bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1069: New panel of patient derived lymphoma xenografts (PDX) for preclinical research and immune oncology
Authors: Brzezicha Bernadette , Becker Michael , Stecklum Maria , Conrad Teresia , Janz Martin , Bittner Aitomi , Schmitt Clemens , Keilholz Ulrich , Hoffmann Jens 
Published: August 2019

Abstract
Lymphomas represent a very heterogeneous group of hematologic malignancies and pose an important challenge in the clinical routine. They frequently develop resistance to the treatment with standard-of-care (SoC) drugs and have a high incidence of disease recurrence.
Recent progress in molecular high throughput profiling has helped to identify genetic drivers and genetic subtypes of diffuse large B-cell lymphomas (DLBCL). Further target validation and drug development projects are highly dependent on corresponding preclinical models representing the different clinical subtypes. Therefore, we started to establish and characterize new patient derived xenografts (PDX) of non-Hodgkin (NHL) and Hodgkin lymphomas (HL) for drug development, translational and immune oncology research.
All lymphoma PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice.
For further characterization, established lymphoma PDX models were treated with SoC and investigational drugs. In addition, the growth of lymphoma PDX on humanized mice was evaluated to establish new models for the evaluation of novel immune therapy approaches. To gain a deeper insight in the molecular biology of the lymphoma models, RNA sequencing of all was performed.
More than 20 new PDX models from NHL (including 8 DLBCL) and HL have been successfully established and characterized. Heterogeneous individual responses to the treatments were observed. Explorative analysis of RNA sequencing data confirmed the representation of the clinical lymphoma subgroups in our panel of models. Likewise, genetic subtypes of DLBCL COO classes could be confirmed by PCA and hierarchical clustering methods. Patterns of genetic driver mutations as revealed by recently published large genomic studies were identified.
Our newly and extensively characterized lymphoma PDX model panel allows the evaluation on novel targeted and immune therapies in preclinical phase II trial settings. They provide an exceptional platform for the identification and validation of new targets and allow the preclinical screening of new combinations in translational research projects.
Citation Format: Bernadette Brzezicha, Michael Becker, Maria Stecklum, Teresia Conrad, Martin Janz, Aitomi Bittner, Clemens Schmitt, Ulrich Keilholz, Jens Hoffmann. New panel of patient derived lymphoma xenografts (PDX) for preclinical research and immune oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1069.
Abstract 1084: The role of tumor-associated neutrophils (TAN) and CD8 positive T lymphocyte in the progression of hepatocellular carcinoma (HCC)
Authors: Yusa Toshihiko , Okabe Hirohisa , Yamashita Yo-ichi , Yamao Takanobu , Umezaki Naoki , Miyata Tatsunori , Nakagawa Shigeki , Hayashi Hiromitsu , Imai Katsunori , Chikamoto Akira , Ishiko Takatoshi , Baba Hideo 
Published: August 2019

Abstract
[Background]Neutrophils are known as immune cells involved in biological defense against foreign substances. On the other hand, in the tumor microenvironment, it is said that neutrophils affect on tumor progression as a tumor-associated neutrophil (TAN). Although, TAN and other immune cells in the progression of HCC is unclear.
[Method]One hundred twenty eight patients who underwent curative hepatectomy for HCC in our institution were enrolled. Immunohistochemistry was performed with CD66b and CD8 antibody to evaluate TAN and CD8+ T lymphocytes, respectively. Expression high or low was determined by cut-off value of each number of immune cells. We counted the number of each immune cells in both tumor (intra-tumor) and the tumor marginal area (extra-tumor). The relationship between the infiltration of each immune cell and clinicopathological factors was examined.
[Result]Comparing the number of immune cells of intra-tumor and extra-tumor, there were significantly more cells in extra-tumor area (p&lt;0.001). There was no difference in between background clinicopathological factors and the number of TAN or CD8+ T lymphocytes in either intra-tumor or extra-tumor areas. Overall survival was significantly better in the group with high CD8+ T lymphocytes in extra-tumor area compared to the low group (p = 0.0491), intriguingly though CD8+ T lymphocytes in intra-tumor area was not associated with prognosis. In the contrast, overall survival was significantly poor in the group with high TAN in extra-tumor area compared to the low group (p = 0.0296), though TAN in intra-tumor area was not associated with prognosis.
[Conclusion]Infiltration of TAN and CD8+ T lymphocytes not in intra-tumor but in the extra-tumor area may be involved in the progression of HCC.
Citation Format: Toshihiko Yusa, Hirohisa Okabe, Yo-ichi Yamashita, Takanobu Yamao, Naoki Umezaki, Tatsunori Miyata, Shigeki Nakagawa, Hiromitsu Hayashi, Katsunori Imai, Akira Chikamoto, Takatoshi Ishiko, Hideo Baba. The role of tumor-associated neutrophils (TAN) and CD8 positive T lymphocyte in the progression of hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1084.
Abstract 1092: V-ATPase family regulates lysosomal exocytosis and neutralizes with tumor-infiltrating lymphocytes for glioblastoma cells
Authors: Chang Yu-Chan , Hsiao Michael 
Published: August 2019

Abstract
Immunotherapy based on checkpoint inhibitors provides substantial clinical benefit, but only to a minority of cancer patients. Targeted immunological checkpoint pathways have demonstrated anti-tumor cytotoxicity in the treatment of refractory cancers. However, cancer cells release specific “drones”, such as small vesicles, which increase their ability in the blood and released the proteins such as PD-L1 to block the attack from T cells then they have a change to reach the tumor forming. To characterization of exosomes forming, trafficking and secretion can be a novel therapeutic approach to improve immunotherapy in cancer patients. The ATPase H+ Transporting V0 and V1 subunits (V-ATPase, also called ATP6 family) are critical for acidifying a variety of intracellular compartments and lysosomal exocytosis. Nevertheless, the dysfunctional roles of V-ATPases in glioblastoma has not yet been elucidated. For this purposed, we investigated V-ATPase members in lysosomal vesicles and found several candidates are key factors in regulating lysosomal exocytosis in glioblastoma cells. We established transcriptomics datasets by various glioblastoma cell lines, the results showed V-ATPases are highly expressed in malignant cell lines compared to benign or normal immortalized cells. Immunohistochemistry also performed a trend of consistency that increased of V-ATPase expression in tumor parts than normal adjacent tissues. The expression level of several V-ATPase subunits is also associated with clinical parameters and survival rate. Moreover, we observed the number of tumor infiltrating lymphocyte (TILs) was decreased in clinical cohorts and two-way cell models. Therefore, we established V-ATPases related proteomics datasets and found some interaction partners could stabilized protein structure of V-ATPase. Specific peptide can compete between V-ATPase and the interacting partners and further modulate TILs in glioblastoma. This approach can be a novel therapeutic strategy that combines immunotherapy to against glioblastoma in clinical patients.
Citation Format: Yu-Chan Chang, Michael Hsiao. V-ATPase family regulates lysosomal exocytosis and neutralizes with tumor-infiltrating lymphocytes for glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1092.
Abstract 1094: Lipopolysaccharide-induced chronic inflammation promotes lung tumorigenesis in the context of an immunosuppressive microenvironment
Authors: Liu Chia-Hsin , Chen Kong , Di Yuanpu 
Published: August 2019

Abstract
Clinical and epidemiological evidence suggest that chronic infection and inflammation increase risk of lung cancer. Pseudomonas aeruginosa infection is frequently found in patients with chronic obstructive pulmonary disease (COPD) and is associated with increased lung inflammation and acute exacerbations. However, the mechanism of chronic bacterial infection-induced lung inflammation in promoting lung tumorigenesis remains unclear. To elucidate this mechanism, we established a murine lung cancer model by treating mice with or without recurrent lipopolysaccharides (LPS) from Pseudomonas aeruginosa in combination with nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Interestingly, combined LPS and NNK exposure significantly increased tumor number, tumor incidence, and tumor area compared to NNK treatment alone. In addition, the inflammatory cell counts in the bronchoalveolar lavage (BAL) including macrophages, neutrophils, and lymphocytes were significantly increased in the LPS/NNK treatment group. The BAL fluid of chemokines/cytokines, as analyzed by luminex assays, revealed higher levels of IL-17, CXCL10, GM-CSF, G-CSF, MIP-1a, and KC in LPS/NNK than in NNK treatment group. Flow cytometry analysis of the mouse lung tissue revealed that combined LPS and NNK exposure significantly increased CD4+ T cells including Th1, Th17, and Tregs and myeloid-derived suppressor cells recruitment in the lung. Real-time polymerase chain reaction of mouse lung tissue showed T cell exhaustion related genes, including Pdcd1, Ctla-4, Tim-3, Lag-3, and Foxp3, were significantly upregulated in the LPS/NNK treatment than NNK treatment. Moreover, immunohistochemical staining of LPS/NNK-exposed lung tumors showed higher PD-L1 expression than NNK-exposed lung tumors. Our data suggest that chronic LPS exposure-promoted and NNK-induced lung tumorigenesis is associated with immunosuppressive tumor microenvironment. The changes include recruitment of Tregs and MDSCs, increased T cell exhaustion, and upregulated PD-1/PD-L1 pathway, which may be used as the therapeutic target for chronic inflammation-associated lung cancer treatment.
Citation Format: Chia-Hsin Liu, Kong Chen, Yuanpu Di. Lipopolysaccharide-induced chronic inflammation promotes lung tumorigenesis in the context of an immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1094.
Abstract 1104: Targeting the stress response kinase GCN2 to restore immunity in the tumor microenvironment
Authors: Ravishankar Buvana , Adusumilli Lavanya , Pookot Deepa Pookot , Huang Emily , Sreenivasan Raashi , Marshall Lisa , Kaveri Deepika , Talay Oezcan , Suthram Silpa , Miakicheva Svetlana , Okal Abood , Zibinsky Mikhail , Jackson Jeffrey , Shibuya Grant , Leger Paul , Tivitmahaisoon Parcharee , Jacobson Scott , Wong Steve , Wadsworth Angela , Sanchez Jerick , Brovarney Martin , Chian David , Marubayashi Sachie , Jorapur Aparna , Bradford Delia , Colas Christophe , Cutler Gene , Schwartz Jacob , Wustrow David , Kassner Paul , Brockstedt Dirk 
Published: August 2019

Abstract
The tumor microenvironment (TME) is characterized by deficiencies in oxygen and key nutrients, such as glucose and amino acids, resulting in an overall immune-suppressive environment. Key suppressive cell types in the TME include tumor, stromal and myeloid-derived suppressor cells (MDSC) which create a nutrient-poor environment that supports tumor growth and limits immune surveillance. General control nonderepressible 2 (GCN2), a stress response kinase, plays a key role in sensing and modulating the cellular response to amino acid deprivation. GCN2 activation in T cells triggers the integrated stress response pathway and promotes T cell anergy and apoptosis. We have developed small molecule GCN2 inhibitors (GCN2i) that are highly potent and selective in vitro. Culturing primary mouse or human immune cells under low nutrient conditions activates the GCN2 pathway limiting T cell proliferation and function. Treatment of these nutrient-deprived T cells with GCN2i resulted in rescue of CD8+ T cell proliferation and effector functions. In addition, GCN2 inhibition in MDSC alone fully reversed CD33+MDSC-induced T cell suppression and effector functions. Our GCN2 inhibitors are orally bioavailable with drug like in vivo ADME properties. Our GCN2i is currently being evaluated in vivo, in murine syngeneic tumor models. Our results demonstrate that inhibition of GCN2 is an attractive approach for relieving T cell suppression and promoting effector function, demonstrating GCN2 as a promising therapeutic target for the treatment of cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Buvana Ravishankar, Lavanya Adusumilli, Deepa Pookot Pookot, Emily Huang, Raashi Sreenivasan, Lisa Marshall, Deepika Kaveri, Oezcan Talay, Silpa Suthram, Svetlana Miakicheva, Abood Okal, Mikhail Zibinsky, Jeffrey Jackson, Grant Shibuya, Paul Leger, Parcharee Tivitmahaisoon, Scott Jacobson, Steve Wong, Angela Wadsworth, Jerick Sanchez, Martin Brovarney, David Chian, Sachie Marubayashi, Aparna Jorapur, Delia Bradford, Christophe Colas, Gene Cutler, Jacob Schwartz, David Wustrow, Paul Kassner, Dirk Brockstedt. Targeting the stress response kinase GCN2 to restore immunity in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1104.
Abstract 1107: LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target
Authors: Lee Su Jin , Byeon Sun-ju , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Kang Won Ki , Lim Ho Yeong , Kim Kyoung-Mee , Kim Seung Tae 
Published: August 2019

Abstract
We performed prospective immunohistochemical analysis of LAG3 for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic (33.3%, 2 of 6), gastric (24.7%, 21 of 85), colorectal (23.6%, 48 of 203), melanoma (12.5%, 1 of 8), genitourinary (9.5%, 4 of 46), biliary tract (6.3%, 1 of 16), and sarcoma (5.4%, 2 of 37), but not miscellaneous (0.0%, 0 of 14) or hepatocellular (0.0%, 0 of 15) cancer. Among 149 metastatic CRC patients, there was no statistically significant difference in gender, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. non-expressed). Among 53 metastatic GC patients, LAG3 was only significantly associated with EBV status (P = .042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy.
Citation Format: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim. LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1107.
Abstract 111: Tumor microenvironment derived NRG1 promotes antiandrogen resistance in prostate cancer
Authors: Zhang Zeda , Karthaus Wouter , Mota Jose Mauricio , Mu Ping , Wu Chao , Abida Wassim , Linton Eliot , Lee Young Sun , Lee Eugine , Mao Ninghui , Adams Elizabeth , Choi Danielle , Rathkopf Dana E. , Carver Brett , Gopalan Anuradha , Jiang Xuejun , Watson Philip , Sawyers Charles 
Published: August 2019

Abstract
Despite the improved clinical outcomes for patients with advanced prostate cancer due to the use of second generation antiandrogens, acquired drug resistance inevitably occurs and remains the major challenge for prostate cancer therapy. While several cell-autonomous mechanisms of drug resistance have been elucidated previously, for a large number of patients the mechanism of resistance remains unclear. Recent studies point to the importance of the tumor microenvironment (TME), and cancer associated fibroblasts (CAF) in the TME, in mediating tumor progression and resistance to therapy, but whether CAFs specifically contribute to antiandrogen resistance in prostate cancer is not known. Using a preclinical model that faithfully mimics the typical progression of patients on antiandrogen therapy, we found that antiandrogen resistance develops significantly faster when cells are grown in the presence of their cognate CAFs. By carrying out biochemical purification and mass spectrometry analysis, we identified NRG1 as a CAF secreted factor, and found that it can promote antiandrogen resistance in tumor cells, via activation of HER3 in the tumor. Importantly, blocking either NRG1 or HER3 can re-sensitize tumors to antiandrogen treatment in this model. Moreover, NRG1 expression is up-regulated in CAFs after antiandrogen exposure or in androgen deprivation condition. Clinically, increased stroma-NRG1 expression was observed in patients post androgen deprivation therapy but not in hormonally intact men. Taken together, this work has revealed a novel, NRG1-mediated non-cell autonomous mechanism of antiandrogen resistance in prostate cancer, and suggests that therapeutically targeting NRG1 in the setting of metastatic, antiandrogen-resistant prostate cancer with elevated NRG1 could provide significant benefit to patients.
Note: This abstract was not presented at the meeting.
Citation Format: Zeda Zhang, Wouter Karthaus, Jose Mauricio Mota, Ping Mu, Chao Wu, Wassim Abida, Eliot Linton, Young Sun Lee, Eugine Lee, Ninghui Mao, Elizabeth Adams, Danielle Choi, Dana E. Rathkopf, Brett Carver, Anuradha Gopalan, Xuejun Jiang, Philip Watson, Charles Sawyers. Tumor microenvironment derived NRG1 promotes antiandrogen resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 111.
Abstract 1117: The molecular basis of LIF-mediated NPC metastasis
Authors: Liu Shu-Chen 
Published: August 2019

Abstract
Distant metastasis and local recurrence are frequently observed in nasopharyngeal carcinoma (NPC) but the mechanisms remain largely unclear. Here, we report that higher levels of leukemia inhibitory factor (LIF) and LIF receptor (LIFR) are correlated with poorer metastasis/recurrence-free survival. LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically, both in vitro and in vivo, through modulation of LIFR-YAP1-focal adhesion signaling. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer progression, targeting of this pathway presents a promising opportunity to block metastasis.
Citation Format: Shu-Chen Liu. The molecular basis of LIF-mediated NPC metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1117.
Abstract 1120: Proinflammatory milieu promotes leptomeningeal metastasis by activation of LCN2
Authors: Chi Yudan 
Published: August 2019

Abstract
The tumor microenvironment is emerging as a critical regulator of cancer progression, especially in metastatic brain malignancies. The unique properties of leptomeningeal metastasis (LM) require a specific framework for acquisition of metastatic traits within the fluid-filled leptomeningeal space. Here, we discuss a number of the distinct features of the proinflammatory environment, including cancer cells and relevant immune cells. We also highlight the exact role of its contribution to cancer growth in the development of LM. Proinflammatory cytokines induce the secretion of cancer-derived LCN2. Mechanistically, we have uncovered that iron, transported by LCN2, supports cancer cell growth. By pharmacologic interference with iron uptake, we will prove its therapeutic beneficence for targeting LM in pre-clinical models.
Citation Format: Yudan Chi. Proinflammatory milieu promotes leptomeningeal metastasis by activation of LCN2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1120.
Abstract 1128: Metastasis suppressor RKIP modulates gene expression variance in triple negative breast cancer
Authors: Yang Dongbo , Pott Sebastian , Rosner Marsha 
Published: August 2019

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with a highly metastatic phenotype. Conventional chemotherapy and radiotherapy are generally ineffective at treating metastasis. Natural metastasis suppressors such as the Raf kinase inhibitory protein (RKIP) are not functional in many TNBC cases and associated with poorer relapse-free survival. Although tumor cell heterogeneity is strongly implicated in contributing to metastasis, it is unknown whether metastasis suppression by RKIP reduces heterogeneity. Therefore, we performed single-cell RNA sequencing of mouse TNBC tumors as well as cultured cells to study the effect of RKIP overexpression on gene expression variance in tumor cells. Elucidating RKIP’s effect on gene expression variance at the single cell level reveals gene sets that are important in tumor cell transitions from non-metastatic to metastatic states. We predict that the gene sets whose variance is decreased by RKIP are effective drug targets for metastatic breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Dongbo Yang, Sebastian Pott, Marsha Rosner. Metastasis suppressor RKIP modulates gene expression variance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1128.