bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1366: MBD4 guards against DNA damage from methylcytosine deamination
Authors: Chew Edward , Sanders Mathijs A. , Flensburg Christoffer , Zeilemaker Annelieke , Miller Sarah E. , Hinai Adil S. al , Bajel Ashish , Luiken Bram , Rijken Melissa , Mclennan Tamara , Hoogenboezem Remco M. , Kavelaars François G. , Blewitt Marnie E. , Bindels Eric M. , Alexander Warren S. , Löwenberg Bob , Roberts Andrew W. , Majewski Ian J. , Valk Peter J. 
Published: August 2018

Abstract
Spontaneous methylcytosine (5mC) deamination is a common source of cytosine to thymine (C&gt;T) mutations. These mutations accumulate over time, serving as a “molecular clock” that tracks cellular age. MBD4 is a thymine glycosylase that recognises sites of 5mC deamination and initiates base excision repair.
Three patients (of whom 2 are siblings) with germline MBD4 loss of function (LOF) mutations developed acute myeloid leukemia (AML) at a young age (&lt;35 years old). Whole exome (WES) and whole genome sequencing (WGS) showed an elevated C&gt;T mutation rate ~33 times the average for AML. The mutations occurred nearly exclusively at CG dinucleotides. Reduced representation bisulfite sequencing showed the mutations occurred at previously methylated cytosines. The 3 AMLs had somatic C&gt;T mutations in the same driver genes (DNMT3A and either IDH1 or IDH2), suggesting the methylation damage charts a recurrent path towards malignancy in the hematopoietic system.
MBD4 is inactivated in other cancers, although this appears to be a rare event. Nine of 10,638 cancers in the TCGA database had MBD4 LOF mutations. In a uveal melanoma and a glioblastoma multiforme, there was also loss of heterozygosity of the wild-type MBD4. These 2 cancers with MBD4 deficiency exhibit the same mutational signature, with a high C&gt;T mutation rate at CG dinucleotides.
To verify the link between MBD4 and the 5mC damage signature, Mbd4-/- and Mbd4+/+ mouse bone marrow were cultured in semi-solid agar and WGS was performed on individual myeloid progenitor colonies. Mbd4-/- myeloid progenitor colonies displayed the same increase in C&gt;T mutations at CG dinucleotides. This highlights the importance of MBD4 across species.
Mbd4 deficient mice offer a model system to investigate mutation acquisition and cancer pathogenesis. Work on the interaction of MBD4 with other leukaemia initiating genes is underway.
Citation Format: Edward Chew, Mathijs A. Sanders, Christoffer Flensburg, Annelieke Zeilemaker, Sarah E. Miller, Adil S. al Hinai, Ashish Bajel, Bram Luiken, Melissa Rijken, Tamara Mclennan, Remco M. Hoogenboezem, François G. Kavelaars, Marnie E. Blewitt, Eric M. Bindels, Warren S. Alexander, Bob Löwenberg, Andrew W. Roberts, Ian J. Majewski, Peter J. Valk. MBD4 guards against DNA damage from methylcytosine deamination [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 1366.
Abstract 1367: BRCA1 and BARD1 protein interactions that are required for DNA repair function
Authors: Adamovich Aleksandra , Wingo Margaret , Banerjee Tapahsama , Gardner Miranda , Freitas Michael , Parvin Jeffrey 
Published: August 2018

Abstract
Breast and ovarian cancers are prevalent among women, and hereditary breast and ovarian cancers (HBOCs) have been associated with germline mutations in genes such as BRCA1 and BARD1. BRCA1 and BARD1 form an obligate heterodimer, and the BRCA1/BARD1 complex is required for tumor suppression functions. Our lab has tested hundreds of BARD1 and BRCA1 variants and identified many that are deficient in homologous recombination, which we have shown to accurately predict cancer predisposition in the clinic. Several of these functionally defective BRCA1 mutants map to a pocket of amino acids on the surface of the protein that does not have any known binding partners. Repair-deficient mutations are also present on the surface of the BARD1 protein in domains that are not known to be associated with DNA repair. We hypothesize that the DNA repair deficiencies mediated by these BRCA1 and BARD1 mutants are due to differences in protein binding when compared to wild-type protein. We have found that BRCA1 mutants in this protein pocket do not phosphorylate and do not localize to the nucleus following DNA damage, both of which are characteristic of the DNA damage response. However, BARD1 repair-deficient mutants still bind phosphorylated BRCA1, indicating that their deficiencies are not due to loss of BRCA1 function. To investigate protein interaction differences we are creating fusion proteins of wild-type and mutant BRCA1 with BioID2, which will biotinylate proteins that bind to BRCA1. We will then be able to identify, via avidin purification and mass spectrometry, protein interactions that are present in the wild-type but absent in the mutant BRCA1. Novel proteins that we identify will be tested for DNA repair and tumor suppressor function. This information will allow us to better understand both BARD1 and BRCA1 function and the mechanism of homologous recombination.
Citation Format: Aleksandra Adamovich, Margaret Wingo, Tapahsama Banerjee, Miranda Gardner, Michael Freitas, Jeffrey Parvin. BRCA1 and BARD1 protein interactions that are required for DNA repair function [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 1367.
Abstract 1373: Circular RNAs generated from the BRCA1 pseudogene regulates the DNA damage response through SERBP1 RNA-binding protein
Authors: Han Yoo J. , Zhang Jing , Mason Jennifer M. , Yoshimatsu Toshio F. , Du Xinxin , Hurley Ian , Kim Danny E. , Anantharaman Aparna , Brunet Laia P. , Prat Aleix , Kwon John , Prasanth Kannanganattu V. , Olopade Olufunmilayo I. 
Published: August 2018

Abstract
The genomic region encompassing the BRCA1 gene includes the BRCA1P1 pseudogene (BRCA1P1) within ~170kb at chromosome 17q21. The homology and proximity of BRCA1 and BRCA1P1 create a hot spot for recombination, resulting in a large genomic rearrangement found in some families with breast and ovarian cancers. While the significant role of BRCA1 in regulating the DNA damage response (DDR) is well defined, little is known about the biological properties of the BRCA1P1 pseudogene. To functionally annotate BRCA1P1, we conducted a CRISPR-Cas 9 knockout of the pseudogene, as well as knockdown of the expression using antisense oligonucleotides. Both knockout and knockdown of the pseudogene result in increases in apoptosis and sensitivity to DNA damaging drugs. Depletion of BRCA1P1 accumulates spontaneous DNA damage foci and leads to replication fork stalling. Mechanical studies reveal that the BRCA1P1 generates circular RNAs, which are retained in nuclei. Mass spectrometry followed by chromatin isolation by RNA purification (ChIRP) identifies a specific association of the circular RNAs with SERBP1 RNA-binding protein, which was confirmed by ChIRP-Western. Consequently, BRCA1P1 knockout decreased SERBP1 protein expression in the nuclei. Based on the previous report that SERBP1 binds to mRNAs of DDR proteins and controls their translation, we propose a mechanism of BRCA1P1-driven regulation of DDR protein expression through SERBP1. Our data indicate that the BRCA1P1 pseudogene plays a role in regulating replication fork progression and genomic instability in breast cancer cells through an interaction with SERBP1 RNA-binding protein.
Citation Format: Yoo J. Han, Jing Zhang, Jennifer M. Mason, Toshio F. Yoshimatsu, Xinxin Du, Ian Hurley, Danny E. Kim, Aparna Anantharaman, Laia P. Brunet, Aleix Prat, John Kwon, Kannanganattu V. Prasanth, Olufunmilayo I. Olopade. Circular RNAs generated from the BRCA1 pseudogene regulates the DNA damage response through SERBP1 RNA-binding protein [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 1373.
Abstract 1381: Targeting histone acetyltransferases to reprogram high C-MYC expressing cancers
Authors: Costa Elodie M. Da , Armaos Gregory , Beaudry Annie , Richer Chantal , Caron Maxime , St-Onge Pascal , Johnson Jeffrey , Krogan Nevan , Sai Yuka , Downey Michael , Sinnett Daniel , McGraw Serge , Raynal Noël J. 
Published: August 2018

Abstract
In cancer, epigenetic modifications are strongly altered and are responsible for gene expression aberrations. In a drug screening initiative, we recently reported that proscillaridin, a cardiac glycoside (CG), exhibits unsuspected epigenetic and anticancer activities. To understand CG's epigenetic mechanisms of action, we performed RNA sequencing analysis, which showed proscillaridin effects on global gene expressions in acute lymphoblastic leukemia cells (MOLT-4). Genes associated with apoptosis and cell differentiation were upregulated whereas master transcription factors and oncogenic pathway genes were downregulated. Mechanistic studies revealed that proscillaridin decreased histone 3 acetylation, which correlated with histone acetyltransferase (KATs) downregulation (CBP, P300, TIP60, GCN5 and MOZ). Acetylome studies by mass spectrometry showed an acetylation loss in chromatin regulators, the oncogene C-MYC and its associated proteins. Proscillaridin induced C-MYC transcript and protein degradation. Moreover, in a panel of cancer cell lines, we measured that cancer cells sensitivity to proscillaridin treatment was positively correlated with C-MYC protein levels. Conversely, proscillaridin did not affect C-MYC protein level in low C-MYC expressing cancer cell lines. For the first time, we showed that CGs target histone acetyltransferases and C-MYC oncogene in high C-MYC expressing cancers. We propose that CGs can be repurposed as new epigenetic drugs in high C-MYC expressing cancers.
Citation Format: Elodie M. Da Costa, Gregory Armaos, Annie Beaudry, Chantal Richer, Maxime Caron, Pascal St-Onge, Jeffrey Johnson, Nevan Krogan, Yuka Sai, Michael Downey, Daniel Sinnett, Serge McGraw, Noël J. Raynal. Targeting histone acetyltransferases to reprogram high C-MYC expressing cancers [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 1381.
Abstract 1386: Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study
Authors: Albany Costantine , Hashemi Neda S. , Fang Fang , Lowder James , Einhorn Lawrence , Nephew Kenneth 
Published: August 2018

Abstract
BACKGROUND: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Germ cell tumor including platinum-resistant embryonal carcinoma cells lines are extremely sensitive to hypomethylating agents and low dose decitabine can restore cisplatin sensitivity in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT.
METHODS: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of guadecitabine in combination with cisplatin, determine the maximum tolerated and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT02429466.
FINDINGS: Between 2015 and 2017, we enrolled and treated 10 patients. Grade 3 or 4 adverse events were febrile neutropenia, thrombocytopenia, anemia, and diarrhea. The most common serious adverse events were febrile neutropenia and thrombocytopenia. Guadecitabine 45 mg/m2 was associated with prolonged SAE and felt to be unsafe to continue. The maximum tolerated dose was 30 mg/m2 daily × 5. Two patients achieved a complete response to treatment lasting more than 6 months.
INTERPRETATION: Guadecitabine SQ at 30 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with platinum-refractory GCT. The study is still ongoing.
Citation Format: Costantine Albany, Neda S. Hashemi, Fang Fang, James Lowder, Lawrence Einhorn, Kenneth Nephew. Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study [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 1386.
Abstract 1393: JARID1 family inhibitor recovers sensitivity of drug-tolerant subpopulation in lung cancer cell lines
Authors: Ariga Shin , Kinoshita Ichiro , Kikuchi Junko , Shimizu Yasushi , Dosaka-Akita Hirotoshi 
Published: August 2018

Abstract
Epigenetic alteration contributes to tumor initiation, progression and invasion. Epigenetic machinery has become a major focus for the new development of molecular targeted cancer therapeutics. H3K4 trimethylation (H3K4me3) is an epigenetic mark which exist surrounding the transcription start site and have been presumed to be associated with cancer stem like cells. JARID1 family is demethylase of H3K4me2/me3. Especially, JARID1a and JARID1b have been suggested to have oncogenic properties in several cancers, including lung cancer. Here we examined the effects of a JARID1 family inhibitor against human lung cancer cell lines. 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) was screened from more than 15000 small molecules as a JARID1 family inhibitor by Sayegh et al. First, we confirmed that PBIT increased H3K4me3 levels in time-dependent and dose-dependent manners in non-small cell lung cancer cell lines. PBIT inhibited cell growth in a dose-dependent manner with the IC50 value of about 10 µM to 30 µM. Next, we detected drug-tolerant persisters (DTPs) from each cell line by exposing them to very high concentration of the drug that is effective to each of the cell lines (gefitinib 10µ for PC9, PC3 and HCC827; AZD9291 5µM for H1975; CDDP 100µM for H226; paclitaxel 500nM for H460, A549 and H1299). DTPs detected were less than 1% in each cell line after 9-day exposure. These small subpopulations showed increased expression of JARID1a and/or JARID1b. Likewise, side population cells, which are considered to contain cancer stem like cells, showed increased expression of JARID1a and decreased H3K4me3 levels. PBIT in combination with anticancer drugs reduced colony formation of DTPs from all cell lines whose DTPs formed colonies. The DTPs showed decreased H3K4me3 levels and increased expression of cancer stem cell marker Oct-4, while these changes were abrogated by subsequent PBIT treatment. These results indicate that PBIT, a JARID1 family inhibitor, recovers sensitivity of drug-resistant lung cancer cells.
Citation Format: Shin Ariga, Ichiro Kinoshita, Junko Kikuchi, Yasushi Shimizu, Hirotoshi Dosaka-Akita. JARID1 family inhibitor recovers sensitivity of drug-tolerant subpopulation in lung cancer cell lines [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 1393.
Abstract 1394: Resistance to BET inhibitor leads to new therapeutic vulnerabilities in castration resistant prostate cancer
Authors: Pawar Aishwarya S. , Asangani Irfan A. 
Published: August 2018

Abstract
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration resistant prostate cancer (CRPC) cells. Bromodomain and extraterminal protein (BET) inhibitors displace BRD4 protein from chromatin, resulting in the inhibition of oncogenic transcriptional programs. Several BET inhibitors (BETi) are in phase I clinical trials for a variety of malignancies including CRPC. Here we describe a general mechanism of acquired resistance to BETi due to modulation of cellular pathways that are amenable to targeted therapies in CRPC cells. BETi resistant CRPC cells displayed cross resistance to a variety of BETi in the absence of gatekeeper mutations or persistent drug pump activation. Resistant cells exhibited reduced chromatin bound BRD4, and were less sensitive to Proteolysis Targeting Chimeric (PROTAC) -mediated degradation or genetic knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR-signaling due to CDK9-mediated serine-81 phosphorylation of AR, with a consequent increase in sensitivity to CDK9 inhibitors and anti-androgens in BETi resistant cells. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DNA damage response (DDR) genes was observed due to the loss of BRD4 from their proximal promoter regions in the resistant cells, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy in CRPC. However, data showing the reactivation of AR-signaling and increased DNA damage in the BETi resistant cells provide unique opportunities for combination therapies in managing CRPC.
Citation Format: Aishwarya S. Pawar, Irfan A. Asangani. Resistance to BET inhibitor leads to new therapeutic vulnerabilities in castration resistant 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 1394.
Abstract 1397: The regulation of DNMT3B expression by lncRNA-NCRMS in cancer
Authors: Peng Wan-xin , Mo Yin-yuan 
Published: August 2018

Abstract
5-aza-2'-deoxycytidine (decitabine; DAC) is an inhibitor of DNA methyltransferases which catalyze the transfer of a methyl group to DNA. It is well known that aberrant hypermethylation occurs in many types of tumors and often contributes to suppression of important genes such as tumor suppressor genes. Reactivation of the methylated genes by DAC has been shown to induce cytotoxicity and cell cycle dynamics. Increasing evidence indicates that lncRNAs may play critical roles in cancer development through epigenetic regulation of gene expression. However, little is known whether and how lncRNAs are involved in regulation of methylation pathways. In present study, we applies the CRISPR/Cas9-based synergistic activation mediator (SAM) system to a DAC-induced cytotoxicity model to identify potential lncRNAs capable of conferring the resistance to DAC in breast cancer. This screen identified several potential lncRNA candidates and among them is NCRMS which is capable of promoting resistance to DAC. We further confirmed that ectopic expression of NCRMS causes resistance to DAC whereas knockout of NCRMS increases the sensitivity to DAC. Mechanistically, NCRMS functions as a positive regulator of DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B). Further characterizations demonstrated that NCRMS promotes the stability of DNMT3B mRNA. Together, these results suggest that NCRMS may serve as a potential target for cancer therapy. Studies are underway to delineate the detailed mechanism of how NCRMS regulates the stability of DNMT3B mRNA.
Citation Format: Wan-xin Peng, Yin-yuan Mo. The regulation of DNMT3B expression by lncRNA-NCRMS in 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 1397.
Abstract 1399: Passenger deletion vulnerability in glioblastoma
Authors: Oatman Nicole , Komurov Kakajan , Arora Priyanka , Desai Pankaj , Dasgupta Nupur , Choi Kwangmin , Dasgupta Biplab 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM) is the most common, aggressive and lethal primary brain tumor in humans. Despite aggressive therapy the median survival of GBM patients is approximately 15 months. Monoallelic loss of PTEN occurs in ~70% of GBM. Through experimental validation studies in patient-derived primary GBM cell lines, we discovered that the lipogenic gene SCD undergoes unintended co-deletion as a passenger to PTEN, resulting in hemizygous loss of SCD in a subset of GBM. Additional in silico, genetic and biochemical analysis lead to the identification of two distinct PTEN-deleted subgroups: one with hemizygous co-deletion of PTEN and SCD (hereafter SCD-expressing), and another with very little or no PTEN/SCD expression due to PTEN mutation/homozygous loss and epigenetic suppression of the remaining SCD allele (hereafter SCD-non-expressing). SCD is an integral membrane protein of the endoplasmic reticulum (ER), involved in mediating the rate-limiting step of unsaturated fatty acid biosynthesis. SCD catalyzes the desaturation of the saturated fatty acids stearic (C18:0) and palmitic acids (C16:0) to the monounsaturated fatty acids oleic (C18:1) and palmitoleic acids (C16:1), respectively. We showed that the SCD-expressing lines are highly sensitive to SCD inhibition in the absence of dietary oleate and that the SCD-non-expressing lines are resistant to SCD inhibition. In vivo, we showed that mice treated with the SCD inhibitor survive longer than mice treated with vehicle. We also showed that SCD-expressing GBM lines acquire inhibitor resistance upon long-term exposure to the inhibitor in vitro. To understand the mechanism of resistance, we performed Reverse Phase Protein Array (RRPA) and RNA-Seq. Results illustrated the up-regulation of SCD among other genes. To identify the gene/s that provide SCD inhibitor resistance, we are currently performing a targeted shRNA screen of the highly expressed genes that we determined through RPPA and RNA-Seq.
Citation Format: Nicole Oatman, Kakajan Komurov, Priyanka Arora, Pankaj Desai, Nupur Dasgupta, Kwangmin Choi, Biplab Dasgupta. Passenger deletion vulnerability in glioblastoma [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 1399.