bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B
Authors: Li Xiang , Li Haitao , Li Shengqing , Zhu Feng , Kim Dong Joon , Xie Hua , Li Yan , Nadas Janos , Oi Naomi , Zykova Tatyana , Yu Dong Hoon , Lee Mee-Hyun , Kim Myoung Ok , Wang Lei , Ma Wei Ya , Lubet Ronald A. , Bode Ann M. , Dong Ziming , Dong Zigang 
Published: July 2017

Abstract
Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, has antimicrobial activity against both gram-positive and gram-negative organisms. Generally, ceftriaxone is used for a variety of infections such as community-acquired pneumonia, meningitis and gonorrhea. Its primary molecular targets are the penicillin-binding proteins. However, other activities of ceftriaxone remain unknown. Herein, we report for the first time that ceftriaxone has antitumor activity in vitro and in vivo. Kinase profiling results predicted that Aurora B might be a potential ‘off’ target of ceftriaxone. Pull-down assay data confirmed that ceftriaxone could bind with Aurora B in vitro and in A549 cells. Furthermore, ceftriaxone (500 µM) suppressed anchorage-independent cell growth by targeting Aurora B in A549, H520 and H1650 lung cancer cells. Importantly, in vivo xenograft animal model results showed that ceftriaxone effectively suppressed A549 and H520 lung tumor growth by inhibiting Aurora B. These data suggest the anticancer efficacy of ceftriaxone for the treatment of lung cancers through its inhibition of Aurora B.
Citation Format: Xiang Li, Haitao Li, Shengqing Li, Feng Zhu, Dong Joon Kim, Hua Xie, Yan Li, Janos Nadas, Naomi Oi, Tatyana Zykova, Dong Hoon Yu, Mee-Hyun Lee, Myoung Ok Kim, Lei Wang, Wei Ya Ma, Ronald A. Lubet, Ann M. Bode, Ziming Dong, Zigang Dong. Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 7. doi:10.1158/1538-7445.AM2017-7
Abstract 700: Characterization of the mode of action of Fenretinide treatment in alveolar rhabdomyosarcoma cells
Authors: Brack Eva , Wachtel Marco , Schaefer Beat W. 
Published: July 2017

Abstract
Alveolar rhabdomyosarcoma (aRMS) is a highly malicious childhood malignancy characterized by a specific chromosomal translocation encoding the oncogenic transcription factor PAX3-FOXO1. As aRMS cells are addicted to the tumor-specific fusion protein, it may serve as an ideal therapeutic target. Previously, we have identified from a large drug library screen the compound Fenretinide (retinoic acid p-hydroxyanilide), which is already in clinical use, to affect both PAX3-FOXO1 expression as well as aRMS cell viability. The aim of this study was therefore to characterize the mode of action of Fenretinide in more detail. First, we were able to show that Fenretinide induced the generation of reactive oxygen species (ROS) in mitochondria. A more detailed characterization revealed that the Fenretinide-induced ROS derived from an interaction of Fenretinide around complex II of the mitochondrial respiratory chain, leading to the production of superoxides. ROS scavenging as well as complexing of iron ions completely abolished cell death.
To identify the mode of cell death involved, we then used a range of pharmacological inhibitors of specific cell death pathways including Z-vad (pan -caspase inhibitor), Necrostatin-1 (necroptosis pathway inhibitor (RIP-1 kinase inhibitor)), 3-Methyadenine (3-MA) (autophagy pathway inhibitor (phosphatidylinositol 3-kinase inhibitor)) and Ferrostatin (ferroptosis pathway inhibitor) during Fenretinide treatment. Surprisingly, none of these inhibitors alone was able to prevent cell death and even different combinations were not sufficient to completely inhibit cell death. CRISPR/Cas9 mediated depletion of key players in the apoptotic and necroptotic pathway (Bak, Bax and RIPK1) confirmed the pharmacological data. We therefore conclude that other, less characterized cell death pathways or a combination of several pathways including apoptosis and necroptosis might be crucial. Interestingly, electron microscopic examination of cells pointed towards an excessive accumulation of vacuoles to be characteristic.
Taken together, our data show that Fenretinide shows high potential for the treatment of aRMS, inducing several forms of cell death mediated through the production of ROS. These properties open the search for additional compounds acting in a combinatorial manner.
Citation Format: Eva Brack, Marco Wachtel, Beat W. Schaefer. Characterization of the mode of action of Fenretinide treatment in alveolar rhabdomyosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 700. doi:10.1158/1538-7445.AM2017-700
Abstract 706: Combination ionizing radiation and oncolytic Seneca Valley virus injection enhances tumor cell killing of pediatric gliomas
Authors: Du Yuchen 
Published: July 2017

Abstract
Background and Purpose: Radiation therapy is the traditional and only therapy that offers benefits to patients with diffuse intrinsic pontine gliomas (DIPG) which are highly aggressive pediatric central nervous system tumors without known curative therapies. However, unfortunately, efficacy of radiation therapy is transient. Seneca Valley virus-001(SVV-001) is a novel non-pathogenic oncolytic piconavirus that can be systemically administered and pass through brain blood barrier (BBB). Phase I clinical trial of SVV has proven its efficacy in adults patients with cancers with neuroendocrine features and in pediatric patients with non-central nerve system (CNS) tumors. We sought to examine if combining ionizing radiation with an oncolytic virus SVV-001 would lead to synergistically enhanced tumor cell killing and significantly improve therapeutic efficacy in vivo in DIPG patient tumor-derived intra-brain stem orthotopic xenograft mouse models (PDOX).
Methods: By infecting PDOX derived tumor cells with green fluorescent protein (GFP)-coupled SVV (SVV-GFP) or SVV-001, in vitro virus infection and anti-tumor activity of SVV were examined by cell viability assay, Western Blotting for apoptosis and autophagy-related protein and immunohistochemistry (IHC) staining or Flow cytometry for cell mitochondria content. In vivo therapeutic efficacy was evaluated by systemic administration of SVV into PDOX derived DIPG xenografts alone or in combination with irradiation.
Results: We first had established a novel panel of nine PDOX derived orthotopic xenograft mouse models of DIPG. Our data confirmed that SVV can infect and efficiently kill DIPG tumor cells in vitro by inducing apoptosis and autophagy, leading to improved animal survival in a subset of DIPG xenograft models. We found that the lack of mitochondria in the xenograft tumor cells in vivo impaired the intracellular replication of SVV-001 and subsequently compromised its oncolytic cell killing of tumor cells in vivo. Radiation induced elevated mitochondria biogenesis in tumor cells therefore boosted SVV oncolysis of tumor cells. Moreover, combining fractionated radiation with single i.v.injection of SVV led to significant improvement of animal survival in a subset of DIPG models.
Conclusion: SVV-001 killed DIPG xenograft cells in vitro. Radiation activated mitochondria content of tumor cells in vivo, which restored impaired SVV oncolytic function.Combining radiation with single systemic administration of SVV synergistically enhanced animal survival in a subset of DIPG xenograft models.
Citation Format: Yuchen Du. Combination ionizing radiation and oncolytic Seneca Valley virus injection enhances tumor cell killing of pediatric gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 706. doi:10.1158/1538-7445.AM2017-706
Abstract 71: Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker
Authors: Qiu Qifeng , Wu Rui , Lanieri Leanne , Maloney Erin , Skaletskaya Anna , Jin Shan , Wang Lintao , Ab Olga , Ponte Joe , Setiady Yulius , Widdison Wayne , Keating Thomas , Chari Ravi , Gregory Richard , Hong Erica 
Published: July 2017

Abstract
Folate receptor α (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. The differential expression on cancer cells makes FRα an attractive target for antibody-drug conjugates (ADCs), and an ADC targeting FRα, Mirvetuximab soravtansine, has demonstrated promising activity and safety profiles in the clinic. Here, we employed a new linker (NL) to enhance the bystander activity of ADCs, which is the ability of ADCs to generate cell-permeable catabolites that can diffuse into and kill proximal cancer cells with little or no target expression. With the goal of improving the potency of anti-FRα ADC in solid tumors with heterogeneous FRα expression, we constructed the M9346A-NL-DM. M9346A-NL-DM is a conjugate of the tubulin-disrupting maytansinoid (DM), linked via a novel linker to M9346A, a humanized antibody that binds FRα with high affinity. After cellular uptake and catabolism of the ADC, the new linker undergoes lysosomal cleavage followed by self-immolation to generate free DM that can readily penetrate neighboring cancer cells. Correspondingly, M9346A-NL-DM showed enhanced bystander cytotoxic activity against proximal antigen-negative cells in vitro. In the xenograft tumor models in vivo, M9346A-NL-DM demonstrated enhanced efficacy against tumors with heterogeneous expression of FRα. Interestingly, M9346A-NL-DM also showed improved antitumor activity against a tumor model with homogeneous expression of FRα, possibly due to better tumor penetration of the cell-permeable catabolite. In summary, M9346A-NL-DM is a novel ADC with enhanced bystander activity and antitumor activity that can target tumors with heterogeneous expression of FRα.
Citation Format: Qifeng Qiu, Rui Wu, Leanne Lanieri, Erin Maloney, Anna Skaletskaya, Shan Jin, Lintao Wang, Olga Ab, Joe Ponte, Yulius Setiady, Wayne Widdison, Thomas Keating, Ravi Chari, Richard Gregory, Erica Hong. Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 71. doi:10.1158/1538-7445.AM2017-71
Abstract 720: Systematic discovery and evaluation of tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis
Authors: Shi Jianxiang , Zhang Lu , Wang Peng , Ye Hua , Dai Liping , Li Pei , Luo Chenglin , Song Chuhua , Wang Kaijuan , Wang Xiao , Ouyang Jun , Ji Zhenyu , Zhang Jianying 
Published: July 2017

Abstract
Proteins aberrantly over-expressed in tissues from nineteen types of cancers have been identified from the Human Protein Atlas (HPA) database. Among these proteins, some were overexpressed in several types of cancers while certain proteins were found only overexpressed in certain type of cancers. It is demonstrated that aberrantly overexpressed proteins might shed into the blood and trigger the immune system to produce autoantibodies during the process of oncogenesis. Autoantibodies are more stable and often have higher titer compared to autoantigens. Therefore, we hypothesize that autoantibodies against these aberrantly overexpressed proteins may have the potential to serve as diagnostic biomarkers in certain type of cancers. In current study, we have selected 11 proteins, including EDNRB, KRT4, PLAT, MSLN, WFDC2, F5, FOXA1, AURKC, STC1, CAB39L, and SFTPA1, to further evaluate the diagnostic values of their corresponding serum autoantibodies in five types of cancers, including hepatocellular carcinoma, lung cancer, gastric cancer, breast cancer and ovarian cancer. Sera from 470 patients (94 per cancer type), 94 hepatitis patients and 192 age- and gender-matched normal controls were used in current study. Serum autoantibodies were detected by ELISA. Receiver operating curve (ROC) analysis was used to evaluate the diagnostic value of serum autoantibodies against these potential TAAs. The data indicates that several anti-TAA autoantibodies can be found to have diagnostic value for certain types of cancers. Autoantibodies against PLAT can distinguish breast and ovarian cancer while autoantibodies against SFTPA1 and CAB39L can distinguish cancers both in male and female. However, none of these serum anti-TAAs was found to be specific to a single type of cancer. In summary, HPA database has made systematic discovery of cancer biomarkers possible. Whether these in silicon biomarkers can be used to distinguish normal and cancer still needs to be evaluated in more serum samples from normal controls and cancer patients.
Note: This abstract was not presented at the meeting.
Citation Format: Jianxiang Shi, Lu Zhang, Peng Wang, Hua Ye, Liping Dai, Pei Li, Chenglin Luo, Chuhua Song, Kaijuan Wang, Xiao Wang, Jun Ouyang, Zhenyu Ji, Jianying Zhang. Systematic discovery and evaluation of tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 720. doi:10.1158/1538-7445.AM2017-720
Abstract 725: Feasibility and evaluation of exosomal RNAs as novel diagnostic biomarkers for high grade serous epithelial ovarian cancer
Authors: Prendergast Emily N. , Lin Xianzhi , Corona Rosario I. , Hazelett Dennis J. , Karlan Beth Y. , Lawrenson Kate 
Published: July 2017

Abstract
Introduction: High-grade serous ovarian cancer (HGSOC) survival has been essentially unchanged over the last ten years despite new therapeutic strategies. In order to make a large-scale impact on overall survival, early detection strategies are imperative. Exosomes are cell-derived vesicles derived from multivesicular bodies or the plasma membrane that carry a variety of biomolecules, including protein, DNA, and RNA. Exosomal contents represent a novel and underexplored source of tumor biomarkers, in particular for HGSOC. This study aimed to first evaluate approaches to exosomal RNA purification and to then compare the exosomal RNA profiles from serum of patients with benign ovarian disease and HGSOC to determine if unique profiles exist, and to identify biomarkers useful for early detection.
Methods: Cell free serum was obtained from patients in each of the following categories: HGSOC with early (n=24) or late stage (n=24) disease, benign ovarian masses (n=24) and healthy age-matched controls (n=24). We compared ultracentrifugation and a commercial precipitation solution to enrich and isolate exosomes. Exosomal enrichment was confirmed by both transmission electron microscopy (TEM) and western blot using anti-CD63 antibodies. RNA was extracted for each and deep sequencing analysis was performed for 12 candidates within each group. A second cohort of 48 samples will be used for validation of the best performing candidate biomarkers from the discovery cohort via RT-qPCR.
Results: Enrichment of exosomes was confirmed via qualitative assessment using TEM and Western blot analysis. RNA quality was superior when RNA isolations were performed using the QIAgen RNeasy kit compared to the AllPrep kit. Mean RNA yield for each group ranged from 10.3-28.6ng/µl and RNA yield and quality was independent of sample age. RNAseq analyses are ongoing to identify biomarkers specific to HGSOC that can be detected at the earliest stages. The top differentially RNAs for the ovarian cancer groups will be validated in an independent cohort of specimens. A panel will then be generated in combination with CA125 to determine the clinical utility of an integrated -omics approach in early stage detection of HGSOC.
Conclusions: Efficient isolation of exosomes and RNA can be achieved from archived specimens &gt;10 years old. Evaluation of exosomal RNA in HGSOC provides a novel method for biomarker discovery.
Citation Format: Emily N. Prendergast, Xianzhi Lin, Rosario I. Corona, Dennis J. Hazelett, Beth Y. Karlan, Kate Lawrenson. Feasibility and evaluation of exosomal RNAs as novel diagnostic biomarkers for high grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 725. doi:10.1158/1538-7445.AM2017-725
Abstract 733: Detection of HCC-derived major HBV integration junctions in urine and their implications for driver identification
Authors: Lin Selena Y. , Steffen Jamin D. , Su Yih-Ping , Jain Surbhi , Chang Ting-Tsung , Song Wei , Su Ying-Hsiu 
Published: July 2017

Abstract
Chronic Hepatitis B Virus (HBV) infection is a major etiology of hepatocellular carcinoma (HCC), a leading cause of cancer mortality worldwide. Integration of HBV DNA into the host genome occurs during the course of chronic infection. Integrated HBV DNA is observed in most of HBV-associated HCC. The integration junctions derived from the original tumor cell become abundant (referred to as major integration junctions) in the infected liver because of clonal expansion during tumor development. Detection of circulating DNA containing these tumor-derived integration junctions may therefore be useful for cancer detection. We have adapted a method known as Primer Extension Capture (PEC) to enrich integrated HBV DNA for next-generation sequencing (NGS). Our initial studies using this approach to enrich the HBV DR1-2 region (a common site for HBV integrated breakpoints) identified major integration junctions from HBV-HCC tissue samples and matched urine. Further analysis revealed that most recurrently targeted integrations from these HCC tumors have previously reported involvement in cancer. This suggested that identification of recurrently targeted genes is applicable for driver identification. Interestingly, we show how HBV targets the TERT promoter in a localized region even though no two TERT junctions examined are identical. We have further developed this PEC to enrich for the entire HBV genome and applied it to (i) liver tissue DNA from 20 matched HCC and adjacent non-HCC samples, and (ii) DNA from urine of 20 hepatitis, 20 cirrhosis and 20 HCC patients. The HBV enriched libraries were sequenced by NGS and the integration events were analyzed using the in-house developed software. The complexity of HBV junction sites in HCC and non-HCC tissue and urine derived circulating DNA is reported. Our approach has potential to be used for liquid biopsies to study the complexities of HBV integrations in chronic HBV infection and carcinogenesis, and to identify HCC-related DNA modifications for early detection and disease management.
Citation Format: Selena Y. Lin, Jamin D. Steffen, Yih-Ping Su, Surbhi Jain, Ting-Tsung Chang, Wei Song, Ying-Hsiu Su. Detection of HCC-derived major HBV integration junctions in urine and their implications for driver identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 733. doi:10.1158/1538-7445.AM2017-733
Abstract 745: Interleukin-13 conjugated quantum dots to identify glioma initiating cells and exosomes
Authors: Madhankumar Achuthamangalam B. , Mrowczynski Oliver , Zacharia Brad , Glantz Michael , Xu Lichong , Webb Becky , Siedlecki Christopher , Mintz Akiva , Connor James R. 
Published: July 2017

Abstract
High grade brain tumors like glioblastoma multiforme (GBM) and certain other brain metastatic cancers possess high tumor invasive and infiltrating properties making them harder to detect. Identification of cancer stem cells and exosomes secreted by them in the biofluids like cerebrospinal fluid (CSF) will be an ideal way of detecting the presence of residual cancer after therapy. In the current approach, a ligand conjugated quantum dot (QD) was utilized to specifically label the cancer stem cells and exosomes to identify the presence of IL13Rα2 a tumor invasive marker. Human glioma initiating cells were cultured in adherent form and were exposed to interleukin-13 conjugated quantum dots (IL13QD), which binds the glioma initiating cells expressing IL13Rα2 receptor. Similarly the exosomes isolated from cancer stem cell condition media and CSF was briefly incubated with IL13QD, before analyzing their complexing pattern. Exosomes that were isolated from glioma stem cells and patients CSF were demonstrated to express IL13Rα2 receptor. Fluorescent microscopy, transmission electron microscopy and flow cytometry were performed on the exosomes after complexing with IL13QD. IL13QD was demonstrated to specifically bind glioma stem cells both in the monolayer and spheroid culture. The binding affinity of the exosomes to the quantum dots were quantitatively and qualitatively confirmed by atomic force microscopy (AFM). The morphology and size of exosomes before and after complexing with exosomes were confirmed by electron microscopy and AFM. The density plot from the flow cytometry experiments with IL13QD-exosomes complex indicates a possibility to identify the tumor associated exosomes. Our experiment infers that tumor targeted quantum dots can selectively bind with glioma stem cells and extracellular vesicles (exosomes) that are secreted by cancer cells. This binding profile could be utilized to identify the expression of certain tumor promoting receptors and antigens on the surface of exosomes present in the CSF and cancer stem cells from the glioma patients. Experiments are in progress to identify the tumor initiating cells in an orthotopic mouse glioma tumor model after intravenous administration of wild type IL13 and certain high affinity mutated IL13 conjugated quantum dots, by non-invasive way.
Citation Format: Achuthamangalam B. Madhankumar, Oliver Mrowczynski, Brad Zacharia, Michael Glantz, Lichong Xu, Becky Webb, Christopher Siedlecki, Akiva Mintz, James R. Connor. Interleukin-13 conjugated quantum dots to identify glioma initiating cells and exosomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2017-745