bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3429: Targeting gain-of-function of mutant p53 C-terminal and oligomerization domains to disrupt activated DNA replication in breast cancer
Authors: Lundine Devon , Annor George , Ellison Viola , Xiao Gu , Prives Carol , Bargonetti Jill 
Published: September 2020

Abstract
We recently documented that gain-of-function (GOF) mutant p53 (mtp53) R273H in triple negative breast cancer (TNBC) cells interacts with replicating DNA and PARP1 (Xiao et. al., Cancer Research 2019). The missense R273H GOF mtp53, without a functional central DNA binding domain, has the capacity to interact tightly with chromatin but it is unclear what regions of mtp53 are responsible for the chromatin-based DNA replication activities. GOF mtp53 proteins possess an intact C-terminal domain (CTD) and oligomerization domain (OD). In wild-type p53 the CTD and OD domain regulate non-specific DNA binding, post-translational modification, and protein tetramerization. We are targeting the CTD and OD regions of mtp53 to test if their disruption limits oncogenic GOF activity. We generated CRISPR/Cas9 edited R273H CTD and OD in the TNBC cell line MDA-MB-468, and also exogenously expressed such dual mutant proteins in p53 null cancers, to evaluate the roles played by oligomerization and non-specific DNA binding in mtp53 interactions with replicating DNA and PARP1. We determined the oligomerization state of R273H mtp53 using the glutaraldehyde crosslinking assay and observed that GOF mtp53 R273H mtp53 in breast cancer cells exists as a tetramer. Experiments are in progress to evaluate cell cycle progression, replication initiation, and mtp53 chromatin interactions in cells expressing missense mtp53 proteins with co-associated mutated CTDs or ODs. Our preliminary data suggests that disrupting the mtp53 CTD inhibits its interactions with chromatin and progression through the S-phase. Unpublished data on the roles played by the mtp53 CTD and OD in DNA replication will be presented at the 2020 AACR meeting. Acknowledgements: This work was funded by grants from the Breast Cancer Research Foundation BCRF-18-011 and BCRF-19-011 to Jill Bargonetti. Devon Lundine and Gu Xiao also received project support from TUFCCC/HC Regional Comprehensive Cancer Health Disparity Partnership, Award Number U54 CA221704(5) from the National Cancer Institute. Special thanks to Ella Freulich for help with CRISPR/Cas9 work and James J. Manfredi for mutant p53 plasmids to exogenously express protein.
Citation Format: Devon Lundine, George Annor, Viola Ellison, Gu Xiao, Carol Prives, Jill Bargonetti. Targeting gain-of-function of mutant p53 C-terminal and oligomerization domains to disrupt activated DNA replication in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3429.
Abstract 3444: Intratumor regulatory T cells prevent IFN-gamma-dependent tumor vessel regression and can be selectively targeted by anti-CD25 near-infrared photoimmunotherapy
Authors: Kurebayashi Yutaka , Choyke Peter L. , Kobayashi Hisataka , Sato Noriko 
Published: September 2020

Abstract
Regulatory T cells (Tregs) play pivotal roles in inhibiting anti-tumor immunity at different phases and locations (priming phase in lymph node and effector phase in tumor tissue) through their ability to suppress the function of T, NK, and antigen-presenting cells. However, our knowledge about the roles of Tregs in tumor immunity has largely derived from analyses after systemic depletion of Tregs or systemic manipulation of Treg functions in murine tumor models. The specific roles that intra- and extra-tumor Tregs play remain unclear due to technical difficulties to deplete or manipulate Tregs in a spatially specific manner. In order to achieve spatially specific depletion of Tregs in a clinically applicable manner, we have previously developed an anti-CD25 F(ab')2 near-infrared photoimmunotherapy (NIR-PIT), in which an intravenous injection of IR700-conjugated anti-CD25 F(ab')2 followed by irradiation of near-infrared light on tumors achieves selective depletion of intratumor Tregs and suppresses tumor growth. The suppression of tumor growth by the anti-CD25 F(ab')2 NIR-PIT depends on CD8 T and NK cells and their production of IFN-γ; however, the exact target of IFN-γ and the mechanisms of tumor regression remain to be elucidated. In this study, we aimed to dissect the mechanisms of the anti-tumor effect of intratumor Treg depletion by anti-CD25 F(ab')2 NIR-PIT using a series of Ifngr1 knockout mice models including bone-marrow chimera and conditional knockout models. Unexpectedly, we found that the target of IFN-γ in anti-CD25 F(ab')2 NIR-PIT was endothelial cells of tumor vessels. In both MC38 and EO771 tumor models (murine colon and breast cancer, respectively), CD8 T cells, NK cells, and Tregs were mainly located along the tumor vessels, and depletion of intratumor Tregs by anti-CD25 F(ab')2 NIR-PIT induced IFN-γ expression from these perivascular CD8 T and NK cells for up to 6 hours. This transient but synchronized induction of IFN-γ/STAT1 signaling along tumor vessels caused rapid vessel regression, intratumor ischemia, and apoptotic death of tumor cells. Combination with IL-15 treatment further eradicated residual tumor cells to achieve complete remission of MC38 and EO771 tumors.
Citation Format: Yutaka Kurebayashi, Peter L. Choyke, Hisataka Kobayashi, Noriko Sato. Intratumor regulatory T cells prevent IFN-gamma-dependent tumor vessel regression and can be selectively targeted by anti-CD25 near-infrared photoimmunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3444.
Abstract 3516: Commercial gene expression tests for prostate cancer outcome risk in men of West African ancestry
Authors: Gaston Sandra M. , Kittles Rick A. , Stoyanova Radka , Giret Teresa M. , Ansari Saba A. , Punnen Sanoj , Pollack Alan 
Published: September 2020

Abstract
Both incidence and mortality data show that the burden of prostate cancer (PrCa) is greater for African Americans (AA) than for European Americans (EAs), with AAs about 1.7 times more likely to be diagnosed with PrCa than EAs and about 2.4 times more likely to die of this disease. Molecular testing of prostate cancer tissue is increasingly being incorporated into patient management. Current National Comprehensive Cancer Network (NCCN) guidelines recommend three commercially available gene expression based tests for PrCa prognosis: Decipher (GenomeDX), Oncotype GPS (Genomic Health) and Prolaris (Myriad). All three of these tests were developed in predominantly EA patient populations and subsequent studies in AA patients have not included ancestry genotyping to assess genetic admixture. In a pilot study we used the Genomics Resource Information Database (GRID) to compare the research versions of these three commercial gene expression tests for PrCa outcome risk in 157 cancer positive biopsy cores from 55 patients. We also performed ancestry genotyping to estimate each patients European, West African and Native American Ancestry. The overall distribution of scores predicting average, higher than average and lower than average outcome risk differed for the three tests, with higher risk scores in 17%, 7% and 27% and lower risk scores in 69%, 73% and 43% of the cores for the Decipher, GPS and Prolaris tests, respectively. Interestingly, 25%, 37%, and 16% of 56 Cores with high risk pathology (grade group 3-5) were classified as low risk by the Decipher, GPS and Prolaris tests, respectively. In the 21 cores from men with &gt; 70% WA ancestry, 100%, 80% and 30% of cores with intermediate and high risk pathology (grade group 2-5) were paradoxically classified as low risk by the research Decipher, GPS and Prolaris tests, respectively. These preliminary results are consistent with the evidence recently published by Creed et al (2019) suggesting that the currently available commercial genomic tests may underestimate prostate cancer outcome risk in AAs. Ancestry genotyping may be useful in rescaling genomic prostate cancer outcome risk tests that were developed in predominantly EA cohorts for use in AA patients. Reference: Creed JH et al. Cancer Epidemiol Biomarkers Prev, published online 2019.
Citation Format: Sandra M. Gaston, Rick A. Kittles, Radka Stoyanova, Teresa M. Giret, Saba A. Ansari, Sanoj Punnen, Alan Pollack. Commercial gene expression tests for prostate cancer outcome risk in men of West African ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3516.
Abstract 3529: Detection of genomic structural variations associated with drug sensitivities and resistance in AML using novel whole genome imaging
Authors: Finlay Darren , Murad Rabi , Hong Karl , Lee Joyce , Pang Andy , Lai Chi-Yu , Burian Carol , Mason James , Hastie Alex , Yin Jun , Vuori Kristiina 
Published: September 2020

Abstract
Acute myeloid leukemia (AML) is a particularly devastating collection of hematological cancers and whilst somewhat rare, the patient survival rate is abysmal without bone marrow transplantation. Traditional chemotherapies administered to AML patients cause significant and devastating side effects. Additionally, more than 30% of patients fail to respond to these initial treatments and most patients that do respond will eventually relapse within 5 years. As such, understanding the evolution of AML to identify novel targets, and therefore drug treatment regimens, is a significant medical need.
Genomic rearrangements and other Structural Variations (SVs) have long been known to be causative and pathogenic in multiple cancers, including leukemias. Indeed the discovery of the “Philadelphia chromosome” (eventually identified as a BCR-ABL translocation) as causative in Chronic Myeloid Leukemia has prompted much research into SVs in cancers, including the development of targeted therapeutics against oncogenic proteins resulting from genomic rearrangements. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual AML patients may help guide therapeutic options.
Here we show utilization of an innovative whole genome imaging technology to detect known, and novel, SVs in AML patients' samples. Importantly, this new technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and it allows an unbiased detection of novel SVs, which may be relevant for disease pathogenesis and/ or drug resistance. Coupled with standard gene expression analyses we have also assessed the chemosensitivities of these samples to 120 FDA approved oncology drugs and 335 epigenetic modulating agents. Here we show how integrative analysis of these diverse datasets is used to associate the detected genomic rearrangements with drug sensitivity profiles, potentially identifying novel therapeutic targets for individual AML patients.
Citation Format: Darren Finlay, Rabi Murad, Karl Hong, Joyce Lee, Andy Pang, Chi-Yu Lai, Carol Burian, James Mason, Alex Hastie, Jun Yin, Kristiina Vuori. Detection of genomic structural variations associated with drug sensitivities and resistance in AML using novel whole genome imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3529.
Abstract 3546: Prevalence of Lynch Syndrome among Middle Eastern endometrial cancer using targeted next generation sequencing
Authors: Parvathareddy Sandeep K. , Siraj Abdul K. , Bu Rong , Masoodi Tariq , Azam Saud , Haqawi Wael , Alobaisi Khadija , Alrasheed Maha , Balde Valorie , Siraj Nabil , Diaz Mark R. , Ghazwani Laila , DeVera Felisa , AlDossari Hassan , Al-Kuraya Khawla S. 
Published: September 2020

Abstract
Endometrial carcinoma (EC) is the second most common gynecologic cancer worldwide. Although most ECs are sporadic, 2%-5% tend to be familial, with Lynch syndrome (LS) being the most commonly associated. The purpose of this study was to identify the incidence of LS in a large cohort of Middle eastern ECs and determine the feasibility of microsatellite instability (MSI) screening by immunohistochemistry (IHC) followed by molecular screening in deficient cases. We performed screening of 436 unselected EC for MSI status using IHC, followed by Target Capture sequencing of MSI deficient cases. MLH1 methylation analysis was performed by Real-time PCR, for cases showing deficient MLH1 by IHC. Complete loss of tumor nuclear protein expression in at least one of the four MMR genes was noted in 12.2% (53/436) of EC cases with 32 cases being MLH1 deficient, 10 MSH2 deficient, five MSH6 deficient and six PMS2 deficient. Of the 53 EC cases showing loss of expression in MMR genes, germline MMR mutations were found in four cases (0.9%). Promoter methylation analysis of 32 MLH1 deficient cases showed four cases to be unmethylated (12.5%). Our current study highlights the incidence of LS among patients with EC in Saudi Arabia. Screening of all EC patients using immunohistochemistry and reflex MLH1 promoter methylation testing followed by gene sequencing is feasible and desirable.
Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Tariq Masoodi, Saud Azam, Wael Haqawi, Khadija Alobaisi, Maha Alrasheed, Valorie Balde, Nabil Siraj, Mark R. Diaz, Laila Ghazwani, Felisa DeVera, Hassan AlDossari, Khawla S. Al-Kuraya. Prevalence of Lynch Syndrome among Middle Eastern endometrial cancer using targeted next generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3546.
Abstract 3584: CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0
Authors: Mullen Daniel J. , Yan Chunli , Kang Diane S. , Zhou Beiyun , Borok Zea , Marconett Crystal N. , Farnham Peggy J. , Offringa Ite A. , Rhie Suhn K. 
Published: September 2020

Abstract
Lung cancer is the leading cause of cancer-related death in the United States, with lung adenocarcinoma being the most common subtype. Although a number of genetic alterations have been identified as potential drivers in lung adenocarcinoma, there is still a large gap in our understanding of tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations that drive lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We identified over 17,000 enhancers that appear activated in lung adenocarcinoma but not in normal lung and linked the activity of these enhancers to transcriptional regulators. We identified that CENPA, MYBL2, and FOXM1 are key transcriptional regulators activated in a subgroup of lung adenocarcinomas and they are linked to numerous cancer-specific enhancers. High expression of these regulators is associated with poor patient survival. In addition, we identified individual enhancers that are linked to these regulators and whose increased activities are strongly associated with poor patient survival. Knockdown experiments of MYBL2 and FOXM1 suggested that they regulate genes involved in controlling cell cycle progression and cell division. We also showed that high expression of TK1, a presumed target gene of a MYBL2-linked enhancer, is strongly associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated cancer-specific enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma transcriptomes and novel potential targets for clinical intervention.
Citation Format: Daniel J. Mullen, Chunli Yan, Diane S. Kang, Beiyun Zhou, Zea Borok, Crystal N. Marconett, Peggy J. Farnham, Ite A. Offringa, Suhn K. Rhie. CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3584.
Abstract 3595: Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development
Authors: Orgebin Emilien , Ory Benjamin , Lamoureux Francois , O'Donohue Marie-Francoise , Charrier Céline , Gleizes Pierre-Emmanuel , Isidor Bertrand , Baud'huin Marc 
Published: September 2020

Abstract
Variants in genes encoding ribosomal proteins (RPs) have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. We reported recently one de novo missense variant and three de novo splice variants in the RPL13 gene, which encodes ribosomal protein RPL13/eL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G&gt;T, c.477+1G&gt;A, and c.477+2 T&gt;C) result in partial intron retention, which leads to an 18-amino acid insertion. These RPL13 variants define a human ribosomopathy leading to a rare skeletal dysplasia and highlight the role of this ribosomal protein in bone development. It has been shown that patients suffering from ribosomopathies have a highly predisposition to develop cancer compared to general population. Moreover, recent studies have also revealed that mutations in factors involved in ribosome synthesis appear to be drivers of tumorigenesis in sporadic cancers.
In this study, we focused on the role of variants of the riboprotein RPL13 in the bone biology and in the development of osteosarcoma.
Mesenchymal stem cells expressing variants of RPL13 or wild type RPL13 have been cultured for chondrogenic and osteoblastic differentiation. Our results show that RPL13 variants did not modified the capacity of cells to differentiate into osteoblasts. However, the chondrogenic differentiation was increased in cells expressing variants of RPL13. The expression of sox9 and collagen type X were investigated by immunochemistry on chondrocyte micromass and revealed an increase of expression of these markers in RPL13 variants cells. We next investigated the role of variants of RPL13 in osteosarcoma cell lines. Several cell lines were transduced by lentiviral vector to produce variants of RPL13. The variants induced an increase of cell proliferation and survival. The clonogenecity and the invasion have been also studied.
Taken together, these data show that variants of a gene encoding for a riboprotein causing a ribosomopathy could have an effect on chondrogenic differentiation and on osteosarcoma development.
Citation Format: Emilien Orgebin, Benjamin Ory, Francois Lamoureux, Marie-Francoise O'Donohue, Céline Charrier, Pierre-Emmanuel Gleizes, Bertrand Isidor, Marc Baud'huin. Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3595.
Abstract 3608: Identification of differentially expressed genes in 4T1 mice triple-negative mammary gland cancer during the early phase of combination treatment with indomethacin and radiation
Authors: Cheng Robert Yuk Sing , Ridnour Lisa , Back Timothy , Basudhar Debashree , Anderson Stephen , McVicar Daniel , Wink David 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. In order to develop the most effective treatment against TNBC, we tested the effects of the combination treatment with indomethacin and radiation on TNBC utilizing a mouse experimental TNBC equivalent model. Seven weeks old BALB/c mice were implanted with 4T1 mice triple-negative mammary gland tumor cells on the right hind leg one week before the treatments started. Mice were divided into four groups treated with vehicle control, 6 Gy radiation, 30 mg/L (in water) indomethacin, or combination regime of 6 Gy radiation and 30 mg/L indomethacin. 6 Gy radiation was given to mice on Day 0 only while indomethacin was given to mice every day. Mice received the combination treatment with radiation and indomethacin showed a significant tumor growth delay at the end of the treatment regime (Day 30). We next elucidated if there are changes in biological pathways during the early phase of combination therapy (Day 3). Total RNAs isolated from the primary tumors were subjected to whole genome transcriptomic analyses (RNAseq). We identified a total of 58 genes with 2-fold changes in expression and p-value &lt;0.05 differentially expressed among the treatment groups. Strikingly, the trend in expression levels of differentially expressed genes identified from the combination treatment group was opposite to that from the other two treatment groups. Results indicate that the effect of combination treatment with indomethacin and radiation is neither additive or synergistic. In addition, pathway core analyses revealed “Cancer” as the top associated disease, and “GABA Receptor Signaling and cAMP-Mediated Signaling” as the top canonical pathways among the treatment groups. In conclusion, our findings provided a detailed snapshot of the early events occur in mice subject to either single or combination treatment with indomethacin and radiation. Data will improve our understanding of the treatment responses of TNBC. We believe further time-course and transcriptomic studies may be beneficial for the new therapeutic strategies for TNBC.
Citation Format: Robert Yuk Sing Cheng, Lisa Ridnour, Timothy Back, Debashree Basudhar, Stephen Anderson, Daniel McVicar, David Wink. Identification of differentially expressed genes in 4T1 mice triple-negative mammary gland cancer during the early phase of combination treatment with indomethacin and radiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3608.