bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2664: Mutation characteristics of histone modification related genes in cholangiocarcinoma
Authors: Li Yunfeng , Chen Huanwei , Xu Zanmei , Yao Libo , Li Junying , Cai Chengzhi , You Dong 
Published: July 2021

Abstract
Background and objective: Histone modification, as an important part of epigenetics researches, can cause tumorigenesis and development by changing chromatin status and regulating gene expression. Histone deacetylase (HDAC) inhibitors have made great progress as new drugs, and its mechanism is related to the mutation of HDAC family genes. However, mutations of other related genes lacked reports. Here, we analyzed the mutation characteristics of 13 histone related genes in patients with cholangiocarcinom.
Methods: 380 cholangiocarcinom patients were enrolled. Next generation sequencing targeting 450 cancer genes was performed in OrigiMed. Disease-free survival (DFS) curve after operation was drawn with Kaplan-Meier and compared with Log-rank. Fisher's exact test was adapted to perform other statistical analysis.
Results: 153 mutations were occurred in 13 histone modification related genes (HDAC1, HDAC7, HDAC9, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, EZH2, EP300 and CREBBP), and 66.7% (102/153) was substitution/indel, 31.4% (48/153) truncation and 2.0% (3/153) rearrangement. According to the mutation, patients were divided into histone gene wild type (WT) group and histone gene mutation type (MUT) group, patients with at least one mutation in 13 genes. Co-mutation analysis of 450 genes revealed that KTM2D and KTM6A tended to co-mutate with other genes, including FAT4, ATM, BRAF and ERBB3. KTM2C and KRAS mutation were mutually exclusive (P&lt;0.01). 98 patients (25.8%) had at least one histone modification related mutation; Among them, KTM2C was the highest (10.5%, 40/380), followed by KTM2D (7.9%, 30/380), CREBBP (3.9%, 15/380), EP300 (3.4%, 13/380) , KTM2A (3.4%, 13/380) and HDAC9 (2.6%, 10/380). Furthermore, compared with WT group, patients in MUT group had a short DFS time after operation (mDFS: 7 vs 11.15 months, P=0.0139). Besides, the TMB had no significant difference between two groups, as well as the PD-L1 expression and microsatellite status.
Conclusion: We firstly exhibited 13 histone related mutations in Chinese patients with cholangiocarcinoma. Mutations of histone modification related genes suggested poor outcomes of cholangiocarcinom.
Citation Format: Yunfeng Li, Huanwei Chen, Zanmei Xu, Libo Yao, Junying Li, Chengzhi Cai, Dong You. Mutation characteristics of histone modification related genes in cholangiocarcinoma [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 2664.
Abstract 2677: Clinicopathologic significance of CXCR2-CXCL1 signaling in cholangiocarcinoma
Authors: Yamamoto Yurie , Tsujio Gen , Sera Tomohiro , Sugimoto Atsushi , Kushiyama Syuhei , Nishimura Sadaaki , Kuroda Kenji , Tanaka Ryota , Kimura Kenjiro , Amano Ryousuke , Ohira Masaichi , Yashiro Masakazu 
Published: July 2021

Abstract
Background: Cancer progression has been recognized as not only the proliferation of tumor cells but also an interaction between cancer cells and the surrounding stroma in the tumor microenvironment. Among the tumor stromal cells, cancer-associated fibroblasts (CAF) have been reported to be closely associated with tumor development in various solid carcinomas. We previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling might play an important role for the pathogenic construction of CAF in the gastric cancer (GC) microenvironment, suggesting that GC cells might alter their adjacent stroma to form a permissive environment for tumor progression, and also we reported that chemokine (C-X-C motif) ligand 1 (CXCL1) from cells stimulated the recruitment of bone marrow cells into GC microenvironment via CXCR2 signaling, resulting in the malignant progression of GC. Following these findings, we reported that among the CXCR2 ligands, CXCL1 might play an important role in the malignant progression of GC via CXCR2 signaling. And then, some studies suggest that CXCR2-CXCL1 plays an important role in not only GC but also other solid cancer. However, there is no report about the clinicopathological significance of CXCR2-CXCL1 signal in cholangiocarcinoma. Then, we examined the clinicopathological significance of CXCR2-CXCL1 signal in cholangiocarcinoma in this study.
Patients and Method: We retrospectively analyzed the total cases of 168 patients with cholangiocarcinoma. The expressions of CXCR2 and CXCL1 were investigated by immunohistochemistry, and we then analyzed the correlation between the clinicopathological features of 168 patients and the CXCR2 and CXCL1 expression level.
Results: The CXCR2 and CXCL1 positive expression wad as follows: CXCR2 was 18.5% (31/168), CXCL1 was 72.8% (126/173), both CXCR2 and CXCL1 was 17.9% (30/168). Metastasis negative was correlated with CXCL1 expression. Low depth invasion was correlated with CXCR2 expression. The prognoses of the both CXCR2 and CXCL1 positive patients were significantly better than those of CXCR2 and/or CXCL1 negative patients (p&lt;0.023, log rank).
Conclusion:CXCLR2 and CXCL1 expression might be a better prognostic factor of patients with cholangiocarcinoma, and CXCR2-CXCL1 signaling might play an important role for tumor-suppressing effects of cholangiocarcinoma.
Citation Format: Yurie Yamamoto, Gen Tsujio, Tomohiro Sera, Atsushi Sugimoto, Syuhei Kushiyama, Sadaaki Nishimura, Kenji Kuroda, Ryota Tanaka, Kenjiro Kimura, Ryousuke Amano, Masaichi Ohira, Masakazu Yashiro. Clinicopathologic significance of CXCR2-CXCL1 signaling in cholangiocarcinoma [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 2677.
Abstract 2679: Role of TH2 cells in pancreatic cancer progression
Authors: Alam Aftab , Bhatta Maulasri , Denz Parker , Levanduski Eric , Dey Prasenjit 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. Here, we explored the role of oncogenic Kras (KrasG12D=Kras*) in pro-tumorigenic signaling interactions between cancer cells and host cells. We found that TH2 cells infiltrate the pancreas in the early stage of the tumorigenesis and secrete type 2 cytokines [interleukin (IL)4 and IL13]. Further, Kras* signaling is involved in establishing this paracrine circuit utilizing type 2 cytokines in the PDAC tumor microenvironment (TME)2. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC. This study and the work of others expanded the role of immune cell derived cytokines in the context of Kras* driven PDAC through its promotion of cancer cell proliferation. Importantly, perturbation of the IL4 and/or IL13 mediated signaling restricts tumor growth and increases survival in a mouse model of PDAC. Notably, PDAC patients with predominantly TH2 (Gata3+) polarized lymphoid cell infiltration show reduced survival compared to tumors with higher TH1 (Tbet+) cells. Finally, the presence of TH2 cells in the PDAC TME might explain the immense immunotherapy resistance observed in PDAC patients and anti-TH2 treatment might sensitize these patients to immune checkpoint inhibitors. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as Tregs. Inhibition of IL33 leads to a decrease in the infiltration and activation of TH2 cells and Treg cells, accompanied by significant PDAC tumor regression.
Citation Format: Aftab Alam, Maulasri Bhatta, Parker Denz, Eric Levanduski, Prasenjit Dey. Role of TH2 cells in pancreatic cancer progression [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 2679.
Abstract 2686: Preventive effects of saffron in a colitis mouse model
Authors: Banskota Suhrid , Khan Waliul , Singh Gulshan , Habtezion Aida , Brim Hassan , Ashktorab Hassan 
Published: July 2021

Abstract
Background: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract with rising incidence and no effective cure. IBD increases the risk of colon cancer through a Colitis-Associated-Cancer (CAC) pathway. Despite available anti-inflammatory or immunosuppressive drugs, many patients fail or loose response over time and many others experience drug-induced adverse events. Natural plant products are increasingly used by IBD patients and reported to have some efficacy for IBD in experimental models and clinical trials. Saffron (Crocus sativus), has been reported to play a key role in treatment of different digestive system disorders but its preventive role in IBD has not been explored.
Aim: To establish whether saffron treatment modulates immunity in intestinal inflammation and ameliorates experimental colitis.
Methods: Mice were pre-treated with either saffron (10 or 20 mg/kg body weight) or vehicle through daily oral gavage for 4 days before dextran sulfate sodium (DSS) administration. Then, we induced acute colitis in C57BL/6 mice with 2.5% DSS. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for protein expression from the colon for immunophenotyping using ELISA. TNF-a, IL-b, and IL6 expression was analyzed by immunoblot analysis.
Results: Saffron Pre-treatment improved gross and histopathological characteristics of colonic mucosa in experimental colitis mice. Saffron dose 10 and 20 mg/kg body weight showed a significant improvement in body weight, disease activity index (DAI), colon length, and histology score, when compared to vehicle treated DSS mice group. Immunoblot analysis showed saffron pre-treatment significantly decreases pro-inflammatory TNF-a, IL-b, and IL-6 in the colon tissues indicating saffron mediates its preventive effect through anti-inflammatory pathways.
Conclusion: These data suggest saffron therapeutic potential of saffron and its preventive role in treating experimental colitis in part via immune response modulation and a switch from pro- to anti-inflammatory profile. The study also gives insights in developing an alternative treatment for IBD-associated colitis.
Citation Format: Suhrid Banskota, Waliul Khan, Gulshan Singh, Aida Habtezion, Hassan Brim, Hassan Ashktorab. Preventive effects of saffron in a colitis mouse model [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 2686.
Abstract 2688: The landscape of precision cancer combination therapy: a single-cell perspective
Authors: Ahmadi Saba , Sukprasert Pattara , Vegesna Rahulsimham , Sinha Sanju , Artzi Natalie , Khuller Samir , Schäffer Alejandro A. , Ruppin Eytan 
Published: July 2021

Abstract
The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we explore the landscape of optimal combination therapy targets in solid tumors (including brain, head and neck, melanoma, lung, breast and colon cancers). To this end, we developed MadHitter (https://github.com/ruppinlab/madhitter), which analyzes tumor single-cell transcriptomics data using combinatorial algorithms to identify precision combination of treatment targets that are predicted to maximize the killing of cancer cells while minimizing the killing of noncancerous ones. We started with a predefined set of 533 proteins that are lowly abundant across healthy tissues and thus may have low off-tumor targeting and toxicity if targeted via chimeric antigen receptors (CAR) T cell therapy. In most cancer types analyzed, we find that combinations composed of a single-digit number of targets are sufficient to kill at least 80% of the tumor cells while killing at most 10% of the non-tumor cells in each patient. We identify targets that are shared across datasets of the same cancer type (e.g., TNR) or across different cancer types (the SOX family, MAGE family, and KRT16). Next, we expanded our search for a set of 1269 known cell surface receptors, which may be precisely targeted by antibody or nanoparticles delivering a toxin into cells via receptor mediated endocytosis. The resulting optimal target sets are encouragingly also in the single-digit size. The gene PTPRZ1, a tyrosine phosphatase receptor, is frequently found in the optimal combinations for brain and head and neck cancers, and EGFR is a high-coverage target in multiple tumor types. Notably, requiring more stringent levels of cancer killing, the number of targets that need to be combined rises sharply in both search spaces described above. In sum, this analysis provides the first systematic characterization of potential combinatorial targets in solid tumors, uncovering promising future targets for both CAR therapy and conjugated toxin delivering antibodies and nanoparticles.
Citation Format: Saba Ahmadi, Pattara Sukprasert, Rahulsimham Vegesna, Sanju Sinha, Natalie Artzi, Samir Khuller, Alejandro A. Schäffer, Eytan Ruppin. The landscape of precision cancer combination therapy: a single-cell perspective [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 2688.
Abstract 2709: CD44 inhibits DCIS progression to invasive carcinoma
Authors: Liu Fang , Zhou Jun , Kundu-Roy Tanima , Wahler Joseph , So Jae Young , Lin Yong , Lou You-Rong , Barnard Nicola J. , Matsuura Isao , Suh Nanjoo 
Published: July 2021

Abstract
Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the spontaneously immortalized human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is the most commonly used model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Our finding is supported by a previous study which showed that CD44 expression was lower in invasive human breast carcinomas than in DCIS, especially in the luminal A subtype. Our study uncovered an unexpected role of CD44 in the inhibition of DCIS transition to invasive carcinoma. We will also present a model for the underlying mechanisms for the protective role of CD44 in the inhibition of transition from DCIS to invasive carcinoma. Our findings have important implications for breast cancer.
Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits DCIS progression to invasive carcinoma [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 2709.
Abstract 2712: Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers
Authors: Cheng Liqing , Chen Jane , Yu Qunyan , Malkova Natalia , Cortez-Retamozo Virna F. , Sun Fangxian , Sidhu Sukhvinder 
Published: July 2021

Abstract
The success of early cancer immunotherapies has led to the development of novel therapeutic approaches including multi-specific antibodies engaging innate and adaptive effector cells. To evaluate the antitumor potency of these multi-specific cell engagers, we have established a protocol to select human PBMCs from donors of a commercial frozen source by their potency to produce inflammatory cytokines and the capacity to engraft into NOD-Scid IL2Rgammanull (NSG)mice. The selected human PBMCs were used to reconstitute NSG mice, or as donors of effector cells that upon in vitro expansion were adoptively transferred to NSG mice for humanization. We have employed these humanization strategies to evaluate T cell engagers, which are typically multi-specific antibodies directed against the T cell and one or multiple tumor-associated antigen (TAA), whose therapeutic strategy is to 1) engage T cells, 2) activate the T cells and 3) engage tumor cells, and thus induce tumor cell killing. We will present representative data from several humanization approaches using liquid and solid orthotopic tumor models to assess the effectiveness of multi-specific T cell engagers in mediating antitumor responses. Thus, pre-clinical evaluations rely on the development of optimized tumor bearing humanized models that mirror key properties of a human setting, to assess the therapeutic potential of anti-tumor multi-specific biologics.
Citation Format: Liqing Cheng, Jane Chen, Qunyan Yu, Natalia Malkova, Virna F. Cortez-Retamozo, Fangxian Sun, Sukhvinder Sidhu. Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers [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 2712.
Abstract 2714: Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes
Authors: Carr-Ascher Janai 
Published: July 2021

Abstract
Approximately 13,000 people this year in the United States alone will be diagnosed with sarcoma and nearly 5,000 will lose their lives to this devastating disease. Soft tissue sarcomas are a clinically and biologically heterogeneous group of tumors made up of approximately fifty subtypes that are classified by their presumed mesenchymal origin. The development of novel therapies for sarcoma has been hampered by the considerable heterogeneity of the disease and the limited understanding of the molecular mechanisms driving sarcoma formation and evolution. Due to this, clinically, the majority of patients with aggressive soft tissue sarcoma subtypes are treated similarly despite evidence these subtypes are unique. Our lab has focused on the development of a new model for the study of sarcoma subtypes using a primary human transformation system. Based on TCGA data, one characteristic that is shared between sarcoma subtypes is the loss or silencing of p53 and Rb1. We have started with immortalized mesenchymal stem cells (MSC), the presumed cell of origin for sarcoma and introduced lentiviral constructs targeting p53 and Rb1 by CRISPR technology to delete these genes. Following this, we have added a barcoded oncogene library with genes implicated in sarcoma specific biology or across cancer subtypes. Using this system, we have successfully transformed these MSCs into high grade soft tissue sarcomas. The current goal is to continue to manipulate this system to develop multiple soft tissue sarcoma subtypes. By starting with the same cell of origin and arriving at different sarcoma subtypes, we can begin to understand the relationship between these subtypes which will inform clinical trial design. Using this system, we can investigate the development of sarcoma, understand subtype heterogeneity, and utilize this tool to develop novel therapies for our patients.
Citation Format: Janai Carr-Ascher. Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes [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 2714.