bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2022: Palmitate promotes breast cancer progression in vitro through induction of a senescent-like phenotype in fibroblasts
Authors: Harlow Brittany Susanne , Davalos Albert R. , Brenner Andrew J. , Jolly Christopher , Tiziani Stefano , Hursting Stephen D. , deGraffenried Linda A. 
Published: July 2021

Abstract
Background: Obesity confers a worse breast cancer prognosis, including an increased risk of recurrence and mortality. While the causative mechanisms have yet to be fully uncovered, emerging evidence implicates palmitate, increased in the obese state, in development of cellular senescence, an inflammatory state associated with breast tumorigenesis in preclinical models. However, studies are warranted to corroborate the impact of palmitate on induction of a cohesive senescent-like phenotype as well as the extent to which palmitate-induced senescence impacts breast tumorigenesis either in vitro or in vivo. This said, we hypothesize that palmitate exposure induces a senescent-like phenotype in fibroblasts, contributing to measures of breast cancer progression.
Methods: HCA2, IMR-90, and human mammary fibroblasts were exposed to bovine serum albumin or palmitate in media supplemented with 2% charcoal-stripped fetal bovine serum, after which the cells were measured through qPCR for expression of IL-1a, IL-6 and IL-8, some of the most prominent members of the senescence-associated secretory phenotype. Palmitate-exposed fibroblasts were also stained for senescence-associated beta-galactosidase and BrdU incorporation, well-established senescence markers. Experiments were then repeated with administration of eicosapentaenoic and docosahaexanoic acids to evaluate the potential of omega-3 fatty acids to limit the effects of palmitate on fibroblast senescence. Finally, we assessed the tumor-promoting potential of these palmitate-exposed fibroblasts by culturing MCF-7 and T47D breast cancer cells in their conditioned media and assessing changes in carcinogenic measures.
Results and Conclusions: Palmitate induced pro-inflammatory gene expression and SA-beta-gal positivity and decreased proliferation in fibroblasts, while omega-3 fatty acid supplementation reversed these effects. These palmitate-exposed fibroblasts also appeared to be of pathological impact, as exposure to their CM increased proliferation in breast cancer cells. These findings are important in that they support emerging evidence implicating obesity-associated factors in the exacerbation of breast cancer progression as well as indicate the potential of omega-3 fatty acids to improve outcome.
Citation Format: Brittany Susanne Harlow, Albert R. Davalos, Andrew J. Brenner, Christopher Jolly, Stefano Tiziani, Stephen D. Hursting, Linda A. deGraffenried. Palmitate promotes breast cancer progression in vitro through induction of a senescent-like phenotype in fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2022.
Abstract 2024: Studying the effects of interfering with doxorubicin-induced senescence in human colon cancer HCT116 cells
Authors: Alotaibi Moureq Rashed , Sobeia Homood As , Alohaydib Munirah , Alaqil Faten , Alhazzani Khalid , Alhoshani Ali , Saleh Tareq , Gewirtz David 
Published: July 2021

Abstract
Colorectal cancer (CRC) is type of cancer that growing in the colon or the rectum. Although CRC can be treated and managed through several means of therapy, the disease mortality is still high in Saudi Arabia. Upon treatment, cancer cells undergo different form of cell death or growth arrest such as apoptosis and senescence. Senescence is a state of proliferation arrest that is considered as a cause of drug resistance. The current study was designed to interfere with Doxorubicin-induced senescence in cancer cells, and shift the cytotoxicity of doxorubicin from proliferation arrest to apoptosis. β-galactosidase (β-gal) staining has demonstrated that Doxorubicin induces senescence in wild-type HCT116 but not in p21 knock-out cells. (DAPI)/TUNEL stating and Annexin V assay indicate that treatment with Doxorubicin promotes apoptosis in p21 knock-out HCT116 significantly more than in wild-type HCT116. β-galactosidase staining and 5-Dodecanoylaminofluorescein Di-β-D-Galactopyranosid (C12FDG) demonstrated that combination of Doxorubicin with Sorafenib, Rapamycin, or Venetoclax has significantly reduced senescence and induced more apoptosis as shown by Propidium iodide (PI)/Annexin v assay and Caspase 3/7 Assay. PCR data analysis demonstrated that not all combination of Doxorubicin with other agents significantly decreased expression of senescence protein, however, the results of this study provide findings that interference with senescence pathways may shift cytotoxicity from senescence to apoptosis.
The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for partly funding this work through the project number (DRI-KSU-1273).
Citation Format: Moureq Rashed Alotaibi, Homood As Sobeia, Munirah Alohaydib, Faten Alaqil, Khalid Alhazzani, Ali Alhoshani, Tareq Saleh, David Gewirtz. Studying the effects of interfering with doxorubicin-induced senescence in human colon cancer HCT116 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2024.
Abstract 2029: The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1
Authors: Son Jeongin , Mogre Saie , Glick Adam 
Published: July 2021

Abstract
UV induced DNA damage is the primary driver of human skin cancer. UV can also cause endoplasmic reticulum (ER) stress, but the role of unfolded protein response (UPR) in the cellular response to UV exposure is not clear. Inositol-requiring enzyme 1α (IRE1α) is one of the key regulators of the UPR but its function in the UV response has not been resolved. Here we show that IRE1α, is transiently dephosphorylated and its RNase activity downregulated by UVB resulting in reduced XBP1 splicing. Keratinocytes with either IRE1α knockout or knockdown have elevated cytosolic calcium and ROS resulting in increased apoptosis after UV. Pharmacological inhibition of the ER inositol triphosphate receptor (IP3R) or phospholipase C (PLC) restored normal cytosolic calcium and ROS levels to cells lacking IRE1α. While loss of IRE1α did not alter the frequency of cells with UV-induced cyclo-pyrimidine dimers (CPD), it significantly reduced the percent of γH2AX positive keratinocytes 6 hours after UVB irradiation. This percent of CPD positive cells and the level of γH2AX 6 hours after UV suggesting a defect in the DNA repair response. Pharmacological inhibition of IRE1α RNase or Xbp1 knockdown did not phenocopy IRE1α loss, but overexpression of IRE1α in IRE1α knockdown cells restored γH2AX expression and reduced keratinocyte apoptosis. IRE1α overexpression also enhanced the survival of keratinocytes deficient in p53 function after UV irradiation. Additionally, mice with an epidermal deletion of IRE1α showed more rapid loss of UV-induced CPD positive keratinocytes compared to wildtype mice, primarily through accelerated sloughing of UV damaged cells from the skin. Knockdown of Calcium and integrin binding protein 1 (CIB1), which binds and inhibits the IP3R, elevated cytosolic calcium in keratinocytes and suppressed UV-induced γH2AX. Knockdown of Apoptosis signal-regulating kinase 1 (ASK1), which can interact with IRE1α through TRAF2 as well as CIB1, restored normal levels of UV-induced γH2AX to IRE1α knockdown keratinocytes. Together these results show that IRE1α is essential for maintaining normal cellular calcium and ROS levels and the UV-induced repair response, and suggest a model where IRE1a activation state drives CIB1 binding either to the IP3R or ASK1 to regulate ER calcium efflux, ROS and DNA repair responses following UV.
Citation Format: Jeongin Son, Saie Mogre, Adam Glick. The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2029.
Abstract 2034: Patient-specific enhancer-gene networks for hundreds of primary cancer samples
Authors: Xu Duo , Forbes Andre Neil , Cohen Sandra , Palladino Ann , Karadimitriou Tatiana , Khurana Ekta 
Published: July 2021

Abstract
Epigenomic alterations at regulatory elements have been implicated in cancer tumorigenesis. As a hallmark for epigenetic changes, chromatin accessibility profiles are generated for cancer patients. However, not all accessible regions are active regulatory elements. We developed a computational model that uses machine learning to integrate ATAC-seq and RNA-seq data and is trained using 3D genomic data. Our model is able to classify accessible regions into active regulatory elements with links to target genes and poised elements with no links to target genes. We used multi-omics data including histone modification profiles from ENCODE to validate our results. Application of our model on chromatin accessibility and transcriptomic data from 400 cancer patients of 22 cancer types revealed novel cancer-type and -subtype-specific enhancer-gene connections for known cancer genes. In one example, we identified two enhancers that regulate the expression of ESR1 in only ER+ breast cancer samples but not in ER- samples. These enhancers explain the high expression of ESR1 in 93% of ER+samples. Functional validation using CRISPRi confirms that inhibition of these enhancers decreases the expression of ESR1 in ER+ samples. Overall, our model predicts the connections of active enhancers to their target genes in a patient-type specific manner revealing key regulatory loci that modulate the expression of key genes.
Citation Format: Duo Xu, Andre Neil Forbes, Sandra Cohen, Ann Palladino, Tatiana Karadimitriou, Ekta Khurana. Patient-specific enhancer-gene networks for hundreds of primary cancer samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2034.
Abstract 2037: Targeting chromosome rearrangements in cancer with CRISPR
Authors: Yang Huibin , Suhas-Hulbatte Radhika , Ljungman Mats 
Published: July 2021

Abstract
Background: We have developed a novel precision and personalized cancer therapeutic approach to specifically target cancer cells using CRISPR technology. This approach is universal to all cancers and not dependent on the unique biology of the tumor. The innovation of this approach is that chromosome rearrangement junctions (CRJs), which typically exist in the hundreds in each tumor cell, are targeted by guide RNAs that bring together two parts of a dCas9-fused endonuclease, Fok1, leading to the induction of DNA double strand breaks (DSBs) at sites of the targeted CRJs in cancer cells specifically.
Materials and Methods: HCT116 colon cancer cells and UMUC-3 bladder cancer cells were engineered to express Fok1-dCas9 and two pairs of CRJ-targeting gRNA under doxycycline regulation. Induction of DSBs at CRJs were assessed by γH2AX foci and γH2AX ChIP-PCR and cell death was assessed by apoptosis (PARP1 & caspase cleavage and flow cytometry for sub-G1 DNA content and Annexin V staining) and clonogenic survival.
Results: Induction of Fok1-dCas9 lead to the induction of 1-2 DSBs per cell and promoted cell death when accompanied with the expression of pairs of CRJ-targeting gRNAs. However, no DSBs or cell death was observed with expression of Fok1-dCas9 alone or in combination with non-targeting gRNAs.
Conclusions: We have shown that we can direct two parts of a dCas9-fused Fok1 endonuclease to sites of CRJs in cancer cells using CRISPR gRNAs leading to the induction of DSBs and loss of cell survival specifically in cancer cells. Recent breakthroughs in CRISPR delivery using lipid nanoparticles will allow us to next explore the utility of our precision CRISPR approach in animal models. If successfully implemented, the impact of our universal approach targeting CRJs in cancer with CRISPR could be transformative for cancer therapy.
Citation Format: Huibin Yang, Radhika Suhas-Hulbatte, Mats Ljungman. Targeting chromosome rearrangements in cancer with CRISPR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2037.
Abstract 2065: Mutations inhibiting KDM4B drive ALT telomere maintenance pathway in ATRX-mutated cancers
Authors: Wong Lee H. , Udugama Maheshi , Hii Linda , Garvie Andrew , Garvie Matthew , Vinod Benjamin , Chan Lyn , Mann Jeffrey , Collas Philippe , Voon Joanna 
Published: July 2021

Abstract
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilized in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet ATRX knockout (KO) alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase which is inactivated in ALT. Mouse ES cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B KO or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. Our data demonstrate that inactivation of KDM4B, either through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in cancers.
Citation Format: Lee H. Wong, Maheshi Udugama, Linda Hii, Andrew Garvie, Matthew Garvie, Benjamin Vinod, Lyn Chan, Jeffrey Mann, Philippe Collas, Joanna Voon. Mutations inhibiting KDM4B drive ALT telomere maintenance pathway in ATRX-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2065.
Abstract 2107: Transcription factor repertoire basis for epigenetic and consensus molecular subtypes of colorectal cancer
Authors: Bhandari Yuba , Powers Rachael , Parmar Sehej , Krishna Vinod , Bachman Kurtis E. , Baylin Steve , Easwaran Hariharan 
Published: July 2021

Abstract
Colorectal cancer (CRC) is classified into distinct subtypes based on genetic, epigenetic and/or transcriptional subtypes. The underlying mechanisms that drive these subtypes are unknown. By integrating whole genome DNA methylation, gene expression, chromatin patterns, and enhancer elements in CRCs, we show that expression of large numbers of transcriptional factors (TFs) is deregulated in CRCs and these expression patterns drive epigenetic and transcriptional subtypes of CRCs. The first key result emerging is a new understanding of important DNA methylation patterns central to classifying CRCs. Of these, different degrees of cancer associated promoter methylation have been recognized that suppress expression, and/or inducibility of important tumor suppressor genes. Stratified by high to low degrees of hypermethylation, this pattern is termed CpG-island promoter DNA methylation phenotypes or CIMP. We now tightly link CIMP to a cancer-specific hypermethylation at enhancer regulatory elements we term, CpG- enhancer methylation phenotype (CEMP). CIMP and CEMP are driven by decreased expression of multiple TFs with binding sites in these regulatory elements, and the involved TFs are frequently identical between the two regions. In contrast, a different set of TF factors are downregulated in non-CIMP tumors, again in conjunction with methylation patterns linking promoter and enhancer target sites for the involved TFs. Further, enhancer regulatory elements that are hypomethylated in cancer relative to normal tissue are associated with increased expression of another distinct set of TFs with target sites in the corresponding enhancers. Importantly, the TF expression patterns, and the above CIMP, CEMP, and hypomethylation patterns, are established early in the pre-malignant adenomas. Importantly, pan-cancer analyses showed that the above CIMP and CEMP subtypes occur across important cancer types in addition to CRC, again in parallel with marked downregulation of TFs that have target sites in the methylated regulatory elements. All of the above newly defined patterns also provide a basis for the transcriptome-based consensus molecular subtypes (CMS) of CRC. Overall, our studies may provide key understanding of how cancers, and their initiation and progression, are diseases which at the end of the day depend on abnormal patterns of TF expression, and how these relate to methylation alterations at target enhancer and promoter regions.
Citation Format: Yuba Bhandari, Rachael Powers, Sehej Parmar, Vinod Krishna, Kurtis E. Bachman, Steve Baylin, Hariharan Easwaran. Transcription factor repertoire basis for epigenetic and consensus molecular subtypes of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2107.
Abstract 2111: RAD6-mediated epigenetic reprogramming contributes to therapy-induced chemo-resistance in ovarian cancer
Authors: Omy Tasmin Rahman , Jonnalagadda Shirisha , Reedy Mark , Palle Komaraiah 
Published: July 2021

Abstract
Epithelial Ovarian Cancer (EOC) is the fifth leading cause of cancer-related deaths in women in the USA, gets diagnosed at an advanced stage (stage III-IV) with local or distant metastasis. The primary therapeutic regimen of EOC involves surgical removal of all the visible tumor mass followed by platinum-based chemotherapy either as a single agent or in combination with a taxane. Despite initial responses, over 70% of EOC patients develop recurrent disease and they are often resistant to available chemotherapeutic drugs, contributing to poor survival. This appalling situation emphasizes the critical need to identify the molecular mechanisms involving recurrence of these tumors' aggressive growth and developing therapeutic resistance. Our analysis from chemo naïve and recurrent tumors from the same patients' samples, and isogenic ovarian cancer cell lines data showed recurrent tumors and resistant cell lines several upregulated cancer stem cell markers including ALDH1A1, SOX2 and altered expression of DNA damage response and repair genes that are involved in the processing of platinum adducts and crosslink repair. Prominently, RAD6, an E2ubiquitin-conjugating enzyme, is significantly (&gt; 6 folds) overexpressed in recurrent ovarian tumors and associated with aggressive tumor cell growth, stemness, chemoresistance to platinum drugs, and poor prognosis. Our studies validated that, chemotherapy induced upregulated RAD6 reprograms epigenetic milieu in tumor cells through ubiquitination of histone variants H2A, H2AX, and H2B, which further recruits additional epigenetic modifiers to these regions and regulates genes involved in DNArepair, cell survival, stemness, and chemoresistance. Additionally, our mechanistic studies demonstrate RAD6 dependent recruitment of several epigenetic modifiers such as histone methylases and demethylases to regions of ubiquitylated histones and their crosstalk. Collectively, our study presents novel chemotherapy induced epigenetic modulator contributing to therapeutic recurrence of EOC and could be an important therapeutic target to treat chemo-resistant EOC and improve the progression-free survival of patients suffering from this deadly disease.
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Citation Format: Tasmin Rahman Omy, Shirisha Jonnalagadda, Mark Reedy, Komaraiah Palle. RAD6-mediated epigenetic reprogramming contributes to therapy-induced chemo-resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2111.
Abstract 2168: Multi-regional RNA-Seq reveals pattern of RNA-editing in brain tumor
Authors: Yan Cheng , Wu Jun , Wang Dan , Su Lan , Yang Yufei 
Published: July 2021

Abstract
Introduction: RNA-editing is widespread across human genome. Previous studies have observed that RNA editing level differs significantly across multiple cancer types and may influence cancer development. Increased level of RNA editing has been found to correlate with enhanced tumorigenesis in some cancers but reduced tumorigenesis in others. In brain tumor, the RNA editing landscape has not been well characterized partially due to the difficulty of sample accessibility. We performed multi-regional RNA-Seq on cancerous, peritumoral and distant tissue collected from 40 brain cancer patients. Our aim is to depict the landscape of RNA editing and to comprehend the relevance of RNA editing with other molecular characteristics of brain cancer.
Methods: We collected 40 cancerous brain tissue sample (30 LGG and 10 GBM), each coupled with a peritumoral tissue and a distant tissue. These 120 samples were subjected to RNA-Seq sequencing. RNACocktail was applied for identification of RNA editing events. RADAR and ANNOVAR were used for identification and annotation of A-to-I editing sites. RNAEditingIndexer was used to estimate sample-wise editing level denoted as AEI. Pathway enrichment analysis was performed using GSEA. Statistical difference of molecular characteristics between sample groups was calculated using either Wilcoxon signed rank test or Kruskal-Wallis test.
Results: A total number of 21,105 and 5,634 informative editing events were identified in LGG and GBM respectively. As expected, most editing events were located within Alu element of intronic and 3'UTR region. In both LGG and GBM, RNA editing level showed decreasing trend from distant to peritumoral to cancerous samples. Compared with normal tissue, we found 5.12‰ up-regulated events and 16.92‰ down-regulated events in LGG samples. Similar pattern was found in GBM as well. We found two editing sites with significant editing differences (adjust p-value &lt; 0.05) within coding region of GRIK2 and NEIL1 gene. In addition, numerous editing sites showed statistical correlation other molecular/pathological characteristics such as IDH1 mutation, existence of seizure, MGMT methylation and pathological classification.
At sample level, the same decreasing trend of RNA editing level was consistently observed from distant to cancerous tissue. Enrichment analysis showed that editing level was positively correlated with neural transmission and oncogenic related pathways. In addition, sample level editing was significant different between WHO as well as pathological classification.
Citation Format: Cheng Yan, Jun Wu, Dan Wang, Lan Su, Yufei Yang. Multi-regional RNA-Seq reveals pattern of RNA-editing in brain tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2168.