of multiple hematopoietic fractions and studies are currently underway to identify the underlying mechanism/s and elucidate how deregulation of SCRIB impacts on hematopoietic malignancies.
Citation Format: Novita Novita, Alysha Dew, Chad Johnson, Carl R. Walkley, Louise E. Purton, Patrick O. Humbert, Phillip K. Darcy, Sarah L. Ellis. Investigating the role of polarity protein, SCRIB, in hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-183.
Abstract LB-191: BET inhibitors kill colorectal cancer cells by activating death receptor 5 through the ER stress response pathway
Authors: Tan Xiao , Tong Jingshan , Yu Jian , Shen Liangfang , Zhang Lin 
Published: August 2018

Abstract
Bromodomain and extra-terminal (BET) family proteins are epigenetic "readers" that are frequently activated in cancer and play an important role in regulating gene expression and oncogenic signaling. Targeting BET proteins using small-molecule inhibitors represents an attractive therapeutic strategy. Several small-molecule BET inhibitors have shown promises in recent preclinical and clinical studies. However, the mechanisms by which BET inhibitors selectively kill cancer cells are not well understood. In this study, we found that the BET inhibitors JQ1 and I-BET151 induce mRNA and protein expression of Death Receptor 5 (DR5) in a variety of colorectal cancer (CRC) cells with different genetic backgrounds. This is an on-target effect as knockdown of the BET family member BRD4 also induces DR5 expression. The induction of DR5 by the BET inhibitors is mediated by C/EBP homologous protein (CHOP) through the endoplasmic reticulum (ER) stress response pathway. Furthermore, knockout of DR5 in colon cancer cells suppresses apoptosis and caspase activation induced by the BET inhibitors, and abrogates their chemosensitization effects in CRC cells. Collectively, our results uncover a key role of DR5 in apoptosis induced by the BET inhibitors in CRC cells, and suggest activation of the death receptor pathway as a novel anticancer mechanism of BET-targeting agents.
Citation Format: Xiao Tan, Jingshan Tong, Jian Yu, Liangfang Shen, Lin Zhang. BET inhibitors kill colorectal cancer cells by activating death receptor 5 through the ER stress response pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-191.
Abstract LB-195: Identifying cooperative effects of tumor suppressor gene mutations in lung adenocarcinoma using paired CRISPR-Cas9
Authors: Perez-Oquendo Mabel G. , Feldser David M. , Walter David 
Published: August 2018

Abstract
Cancer is a heterogeneous disease that arises from the accumulation of genetic mutations that lead to a loss of tumor suppressor genes and activation of oncogenes. Mutational inactivation of genes that regulate epigenetic mechanisms, such as post translational modifications to DNA and histones, also contribute to cancer progression but the mechanisms are poorly understood. Trimethylation on histone 3 lysine 36 (H3K36me3) is encoded by the histone lysine methyltransferase (SETD2). SETD2 is recurrently inactivated by missense and frameshift mutations in multiple tumor types. Previously, we identified that Setd2 loss has potent tumor promoting activities in a mouse model of oncogenic Kras-induced lung adenocarcinoma. However, whether Setd2 loss has cooperating effects with other tumor suppressor gene mutations remains unstudied. To simultaneously inactivate distinct tumor suppressor genes, we use a lentiviral-based CRISPR/Cas gene editing approach to express a combination of specific gRNA-pairs along with Cas9 and Cre recombinase. Inhalation of these lentiviral particles leads activation of an oncogenic KrasLSL-G12D allele and simultaneously inactivation two gRNA-targeted genes. We hypothesize that SETD2 will collaborate with other tumor suppressor gene mutations in lung adenocarcinoma. To clone lentivirus vectors that have two different gRNA we use oligonucleotides encoding gRNAs targeting Setd2 and either Lkb1, Apc, or Rb1 to PCR amplify the 3' region of the murine U6 (mU6) promoter and the 5' region of the gRNA scaffold. Overlapping sequences in the 148-bp PCR amplicon, facilitate recombination with a 415-bp donor fragment derived from BbsI-digested pDonor plasmid using the Gibson cloning method. The newly circularized fragment is then re-linearized via BbsI digestion and cloned into LentiCRISPRv2Cre vector through the Golden Gate method using BsmBI type IIs restriction endonuclease and T4 DNA ligase. Our data demonstrate the development and presence of dual gRNA nucleotides through NotI/EcoRI restriction enzymes digestion and DNA Sequencing. Moreover, to study the cooperative effects of these mutations in mice, we created viruses and corroborated through Flow cytometry and Fluorescence microscopy. In conclusion, we generate lentiviral particles expressing pairs of gRNAs targeting distinct tumor suppressor genes, to identify cooperative effects of their mutation in lung adenocarcinoma models.
Citation Format: Mabel G. Perez-Oquendo, David M. Feldser, David Walter. Identifying cooperative effects of tumor suppressor gene mutations in lung adenocarcinoma using paired CRISPR-Cas9 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-195.
Abstract LB-198: Novel somatic mutations of PRKAR1A in sporadic cardiac myxomacardiac myxoma
Authors: He Jian 
Published: August 2018

Abstract
Background: Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in PRKAR1A. Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated
Methods: We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of PRKAR1A mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens.
Results: 87.5% (7/8) of ICM harbored mutations in PRKAR1A. Three of the 8 ICM harbored biallelic somatic mutations of PRKAR1A, including c.607_610del:p. Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A&gt;G (pathogenic) and c.178-1 G&gt;C (pathogenic) + c. 550+1 G&gt;C (pathogenic). Four of 8 tumors harbored monoallelic PRKAR1A mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating PRKAR1A mutations.
Conclusion: Our findings suggest that loss-of-function mutations of PRKAR1A may play a vital role in the formation of isolated cardiac myxomas.
Citation Format: Jian He. Novel somatic mutations of PRKAR1A in sporadic cardiac myxomacardiac myxoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-198.
Abstract LB-223: Examination of intra-assay variability in a commercial ctDNA NGS assay with triplicate clinical plasma and pooled normal samples
Authors: Stetson Daniel , Dougherty Brian , Ahmed Ambar , Nuttall Barrett , Lubinski Tristan J. , Afshar Fakhera , Raymond Amelia , Barrett Carl 
Published: August 2018

Abstract
The increased reliance on liquid biopsy next generation sequencing assays for oncology clinical decisions has highlighted the importance of understanding the factors that impact the analytical validation and clinical utility of these tests. Although recent studies have been published examining the concordance between tumor and plasma sequencing data from the same patient, there has been a lack of insight into the intra-assay variability within these tests. We have previously performed a replicate study across multiple ctDNA sequencing vendors and found a high degree of variability among assays particularly at low allele fractions (AF&lt;1%). To further extend our analysis, we examined the variability of ctDNA sequencing results from replicate patient plasma samples with the same vendor assay. The cohort consisted of 25 total samples: seven cancer patient plasma samples, representing triplicate 2 ml baseline plasma samples, plus four healthy normal samples, representing two different pools of six subjects in duplicate. The plasma names were blinded and shipped to Guardant Health for Guardant360 panel testing and both the raw data and reported variant calls were returned to AstraZeneca for comparative analysis. A total of 17 unique variants were called in this study, of which four variants were concordant for all three replicate plasmas and 13 variants were reported in only one or two replicates. Examining the raw data for all samples, the majority of the discordant variants were able to be identified at low levels. Plasmas had low amounts of ctDNA, and two patients had low unique molecule counts, with allele fractions ranging from 0.10-1.13%. Interestingly, the reported yield of the extracted DNA did not correlate with the ability to detect low frequency somatic variants. Data will be presented showing the unblinded comparisons between the replicate samples for both the cancer patient plasma data and the pooled normal plasmas. This study highlights the importance of reproducibility studies for ctDNA samples with variants at low allele fractions to discern between false negative and false positive finding.
Citation Format: Daniel Stetson, Brian Dougherty, Ambar Ahmed, Barrett Nuttall, Tristan J. Lubinski, Fakhera Afshar, Amelia Raymond, Carl Barrett. Examination of intra-assay variability in a commercial ctDNA NGS assay with triplicate clinical plasma and pooled normal samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-223.
Abstract LB-244: Overcoming resistance to DNA targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors
Authors: Ghafoor Azam , Tang Sai-Wen , Thomas Anish , Murai Junko , Trepel Jane B. , Bates Susan E. , Rajapakse Vinodh N. , Pommier Yves 
Published: August 2018

Abstract
Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release SLFN11 and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here. Experimental Design: SLFN11 expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on SLFN11 expression and sensitivity to DNA damaging agents. Results: SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11, transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested. Conclusion: This study reports the prevalent epigenetic regulation of SLFN11 and the dominant stimulatory effect of HDAC inhibitors on SLFN11 expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA damaging agents to overcome epigenetic inactivation of SLFN11-mediated resistance to DNA-targeted agents.
Citation Format: Azam Ghafoor, Sai-Wen Tang, Anish Thomas, Junko Murai, Jane B. Trepel, Susan E. Bates, Vinodh N. Rajapakse, Yves Pommier. Overcoming resistance to DNA targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-244.
Abstract LB-264: Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4
Authors: Mistrik Martin , Skrott Zdenek , Hajduch Marian , Friis Søren , Dzubak Petr , Gursky Jan , Majera Dusana , Ozdian Tomas , Vaclavkova Jana , Michalova Martina , Pouckova Pavla , Cvek Boris , Andersen Klaus Kaae , Bartek Jiři 
Published: August 2018

Abstract
Cancer incidence is rising and this global challenge is further exacerbated by resistance of advanced tumors to standard-of-care and emerging precision medicines. A promising approach to such unmet need for innovative and cost-effective cancer treatments is drug repurposing, exploitation of drugs already approved for other indications that show anticancer activity. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug that kills a broad range of cancer types in preclinical studies. Our nationwide population study reveals that patients who continued using disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. More importantly, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, present methods to detect its preferential accumulation in tumors and candidate biomarkers of impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-thought molecular target: NPL4 adapter of the p97/VCP segregase essential for protein recycling involved in multiple stress-response cellular pathways.
Citation Format: Martin Mistrik, Zdenek Skrott, Marian Hajduch, Søren Friis, Petr Dzubak, Jan Gursky, Dusana Majera, Tomas Ozdian, Jana Vaclavkova, Martina Michalova, Pavla Pouckova, Boris Cvek, Klaus Kaae Andersen, Jiři Bartek. Alcohol-aversion drug disulfiram targets cancer via p97 segregase adaptor NPL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-264.
Abstract LB-311: Inhibition of ubiquitin-specific protease 34 (USP34) regenerates mammary glands via induction of epithelial-mesenchymal transition (EMT) and stemness
Authors: Oh Eunhye , Sung Daeil , Kim Yoon-Jae , Cho Tae-Min , Jang Seojin , Kim Ji Young , Seo Jae Hong 
Published: August 2018

Abstract
Mammary stem cells (MaSCs) possess specific biological properties including self-renewal capacity and the ability to differentiate into two primary cell lineages; luminal cells and myoepithelial cells. Epithelial-mesenchymal transition (EMT) is a key process during mammary gland development. Recent study demonstrates that ubiquitin-specific protease 34 (USP34), as a member of the USP family plays a critical role in Wnt/b-catenin signaling pathway. Our objective was to investigate possible roles of USP34 on induction of EMT and properties of mammary epithelial stem cells as well as mammary gland regeneration. We observed that USP34 level was relatively lower in mesenchymal-like phenotype MDA-MB-231 and 4T1 cells, compared to epithelial-like phenotype cells. Inhibition of USP34 induced EMT in NMuMG cells, which was accompanied with upregulation of EMT markers, such as N-cadherin, phospho-smad3, snail and active-β-catenin as well as downregulation of E-cadherin. NMuMG cells exhibited a typical epithelial phenotype with an absence of invasive behavior, while USP34 knockdown NMuMG cells acquired an invasive property. This observation was associated with a significant increased MMP2 level. Furthermore, inhibition of USP34 promotes stemness as evidenced by increased mammosphere-forming ability, concomitant with upregulation of Nanog, Oct4 and Sox2 mRNA levels in NMuMG cells. To examine the importance observations of our in vitro studies physiologically, the CTL-KD or USP34-KD cells were transplanted into the cleared mammary fat pads (CFP), and then mammary gland regeneration was observed for 10 months. Our in vivo data showed that USP34-KD cells regenerated elongated ductal branching and TEB of mammary gland in CFP. Our findings suggest that USP34 may be potentially involved in development of mammary glands.
Citation Format: Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Tae-Min Cho, Seojin Jang, Ji Young Kim, Jae Hong Seo. Inhibition of ubiquitin-specific protease 34 (USP34) regenerates mammary glands via induction of epithelial-mesenchymal transition (EMT) and stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-311.