bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1416: Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis
Authors: Maekawa Shigekatsu , Fujita Masahi , Takata Ryo , Ikarashi Daiki , Matsuura Tomohiko , Kato Renpei , Kato Yoichiro , Kanehira Mitsugu , Sugimura Jun , Abe Takaya , Nakagawa Hidewaki , Obara Wataru 
Published: April 2023

Abstract
Introduction: Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study’s goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses.
Materials and Methods: Frozen kidney samples were obtained from 48 patients who were undergoing dialysis treatment and developed RCC at Iwate Medical University Hospital. Among them, we selected 38 subjects for study from whom matched tumor and adjacent non-tumor tissue samples could be obtained and from which DNA (n=38) or RNA (n=26) could be isolated. We performed whole genome sequencing of genomic DNA using MGIEasy FS DNA Library Prep Set and short read sequencer DNBSEQ-G400. mRNA Sample were sequenced using HiSeq. Driver events, copy-number alteration (CNA) analysis, and mutational signature profiling was performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels, and structural variants as well as CNAs, while transcriptome data was analyzed for differentially expressed genes and through gene set enrichment analysis.
Results: ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All ACD (acquired cystic disease)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation, and targets of Myc.
Conclusion: This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis.
Citation Format: Shigekatsu Maekawa, Masahi Fujita, Ryo Takata, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Jun Sugimura, Takaya Abe, Hidewaki Nakagawa, Wataru Obara. Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1416.
Abstract 1441: p27Kip1 is upregulated in UMSCV-4 cells corresponding to entering a state of quiescence when treated with clobetasol
Authors: Minnuto Gianna , North Luke , Ogden Mack , Haering Kia , Lewis Jani E. 
Published: April 2023

Abstract
Quiescence, the temporary exit from the cell cycle, presents therapeutic challenges to cancer management since it allows evasion of chemotherapy and radiotherapy treatment. Essential to the study of quiescence in carcinogenesis is an established model system. Our studies have found that clobetasol treatment of the vulvar cancer cell line, UMSCV-4 causes these cells to enter a state of dormancy. Subsequent removal of the cells from clobetasol show a return to normal cell proliferation, even after dormancy for 3 months. p27Kip1 protein has been used as marker for entry into quiescence. Using both antibodies against p27Kip1 and transfection of a modified p27Kip1 containing plasmid into the UMSCV-4 cells we found that p27Kip1 is upregulated by addition of clobetasol, reflecting that quiescence is being activated in the treated UMSCV-4 cells. Cells that were incubated in clobetasol for three months and then removed from clobetasol (UMSCV-4 LT), allowing them to reenter the cell cycle, no longer expressed p27Kip1 upon re-exposure to clobetasol. This establishes the UMSCV-4 cells as a good model system for the study of clobetasol induced quiescence in vulvar squamous epithelial cells. The importance of this work is underscored by the observation that clobetasol is often used to treat a common inflammatory disease of the vulva known as vulvar lichen sclerosus (VLS) and up to 65% of vulvar carcinomas arise in the background of VLS.
Citation Format: Gianna Minnuto, Luke North, Mack Ogden, Kia Haering, Jani E. Lewis. p27Kip1 is upregulated in UMSCV-4 cells corresponding to entering a state of quiescence when treated with clobetasol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1441.
Abstract 149: An organoid model for understanding the pathogenesis of Lynch syndrome
Authors: Guild Caroline , Madden-Hennessey Kirby , Heinen Chris 
Published: April 2023

Abstract
Lynch syndrome (LS) is an inherited predisposition for developing cancer caused by germline variants in mismatch repair (MMR) genes. It is estimated that LS is responsible for 1 out of every 35 colorectal cancers and 1 out of every 56 endometrial cancers. Loss of MMR is also seen in many sporadic cancers. Still, the mechanism of tumorigenesis in these patients is unknown. Loss of MMR increases genomic mutation rate, but it is unclear if increased mutational burden alone leads to tumorigenesis. Recent studies of LS patient colon samples show fields of morphologically normal tissue in which cells have lost expression of an MMR protein, suggesting that loss of MMR in these cells is sufficient to confer an advantage over heterozygous cells still proficient in MMR. However, whether MMR loss provides a direct advantage to cell types associated with cancer in LS has not been directly tested. We hypothesize that loss of MMR is sufficient to confer a selective advantage to colonic stem cells and is the first step towards tumorigenesis in LS patients.
To test this, we use a human colonic organoid model to examine competition between MMR-deficient (dMMR) and MMR-proficient (pMMR) cells over time. The colonic organoids are differentiated from human embryonic stem cells.
To track cell populations, dMMR stem cells are labeled with mCherry and pMMR stem cells are labeled with GFP. We have initially observed that dMMR stem cells are much more efficient at generating colonic organoids. Thus, the cells are mixed so that resulting organoids initially contain a small population of dMMR cells in order to mimic the spontaneous loss of heterozygosity that occurs in LS patients’ colonic crypts. Live fluorescent imaging of individual organoids is used to quantify changes in cell population over time. Preliminary data indicate that dMMR cells can outgrow pMMR cells resulting in a shift in the ratio of green to red cells over a two-week time period. These results suggest that loss of MMR function imparts an immediate selective advantage. Furthermore, this assay could be used to find conditions or compounds that decelerate population shifts with the ultimate goal of finding a way to reduce dMMR fields in LS patients. In these ways, this assay can be leveraged for gaining new insights into MMR function, pathogenesis of LS, and potential therapies for LS.
Citation Format: Caroline Guild, Kirby Madden-Hennessey, Chris Heinen. An organoid model for understanding the pathogenesis of Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 149.
Abstract 1494: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma
Authors: Yao Xiaosai , Hong Jing Han , Nargund Amrita , Ng Michelle Shu Wen , Heng Hong Lee , Li Zhimei , Guan Peiyong , Sugiura Masahiro , Chu Pek Lim , Wang Loo Chien , Ye Xiaofen , Yauch Robert , Chang Kenneth Tou-En , Sobota Radoslaw M. , Tan Patrick , Teh Bin Tean 
Published: April 2023

Abstract
PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been examined previously. Here we show that in VHL-deficient ccRCC tumors, PBRM1 deficiency results in altered PBAF complexes that retain the association between SMARCA4 and ARID2 but disengage BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proximal regions to distal enhancer regions containing motifs of pro-tumorigenic factors including NF-κB. Subsequently, PBRM1-deficient cells display heightened NF-κB activity across multiple cell models. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Michelle Shu Wen Ng, Hong Lee Heng, Zhimei Li, Peiyong Guan, Masahiro Sugiura, Pek Lim Chu, Loo Chien Wang, Xiaofen Ye, Robert Yauch, Kenneth Tou-En Chang, Radoslaw M. Sobota, Patrick Tan, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1494.
Abstract 1498: Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer
Authors: Kushwaha Prem Prakash , Verma Shiv , Gupta Sanjay 
Published: April 2023

Abstract
The Melanoma Antigen Gene (MAGE) protein family is a large and highly conserved group of proteins that share a common MAGE homology domain. Interestingly, several MAGE proteins are limited in expression to reproductive tissues but are aberrantly expressed in various types of human malignancies. We have recently demonstrated overexpression of MAGE family member A6 in advance-stage bladder cancer (Cancers 13:23, 5931, 2021). However, the mechanisms involved in MAGE gene overexpression and its coregulators are currently unknown. One hypothesis is that MAGEA6 and androgen receptor (AR) signaling is involved in the etiology of bladder cancer progression. In the present study, we determined the functional relationship between MAGEA6 and AR in bladder cancer. Treatment with DHT, an AR agonist, increased AR and MAGEA6 expression in UMUC3 and J82 bladder cancer cells at the protein and transcript level. On the contrary, exposure of cells to enzalutamide, an antiandrogen, resulted in simultaneous reduction of AR and MAGEA6 more prominently in UMUC3 cells, compared to J82 harboring low MAGEA6 transcript. Dual-sgRNA CRISPR/Cas9 knockout of MAGEA6 in UMUC3 and J82 cells resulted in inhibition of cell proliferation, reduced survival, and migration potential in both cell lines. An induction of S-phase and G0/G1 phase cell cycle arrest was noted in UMUC3 and J82 cells. In silico analysis showed Arg20 and Cys557 amino acid residue of AR interacts with Asp236 and Gln106 amino acid residue of MAGEA6 through hydrogen bonds. Further confirmation of physical interaction between AR and MAGEA6, performed by immunoprecipitation of AR and probed for MAGEA6 and vice versa established interaction of AR-MAGEA6 with each other which was further confirmed by mass spectrometry analysis. In conclusion, these findings confirm the oncogenic role of MAGEA6 and its physical interaction with AR may be involved in bladder cancer progression.
Citation Format: Prem Prakash Kushwaha, Shiv Verma, Sanjay Gupta. Melanoma antigen gene A6 and androgen receptor interaction in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1498.
Abstract 151: Optimization of screening conditions using patient-derived organoids for diagnostic purposes
Authors: Verissimo Carla S. , Smabers Lidwien , Wensink Emerens , Koedoot Esmee , Pitsa Katerina-Chara , Doorn Mayke , van Weersch Inez , Warda Hamdy , Barón Celia Higuera , ten Hag Gerben , Vries Robert G. , Roodhart Jeanine , Boj Sylvia F. 
Published: April 2023

Abstract
Patient-derived organoids (PDOs) are increasingly adopted in preclinical research. PDOs, or HUB Organoids®, are directly established from patient tissue, faithfully recapitulate patient disease, and effectively bridge the gap between the lab and the clinic, bringing a “patient in the lab®”. PDOs can also revolutionize clinical research because they can predict patient response to standard-of-care (SoC) compounds. However, there is an urgent need to refine the assay conditions to evaluate the activity of SoC drugs with different mechanisms of action (topoisomerase inhibitors, alkylating agents, targeted agents) and various types of molecules (small molecules, antibodies) and achieve optimal results from the PDO-based assay. Specifically, for metastatic colorectal cancer (mCRC), we have optimized the media composition required for drug screening assays to test response to SoC, such as oxaliplatin and panitumumab. Our results indicate that optimal media conditions are essential to observe an in vitro drug response in PDOs similar to the patient response in the clinic. In addition, an image-based readout was developed that enables precise quantification of organoid numbers ensuring high assay quality. Optimizing screening conditions to evaluate SoC compounds in PDOs is a required step to accelerate the implementation of the HUB Organoid Technology as a diagnostic platform to accurately predict treatment response and improve clinical outcomes for cancer patients.
Citation Format: Carla S. Verissimo, Lidwien Smabers, Emerens Wensink, Esmee Koedoot, Katerina-Chara Pitsa, Mayke Doorn, Inez van Weersch, Hamdy Warda, Celia Higuera Barón, Gerben ten Hag, Robert G. Vries, Jeanine Roodhart, Sylvia F. Boj. Optimization of screening conditions using patient-derived organoids for diagnostic purposes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 151.
Abstract 1561: Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas
Authors: Hayden Elisha , Franshaw Laura , Upton Dannielle , Liu Jie , Nguyen Hieu , Joshi Swapna , Tsoli Maria , Dolman Emmy , Rayner Benjamin , Ziegler David 
Published: April 2023

Abstract
Diffuse Midline Gliomas (DMGs) are devastating and incurable pediatric brain tumours. DMGs are characterised by epigenetic aberrations in the form of histone modifications, coupled with mitotic abnormalities, which together drive a stem-like transcriptional cell state that is critically dependent on the cell cycle. Polo-like kinase 1 (PLK1) is a pivotal regulator of mitosis and cell cycle progression. To determine an effective therapeutic strategy against DMG, we characterised the anti-tumour potential of PLK1 inhibition, either alone or in combination with radiotherapy. We show that targeting PLK1 with small molecule inhibitors BI2536 and BI6727 (volasertib) reduced DMG colony formation and cell proliferation, and induced G2/M checkpoint arrest and apoptosis in vitro at physiologically achievable, clinically relevant concentrations. When combined with radiotherapy, PLK1 inhibitors acted as potent radiosensitisers with synergistic suppression of DMG survival. We further show that PLK1 inhibitors exert potent anti-tumour effects in highly aggressive orthotopic DMG models, effectively extending the median survival of tumour harbouring mice both as a single agent and enhanced in combination with radiotherapy. We further demonstrate a potential novel role for PLK1 in defining an oncogenic transcriptional state in DMG by acting as a conduit between cell cycle progression and the DMG epigenome through modulation of polycomb repressive complex 2 (PRC2) activity and its resultant histone methyltransferase function. Together, these data indicate that targeting PLK1 is a highly promising therapeutic strategy to arrest DMG tumorgenicity. This data has formed the basis for a planned international Phase 1/2 trial of the PLK1 inhibitor volasertib in combination with radiotherapy in paediatric patients with DMG.
Citation Format: Elisha Hayden, Laura Franshaw, Dannielle Upton, Jie Liu, Hieu Nguyen, Swapna Joshi, Maria Tsoli, Emmy Dolman, Benjamin Rayner, David Ziegler. Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1561.
Abstract 1569: OXC-101 kills cancer by disturbing microtubule polymerization and inhibiting MTH1
Authors: Berglund Ulrika Warpman , Gad Helge , Sanjiv Kumar , Jemth Ann-Sofie , Mortusewics Oliver , Brautigam Lars , Rantala Juha , Helleday Thomas 
Published: April 2023

Abstract
Many cancers suffer from replication stress, oxidative stress, a dysfunctional redox status, and high levels of endogenous oxidative DNA damage. OXC-101 (karonudib, TH1579) targets these vulnerabilities by stopping the cancer cells in mitosis, generating ROS which increases oxidative stress and oxidative DNA damage, thereby killing the cancer cells. The aim of this study was to further investigate the underlying mechanism of OXC-101 and the cancer specific effects in solid cancers. Using e.g. microtubule polymerization assays, co-immunoprecipitation and immunofluorescence microscopy, we show a dual mechanism of action of OXC-101, disturbing microtubule function and inhibiting the nucleotide pool sanitizing enzyme MTH1. Furthermore, we demonstrate the importance of a functional spindle assemble checkpoint (SAC) for the response of OXC-101, since knocking down MAD2,using siRNA, or inhibiting SAC with reversine, results in treatment resistance. We show that the excess of oxidized nucleotides is cytotoxic when inhibiting or knocking out MTH1 in zebrafish embryos, and that pretreatment with ROS scavenger rescues the effect of OXC-101 in cancer cells. These data indicate that the increased incorporation of oxidized nucleotides into DNA is, together with the mitotic arrest, an important part of the mechanism of action and response. OXC-101 has a broad anti-cancer effect. In an ex vivo drug sensitivity study of 157 primary biopsies from solid cancer patients, OXC-101 was efficacious in a large proportion of the patient derived samples, with best responses in endometrial (73%), HNSCC (73%), bladder (70%) and prostate (83%) cancer samples. Biomarker searches for genetic alterations explaining responders/non-responders are presently on-going. In summary, the dual mechanism of action of the mitotic MTH1 inhibitor OXC-101 explains its strong anti-cancer effect.
Citation Format: Ulrika Warpman Berglund, Helge Gad, Kumar Sanjiv, Ann-Sofie Jemth, Oliver Mortusewics, Lars Brautigam, Juha Rantala, Thomas Helleday. OXC-101 kills cancer by disturbing microtubule polymerization and inhibiting MTH1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1569.
Abstract 1595: Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma
Authors: Yang Zeng-Jie , Yang Yijun Yang , Heller Allie 
Published: April 2023

Abstract
Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity by regulating terminal differentiation of tumor cells. Elimination or reduction in the levels of TH frees the unliganded TH receptor, TRα, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives terminal differentiation of neuronal progenitors as well as MB cells. However, increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and reducing MB growth. Moreover, TH promotes extensive differentiation and reduced proliferation of tumor cells from multiple molecular subtypes of MB including the hedgehog (HH) group as well as group 3 (G3) MB, indicating that TH-induced differentiation is not restricted by the oncogenic driver mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB by promoting tumor cell differentiation, with no obvious increase in tumor cell death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, and they establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality targeting tumor cell differentiation.
Citation Format: Zeng-Jie Yang, Yijun Yang Yang, Allie Heller. Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1595.