bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5309: Inhibition of cancer stem-like cells in esophageal squamous cell carcinoma with SOCS-1 gene therapy
Authors: Yamamoto Ayumi , Munekage Eri , Serada Satoshi , Tsujii Shigehiro , Hiramatsu Kosuke , Fujimoto Minoru , Hanazaki Kazuhiro , Naka Tetsuji 
Published: August 2019

Abstract
INTRODUCTION: Cancer stem-like cells are thought to be one of the causes of cancer initiation and progression. They are associated with the resistance to radiotherapy and chemotherapy for various types of tumor including esophageal squamous cell carcinoma (ESCC). Therefore, cancer stem-like cells are promising therapeutic targets of cancer. Suppressor of cytokine signaling-1 (SOCS-1) was identified as a negative regulator of various cytokine signaling. We have previously demonstrated that overexpression of SOCS-1 showed a potent anti-tumor effect on ESCC through inhibiting of the JAK/STAT signaling pathway. This study aimed to evaluate the anti-tumor effect of SOCS-1 gene therapy using adenoviral vector (AdSOCS-1) against cancer stem-like cells in ESCC.
METHODS: ESCC cell lines were separated into aldehyde dehydrogenase (ALDH) positive and ALDH negative cells by ALDEFLOUR, and then sphere formation assays were performed. The inhibitory effects of AdSOCS-1 and AdLacZ on the sphere formation were evaluated using TE8, TE14 ESCC cell lines. The inhibition of sphere formation was also evaluated using ESCC cells obtained from ESCC PDX mice (ESCC8). Next, the expression of transcription factors associated with cancer stem-like cells in ESCC was evaluated by RT-PCR. The inhibitory effects on tumor formation by AdSOCS-1 were evaluated by tumorigenicity assay using TE8 xenograft mice.
RESULTS: In the sphere formation assay, ALDH positive TE8 cells and TE14 cells represented strong sphere formation capacity. Compared with AdLacZ infected ALDH positive cells, sphere formation of AdSOCS-1 infected ALDH positive cells was significantly inhibited. The inhibition of sphere formation was also confirmed in ESCC cells obtained from ESCC8 PDX mouse tumor tissue. Interestingly, the expression level of Sox2, a critical stem cell factor regulated by STAT3, was also decreased by AdSOCS-1. Furthermore, AdSOCS-1 decreased the tumorigenic activity of the ALDH positive ESCC tumor cells. CONCLUSIONS: A potent anti-tumor effect of SOCS-1 gene therapy on ESCC may be partially explained by inhibiting the expression of a STAT3 regulated transcription factor critical for cancer stem-like cells.
Citation Format: Ayumi Yamamoto, Eri Munekage, Satoshi Serada, Shigehiro Tsujii, Kosuke Hiramatsu, Minoru Fujimoto, Kazuhiro Hanazaki, Tetsuji Naka. Inhibition of cancer stem-like cells in esophageal squamous cell carcinoma with SOCS-1 gene therapy [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 5309.
Abstract 5314: Smad4 loss upregulates chemokine expression and promotes tumor inflammation and growth in head and neck cancer
Authors: Masannat Jude , Wang Xuefeng , Cao Biwei , Song FeiFei , Chaudhary Ritu , Iglasia Janis de la , Gorgoglione Ciaara , Slebos Robbert , Chung Christine 
Published: August 2019

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. Of the patients diagnosed with HNSCC, previous findings show that SMAD4 loss is more common in recurrent HNSCC patients compared with newly diagnosed cases and is strongly associated with poor patient survival and metastases. SMAD4 is a tumor suppressor gene and is a central mediator of the transforming growth factor β (TGF-β) signaling pathway and acts as a co-SMAD which binds receptor-regulated SMADs such as SMAD2 and 3. SMAD2/3/4 complex is important for regulating downstream gene transcription that is involved in tumor invasion and metastasis.
Purpose: Since the TGF-β pathway is highly dysregulated in HNSCC, we investigate in this study how SMAD4 downregulation alters TGF-β pathway signaling and the tumor microenvironment.
Results: Using isogenic HNSCC cell lines, we visualized using immunofluorescence staining that levels of activated phospho-SMAD2 in the nucleus are correlated with expression of SMAD4. Genome-wide screening using Gene Set Enrichment Analysis (GSEA) further revealed changes in gene expression during SMAD4 knockdown in HNSCC cells. From GSEA results, the 20 most significantly altered Gene Ontology (GO) pathways were determined. It was shown that majority of these GO pathways are associated with regulating neutrophil migration and chemotaxis with an upregulation of CXC chemokine gene expression, specifically with CXCL1. In contrast, anti-tumor chemokines, such as CXCL9 and CXCL11, were downregulated during loss of SMAD4 expression. Using an orthotopic mouse model we show that in vivo, decreased expression of SMAD4 promotes tumor take and growth.
Conclusion: Collectively, these results suggest that HNSCC tumors with SMAD4 loss may have poor prognosis attributed to immunosuppressive functions of chemokine expression that acts on tumor-associated neutrophils.
Citation Format: Jude Masannat, Xuefeng Wang, Biwei Cao, FeiFei Song, Ritu Chaudhary, Janis de la Iglasia, Ciaara Gorgoglione, Robbert Slebos, Christine Chung. Smad4 loss upregulates chemokine expression and promotes tumor inflammation and growth in head and neck 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 5314.
Abstract 536: NBTXR3 potentiate cancer-cell intrinsic interferon beta response to radiotherapy
Authors: Rodriguez-Ruiz Maria E , Pilones Karsten , Daviaud Camille , Kraynak Jeffrey , Darmon Audrey , Paris Sebastien , Demaria Sandra 
Published: August 2019

Abstract
NBTXR3 represent first in class functionalized radioenhancer optimized for efficient tumor binding and sustained local permanence after intratumoral injection. Recent results of phase III in locally advanced Soft Tissue Sarcoma patients established the significant clinical benefits of NBTXR3 activated by radiation therapy compared to radiotherapy alone. Moreover, preclinical studies using CT26 cells have demonstrated that NBTXR3 activated by RT can induce an anti-tumor immune-response and the abscopal effect. Radiotherapy (RT) can induce T cell-mediated anti-tumor immune responses by multiple mechanisms which include enhancing the recruitment of Batf3-dependent cross-priming dendritic cells (DCs). The latter is contingent on tumor-intrinsic IFN-I induction by cytosolic dsDNA via cGAS/STING pathway, a process that is regulated by the upregulation of Trex1 in a RT dose-dependent fashion (Nat Commun 2017; 8:15618). Here, we utilized the murine TSA breast cancer cell line to test the hypothesis that NBTXR3 strengthens the pro-immunogenic effect of local RT by potentiating tumor cells IFN-I response. For in vitro experiments, TSA cells were exposed to NBTXR3 (800uM) 16 hours prior to RT delivered by a 220-kV source (SARRP) at a dose rate of 283.2 cGy/min. Secreted IFNb in the supernatants was measured by ELISA. Pre-treatment with NBTXR3 enhanced TSA cell radiosensitivity as determined in clonogenic assays. Cell death, as measured by loss of plasma membrane integrity was accelerated by NBTX3 after irradiation of TSA cells with 6 and 8Gy after 24 hours of treatment. NBTXR3 enhanced the secretion of IFNb by irradiated cells. Data suggest that NBTXR3 may enhance the effectiveness of radiation and improve tumor immunogenicity, likely via the induction of IFN-I. The role of the cGAS/STING pathway in the effects of NBTX3 are under investigation in vitro and in vivo.
Citation Format: Maria E Rodriguez-Ruiz, Karsten Pilones, Camille Daviaud, Jeffrey Kraynak, Audrey Darmon, Sebastien Paris, Sandra Demaria. NBTXR3 potentiate cancer-cell intrinsic interferon beta response to radiotherapy [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 536.
Abstract 547: Recombinant immunotoxins targeting B-cell maturation antigen induce complete responses in bone marrow myeloma mouse model
Authors: Shancer Zoe , Liu Xiu-fen , King Emily , Bera Tapan , Pastan Ira 
Published: August 2019

Abstract
Background: Multiple myeloma (MM) is a B-cell malignancy for which new treatments are urgently needed. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed on MM and an ideal target for immunotherapy of MM. Recombinant immunotoxins (RITs) are chimeric proteins composed of the Fv or Fab portion of an antibody fused to a fragment of Pseudomonas Exotoxin A (PE). One of these, Lumoxiti, is FDA approved for the treatment of drug-resistant hairy cell leukemia, another B-cell malignancy. LMB-75 is an immunotoxin with an anti-BCMA dsFv of mAb BM306 fused to domain III of PE, and LMB-70 is an anti-BCMA Fab fused to domain III of PE. We previously treated H929 myeloma cells grown as subcutaneous tumors with anti-BCMA immunotoxins that are very effective in killing cultured cells and cells from patients. We observed tumor growth inhibition but not complete tumor responses. Goal: Here we used H929 cells to develop a bone marrow mouse model that is more relevant to human disease and to determine if these immunotoxins are more active against H929 cells growing in bone marrow.
Methods: The NCI-H929 cell line was transfected with luciferase and GFP, recycled through the bone marrow of a mouse and enriched by flow to isolate cells with high GFP expression, which were used to inoculate tumors IV into NSG mice. Mice were treated IV with immunotoxins and tumor burden was assessed using bioluminescence imaging.
Results: H929-luc-GFP cells grow uniformly in the bone marrow of mice, cause hind limb paralysis around day 40, and provide a relevant in vivo model for testing RITs. We achieved complete responses when treating mice with 1.5 mg/kg LMB-75 or LMB-70 given QODX5 beginning on days 4 or day 8. Mice in all treatment groups were disease free at 3 months. An immunotoxin targeting CD22, which is not expressed on H929 cells, or an anti-BCMA immunotoxin with a mutation that inactivates toxin activity did not have any anti-tumor activity.
Conclusions: LMB-75 and LMB-70 induce complete, durable remissions of H929-luc-GFP cells growing in mouse bone marrow without toxicity to mice. These promising results support further pre-clinical development of these agents for MM.
Citation Format: Zoe Shancer, Xiu-fen Liu, Emily King, Tapan Bera, Ira Pastan. Recombinant immunotoxins targeting B-cell maturation antigen induce complete responses in bone marrow myeloma mouse model [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 547.
Abstract 614: Cytomegalovirus (CMV) reactivation and patient survival in head and neck cancer
Authors: Nelson Heather H. , Miller Jeffrey S. , Hunter-Schlichting DeVon , Butler Rondi A. , Kelsey Karl T. 
Published: August 2019

Abstract
There is building evidence that cytomegalovirus (CMV) may contribute to the development of solid tumors, however to date this has not been investigated in head and neck cancer (HNC). CMV is a highly prevalent, latent herpesvirus infecting over 50% of the population. CMV maintains latency in CD34+ cells, and recent work has demonstrated these latently infected cells preferentially differentiate into immunosuppressive monocytes. However, CMV is not solely immune suppressive as highly cytotoxic adaptive natural killer (NK) cells arise specifically in response to CMV reactivation. Here, we have investigated whether biomarkers of CMV reactivation are associated with patient survival in non-smoking HNC (n=184). CMV DNAemia was assessed using digital PCR, and a threshold of 1000 copies/mL serum was defined as reactivation; 22% of patients met this definition of CMV reactivation, however they did not have significantly worse survival than those without CMV reactivation (HR 1.5 (95% CI 0.7 - 3.0)). Monocytes that mobilize to the cancer site contribute to tumor-associated inflammation. Therefore, we explored whether a biomarker of inflammation, CRP, modified the association of CMV reactivation and HNC patient survival. In the absence of inflammation, there was no association between CMV reactivation and patient survival (HR 0.90 (95% CI 0.30 - 2.71)). However, those with both CMV reactivation and high inflammation had dramatically worse survival (HR 8.86 (95% CI 3.63 - 21.64)). These data are consistent with the recent report that CMV infected monocytes are immunosuppressive and suggest that stimulation of these monocytes to the tumor site may negatively impact patient survival. Future work should address the generalizability of this finding to other cancer types and determine whether CMV infected myeloid cells are present in the tumor microenvironment.
Citation Format: Heather H. Nelson, Jeffrey S. Miller, DeVon Hunter-Schlichting, Rondi A. Butler, Karl T. Kelsey. Cytomegalovirus (CMV) reactivation and patient survival in head and neck 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 614.
Abstract 625: Association between obesity and prostate cancer disease risk and mortality among African American men
Authors: Pichardo Margaret Saira , Minas Tsion , Tang Wei , Dorsey Tiffany H. , Ambs Stefan 
Published: August 2019

Abstract
Prostate cancer (PCa) is a major cause of cancer death in U.S. men. Age-adjusted mortality rates for men of African ancestry (40.8 per 100,000) are more than twice that of men of European ancestry (18.2 per 100,000). Men of African ancestry are more likely to have advanced stage cancer at diagnosis and lower prostate cancer survival rates relative to men of European ancestry of similar age and stage at diagnosis. Risk factors that may explain this survival disparity remain poorly understood. Obesity, a major risk factor for cancer development, aggressiveness and progression, disproportionately affects US men of African ancestry. Age-adjusted prevalence of obesity are higher among men of African ancestry (38.0%) compared to men of European ancestry (34.7%). While it has been previously suggested that obesity may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer mortality remains unclear, with studies showing mixed or null results in men of African ancestry. Less is known about the underlying biological mechanisms that may contribute to the racial differences observed in the link between obesity and prostate cancer. We previously reported an obesity paradox among African-American men in the NCI-Maryland Prostate Cancer-Case Control Study, with overweight and obese men having a lower risk of being diagnosed with the disease. Here, using Cox proportional hazard regression modeling, we estimated the risk of a PCa mortality for the 976 cases in the study. Our primary analysis suggests an obesity paradox, where obesity may protect against disease mortality among the African-American men. In subsequent analyses, we will examine the role of immune and inflammation markers in mediating or moderating the observed relationship of obesity with PCa in these men.
Citation Format: Margaret Saira Pichardo, Tsion Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Association between obesity and prostate cancer disease risk and mortality among African American men [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 625.
Abstract 637: A prospective study of tea and coffee intake and risk of glioma
Authors: Cote David J. , Bever Alaina M. , Wilson Kathryn M. , Smith Timothy R. , Smith-Warner Stephanie A. , Stampfer Meir 
Published: August 2019

Abstract
Background: Tea and coffee have anti-inflammatory, anti-oxidant and neuroprotective effects mediated by a variety of compounds, including polyphenols. Observational studies suggest that tea and coffee intake may reduce risk of certain cancers, although the data on glioma risk are limited and inconclusive.
Methods: We evaluated the association between tea, coffee, and caffeine intake and risk of glioma in the female Nurses’ Health Study (NHS, n=92,389, followed 33 years) and Nurses’ Health Study II (NHSII, n=95,242, followed 23 years) and the male Health Professionals Follow-up Study (HPFS, n=49,885, followed 29 years). Cumulatively updated tea and coffee intake were derived from validated quadrennial food frequency questionnaires. Glioma cases were confirmed by medical record review. Age-adjusted hazard ratios of glioma by category of beverage intake were estimated using Cox proportional hazards models. Associations across the combined cohorts were calculated using fixed effect meta-analysis.
Results: We documented 554 incident cases of glioma, including 256 in NHS, 87 in NHSII, and 211 in HPFS (159, 52, 151 glioblastomas, respectively). Compared to &lt;1 cup/week, higher tea consumption was inversely associated with glioma risk in women (HR=0.65, 95% CI 0.41-1.03 for &gt;2 cups/day, p-trend=0.03), and was inversely, but not significantly, associated in men (HR=0.70, 95%CI 0.30-1.61 for &gt;2 cups/day, p-trend=0.30). In women and men combined, the corresponding HR was 0.66 (95% CI 0.44-0.99) for &gt;2 cups/day (p-trend=0.02). We observed no significant associations between caffeinated, decaffeinated, or total coffee intake and glioma risk in men or women. We found no material differences in the results when baseline values were used, when responses were lagged by eight years, or when cases were limited to glioblastoma only.
Conclusion: In three large, prospective cohort studies of men and women, tea intake was inversely associated with glioma risk, particularly in women. No significant associations were observed for coffee intake of any type and glioma risk. These results merit further exploration in other prospective studies.
Note: This abstract was not presented at the meeting.
Citation Format: David J. Cote, Alaina M. Bever, Kathryn M. Wilson, Timothy R. Smith, Stephanie A. Smith-Warner, Meir Stampfer. A prospective study of tea and coffee intake and risk of glioma [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 637.
Abstract 671: Evaluation of machine learning tools for cancer drug response prediction with genomic profile data and drug response data from PDX model studies
Authors: Gu Henry , Jiang Jingjing 
Published: August 2019

Abstract
Cancer are diseases caused by genomic aberrations which lead to abnormal cell proliferation and metastasis. Cancer treatment based on cancer mutation profiles are the focus of research and development of cancer precision medicine. Currently only a small percentage of cancer patients’ genomic information are associated with known drug responses, while others lack known cancer drivers or have cancer drivers that are not druggable. Machine learning (ML) tools have been developed recently for cancer biomarker discovery and cancer drug response prediction. However, due to a lack of sufficient amount of high quality drug response data, especially data for new drugs, the application of ML tools in this area is still in its early stage. In this study, we compared the performance of about a dozen ML methods, such as random forest classifiers, logistic regression classifiers, and support vector machines (SVM), trained on data of about 2300 treatment responses to average 12 different cancer drugs in 98 NSCLC, 55 gastric and 38 HCC PDX models with WES, CNV and RNA-seq information. Data preparation including genomic profile data selection, dimensionality feature reduction and processing was performed with considerations of known cancer gene functions, signal pathways, and pharmacodynamics information. Each dataset was randomly divided into training dataset and test dataset for ML algorithm training and evaluation. Performance of ML algorithms in testing was measured by their drug response prediction accuracy. Different regularization methods, such as LASSO and Elastic Net, were also evaluated in order to improve classification accuracy and identify relevant biomarker features. From comparing results from different algorithms or from the same algorithms but with differently prepared datasets, it seems that selection of functionally unknown gene aberrations for data preparation plays a significant role in prediction accuracy. Increasing dataset number or different data selection in different cancer types can improve prediction accuracy.
Citation Format: Henry Gu, Jingjing Jiang. Evaluation of machine learning tools for cancer drug response prediction with genomic profile data and drug response data from PDX model studies [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 671.