bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5525: Rgs8 and Rgs16 protect against pancreatitis and PDA progression
Authors: Choudhuri Shreoshi Pal , Zolghadri Yalda , Mascarenhas Luke , Wilkie Thomas 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDA) has the highest death rate among major cancers, and new treatments are desperately needed. The mice we developed in this study, KCR8-16, are an excellent mouse model for identification, characterization, and in vivo validation of novel PDA therapeutics. Kras oncogenic mutations (e.g., KrasG12D) are found in over 90% of human PDA. Kras can be activated by protein kinase and G-protein coupled receptor (GPCR) signaling. Regulator of G-protein signaling (Rgs) proteins regulate GPCR signaling by accelerating the GTPase activity of Gq- and Gi class alpha subunits. Activating alleles of Gq that are resistant to Rgs inhibition are found in benign precursors of PDA in humans. We previously reported that Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression in KIC;Rgs16::GFP mice (p48::Cre/+; KrasG12D/+; Cdkn2af/f; Rgs16GFP ) (DMM 8, 2015). To identify the role of Rgs 8 and 16 in PDA, we crossed the Rgs8-16 double knockout into pancreas-specific KrasG12D (KC) mutant mice (termed KCR8-16). We found that deletion of Rgs8 and Rgs16 in KC accelerated PDA progression. Additional pancreatic stress evoked by caerulein treatment caused immediate and pancreas-wide progression to PDA in KCR8-16 mice. Our study suggests that Rgs8 and Rgs16 act as tumor-suppressor genes in PDA initiation and progression. Moreover, KCR8-16 and KIC;Rgs16::GFP mice can be used as an excellent model for identification and rapid in vivo validation of PDA therapeutics.
Citation Format: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Thomas Wilkie. Rgs8 and Rgs16 protect against pancreatitis and PDA progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5525.
Abstract 5545: Heterodimeric interleukin 15 (hetIL-15) treatment decreases primary breast cancer 4T1 tumors and alleviates the metastatic burden
Authors: Stellas Dimitris , Dimas Konstantinos , Nagy Bethany A. , Valentin Antonio , Felber Barbara K. , Pavlakis George N. 
Published: August 2018

Abstract
Introduction: In this preclinical study, we tried to model the therapeutic strategies often used in the clinic to treat breast cancer patients. We analyzed the role of hetIL 15 immunotherapy alone and in combination with chemotherapy and surgery using the 4T1, a triple-negative breast cancer cell line, murine breast cancer model.
Experimental Procedures: We evaluated the therapeutic potential of combining surgery, chemotherapy (doxorubicin) and immunotherapy (hetIL-15) in the murine 4T1 breast cancer model. Cancer cells were orthotopically implanted into the mammary fat pad of Balb/c mice, and the efficacy of hetIL-15 in combination with doxorubicin on the growth of primary tumors and metastatic disease was assessed. In addition, we monitored the impact of surgery alone in the development of metastatic disease, and, finally, we evaluated the effects on the metastatic burden of the three different approaches combined.
Results: hetIL-15 monotherapy and combination of doxorubicin chemotherapy with hetIL-15 immunotherapy inhibited the growth of primary tumors. Interrogating the role of these treatments on lung metastatic disease, the results were unexpected. Doxorubicin alone did not affect the numbers of the metastatic lesions in the lungs. In contrast, hetIL-15 monotherapy reduced the metastatic burden. The combination strategy did not show advantage as compared to hetIL-15 monotherapy. Surgical removal of the growing tumor also decreased metastatic burden, especially when performed at an early point. Chemotherapy with doxorubicin prior to and post-surgery had no impact on the metastatic disease. In contrast, hetIL-15 treatment strongly diminished or eliminated the metastatic burden.
Conclusion: Our data strongly suggest that treatment with hetIL-15 as an adjuvant therapy after surgery, or as a neoadjuvant agent before surgery, significantly impacts metastatic disease.
Citation Format: Dimitris Stellas, Konstantinos Dimas, Bethany A. Nagy, Antonio Valentin, Barbara K. Felber, George N. Pavlakis. Heterodimeric interleukin 15 (hetIL-15) treatment decreases primary breast cancer 4T1 tumors and alleviates the metastatic burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5545.
Abstract 5547: Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma
Authors: Chae Young Kwang , Cho Anderson , Rhee Kyunghoon , Davis Andrew , Iams Wade , Bhave Manali , Cruz Marcelo , Park Lee Chun 
Published: August 2018

Abstract
Thymic carcinoma is a rare neoplasm with poor prognosis that forms on the outside surface of the thymus. Due to the rarity of the disease, there are no randomized clinical trials that guide therapy. Currently, there are clinical trials under way to assess the efficacy of anti-programmed death 1 (PD-1) monoclonal antibodies for the treatment of advanced thymic carcinomas. However, the role of PD-1 inhibitors in treating thymic carcinoma remains mostly unknown. Here we present a case of a patient with thymic carcinoma who showed durable remission when treated with nivolumab. 61-year-old male was diagnosed with thymic carcinoma during an episode of COPD exacerbation in April 2015. The patient was treated with neoadjuvant chemotherapy regimen consisting of four cycles of carboplatin and paclitaxel every three weeks from June to September 2015. The mass was resected in October 2015. Margins were found to be grossly positive. The patient was deemed a poor candidate for adjuvant chemotherapy, and in February 2016 the decision was made to begin 3 mg/kg nivolumab therapy considering the poor prognosis of disease and high risk of recurrence. Close to two years after initiating therapy, he currently has no measurable disease and tolerates the medication without side effects. This is the first report demonstrating durable remission of thymic carcinoma with nivolumab treatment. Our case suggests that prospective trials evaluating the use of nivolumab in patients with thymic carcinoma are warranted.
Citation Format: Young Kwang Chae, Anderson Cho, Kyunghoon Rhee, Andrew Davis, Wade Iams, Manali Bhave, Marcelo Cruz, Lee Chun Park. Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5547.
Abstract 5548: The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies
Authors: Han Tae H. , Guenot Jeanmarie , Denney William S. , Feldman Eric J. 
Published: August 2018

Abstract
AMV564 is a novel bispecific bivalent (2x2) immunotherapy that initiates an immunological synapse between T cells and CD33-expressing cells by binding both CD33 and CD3 with strong avidity. CD33 (Siglec-3) is a clinically-validated antigen target that is broadly expressed on the surface of malignant cells in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and other hematologic malignancies, as well as on cells that potently suppress immune function, such as myeloid-derived suppressor cells (MDSC). AMV564 has been shown to eliminate MDSCs and restore hematopoiesis, induce potent cytolysis of leukemic cells in patient blood and bone marrow samples, and produce robust antitumor activity in a disseminated model of AML. In vitro studies, including cytotoxicity assays with AML patient samples, human T-cell activation assays, and cytokine-release assays, as well as animal safety studies were performed to characterize the pharmacokinetics, pharmacodynamics, and potential toxicities of AMV564. AMV564 demonstrated potent in vitro antitumor activity with EC50 values of approximately 0.7 - 3 pM. In vitro studies also demonstrated that leukemic cells are more sensitive to T-cell engagement using AMV564 than peripheral blood mononuclear cells by approximately 10-fold. In animal safety studies, AMV564 was tolerated at exposures that exceed those expected to have clinical antitumor activity by &gt; 10-fold. Toxicological findings noted in these studies were anticipated based on the pharmacological activity of AMV564; observed findings included events related to CD3-mediated T-cell activation, cytokine release, and decreases in neutrophil and monocyte counts with rapid recovery. Results from a pharmacokinetic/pharmacodynamic model integrating the preclinical data suggest the potential for a wide therapeutic index for patients with AML. Based on the in vitro and in vivo preclinical data, AMV564 is expected to have a wide therapeutic index, with robust antitumor activity in AML and MDS at doses well below those predicted to be associated with dose-limiting toxicities, and a predictable and monitorable adverse event profile.
Citation Format: Tae H. Han, Jeanmarie Guenot, William S. Denney, Eric J. Feldman. The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5548.
Abstract 5572: Circulating tumor cells: The tumor trail left in the blood
Authors: Kulasinghe Arutha , Perry Chris , Kenny Liz , Blick Tony , Warkiani Majid , Vela Ian , O'Byrne Ken , Thiery Jean-Paul , Thompson Erik , Nelson Colleen , Punyadeera Chamindie 
Published: August 2018

Abstract
Background: Metastasis in HNC patients is reflected by measurable levels of circulating tumor cells (CTCs) in the peripheral blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. For patients without CTCs at presentation, the detection of CTCs in the blood and analysis of biomarkers within them provide an opportunity to identify patients "at risk" of developing overt metastasis, accelerating targeted treatment in addition to routing care with the clear aim of improving cure.
Methods: Our study aimed to assess whether CTCs from the blood of HNC patients attending the Princess Alexandra Hospital and Royal Brisbane and Women's Hospital provided early cues of distant metastases (n=250).
Results: With significant advances in CTC isolation technologies, we could demonstrate a higher CTC capture efficiency using epitope-independent platforms. By assessment of single and clustered CTCs, our data showed that HNC patients can be identified 4-6 months prior to developing clinical/radiographically evident metastasis. In these patients, a window for treatment escalation could become a possibility. In a proof-of-principle study, using novel culture formulations and hypoxic conditions (1-2% O2), we were able to demonstrate, for the first time, short-term patient-derived CTC cultures ex vivo from 7/18 HNC samples (4/7 HPV-positive, oropharyngeal) in a clinically relevant time period. Recent advancements have shown that PD-1 immune checkpoint therapies have durable responses in metastatic HNC patients that fail 1st- and 2nd-line therapy. Our preliminary data suggest PD-L1 is frequently expressed on HNC CTCs, and an immunoscore may be able to stratify patients likely to respond to immunotherapy.
Conclusion: Expanding CTCs outside the patient's body allows for the recapitulation of the molecular diversity present within the tumor, understanding the disease progression and testing of therapies. Patients with a high percentage of PD-L1+ CTCs could be potential candidates for anti-PD-L1 therapy, a promising new immunotherapy.
Citation Format: Arutha Kulasinghe, Chris Perry, Liz Kenny, Tony Blick, Majid Warkiani, Ian Vela, Ken O'Byrne, Jean-Paul Thiery, Erik Thompson, Colleen Nelson, Chamindie Punyadeera. Circulating tumor cells: The tumor trail left in the blood [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5572.
Abstract 5579: Increased number of EMT-like CTCs relative to epithelial CTCs reveals signatures of poor outcomes in pancreatic cancer
Authors: Zeinali Mina , Murlidhar Vasudha , Fouladdel Shamileh , Hafner Mathias , Shao Shimeng , Zhao Lili , Cameron Heather , Bankhead Armand Iii , Shi Jiaqi , Cuneo Kyle C. , Sahai Vaibhav , Azizi Ebrahim , Wicha Max S. , Simeone Diane M. , Nagrath Sunitha 
Published: August 2018

Abstract
Objective: Although circulating tumor cells' (CTCs) isolation from pancreatic adenocarcinoma (PaCa) patients is feasible, investigation of their clinical utility has proven less successful than other cancer types, due to poor technology sensitivity and EpCAM-only based CTC assays.
Design: We present an integrated technology and biology-based approach using a microfluidic “Carpet chip” to study the biologic relevance of rare CTCs. We isolate both circulating epithelial CTCs (EpCs) and EMT-like CTCs (EMTCs) simultaneously from whole blood of PaCa patients (n=35), targeting two different surface markers: anti-EpCAM and anti-CD133. Gene expression profiling of CTCs was performed with 96 genes (n=17).
Results: Recovery of cancer cell lines spiked into whole blood is ≥97% with &gt;76% purity. Of the 35 PaCa patients analyzed, 34 had ≥5 EpCs/mL and 35 had ≥15 EMTCs/mL. Higher numbers of EMTCs were observed in patients with lymph node involvement (N1) compared to patients without. The ratio of EpCs to total number of CTCs marginally decreased with advanced stage, while the ratio of EMTCs increased. Gene expression profiling showed CXCR1 was significantly upregulated in EpCs whereas POU5F1/Oct-4 and MYC were upregulated in EMTCs, demonstrating inherent phenotypic differences. Early-stage patients with significantly better overall survival and/or progression-free survival showed significant higher expression of genes including ERCC1 and TTF1.
Conclusions: We demonstrated successful isolation of heterogeneous population of CTCs (EpCs and EMTCs). We recovered significantly higher number of EMTCs in PaCa patients compared to EpCs, reflecting aggressive nature of PaCa. Profiling of CTCs revealed genetic signatures relevant to predicting patients' outcomes.
Citation Format: Mina Zeinali, Vasudha Murlidhar, Shamileh Fouladdel, Mathias Hafner, Shimeng Shao, Lili Zhao, Heather Cameron, Armand Iii Bankhead, Jiaqi Shi, Kyle C. Cuneo, Vaibhav Sahai, Ebrahim Azizi, Max S. Wicha, Diane M. Simeone, Sunitha Nagrath. Increased number of EMT-like CTCs relative to epithelial CTCs reveals signatures of poor outcomes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5579.
Abstract 5585: Extracellular vesicle poly(A)+ RNA analysis for cancer biomarker screening
Authors: Murakami Taku , Yamamoto Cindy , Ogura Mieko , Oakes Melanie , Harada Hiroshi 
Published: August 2018

Abstract
Extracellular vesicles (EV) are a promising biomarker source and present in several biological fluids such as plasma (8.0 x 1011 particles/mL, 121 ± 2.3 nm in diameter) and urine (1.1 x 1011 particles/mL, 152 ± 11.2 nm in diameter). In order to streamline marker screening and validation in translational studies, we developed and optimized high throughput filter-based EV capture, poly(A)+ RNA isolation and gene expression assay protocols for RT-qPCR and RNA-seq. First, we confirmed that plasma and urinary EV mRNA profiles (12 to 15 genes by RT-qPCR) are stable up to 1 week at 4°C, and up to 5 repeats of freeze-thaw cycles, and urinary EV was stable up to 10 months at -80°C, indicating EV mRNA could be a useful biomarker source. Although EV mRNA is less abundant (550 pg mRNA from 1 mL plasma) compared to tissue mRNA or EV non-coding RNA, the optimized protocol allows quantification of about 9,000 genes in average by RNA-seq from 2 mL frozen plasma (N=3) with high reproducibility among the replicates (Spearman correlation: 0.9086 to 0.9326) and between the commercial EV kits (Spearman correlation: 0.9207 to 0.9683). About 77% of the 1000 most abundant genes in plasma EV are expressed ubiquitously throughout various organs but some are expressed specifically in blood (12%), spleen (4.4%), esophagus mucosa (1.2%), etc. according to the Genotype-Tissue Expression (GTEx) database. In urinary EV, other than ubiquitously expressed genes (88%), the genes specific to liver (1.5%), bladder (1%), brain (1%), etc. are present. These data suggest EV mRNA are released from various organs and circulating in biological fluids. The protocol was further applied to biomarker discovery for bladder cancer, and differential gene expression analysis of EV mRNA was conducted using bladder cancer (N=4), cancer remission (N=2), and healthy/disease control urine samples (N=4). Ingenuity pathway analysis indicated that cancer-related molecular and cellular functions are activated in bladder cancer urinary EV but not in remission, while immune-related functions are activated both in cancer and remission. These data indicate that EV mRNA is a promising biomarker source for cancer biomarker screening, and could be used in translational studies.
Citation Format: Taku Murakami, Cindy Yamamoto, Mieko Ogura, Melanie Oakes, Hiroshi Harada. Extracellular vesicle poly(A)+ RNA analysis for cancer biomarker screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5585.
Abstract 561: Circulating DNA clean up and enrichment from liquid biological samples for rare biomarker detection
Authors: Lewis Samantha R. , Cowles Charles , Oostdik Kathryn , Knox Curtis , Hook Brad A. 
Published: August 2018

Abstract
A major roadblock to using circulating cell free DNA (ccfDNA) for cancer biomarker detection is the difficulty of obtaining a pure sample. Contaminating genomic DNA (gDNA) can overwhelm already rare events within a CCF sample and prevent sensitive detection of these key mutations. Unfortunately, liquid biological samples often are not collected and processed in an ideal manner, resulting in decreased quality and purity. Many studies report difficulties in detecting mutations in ccfDNA which may originate from variable levels of gDNA background based how samples are processed. To this end, we present an effective method for purifying relevant small nucleic acids from larger genomic species after DNA purification from plasma.
Using a simple magnetic bead based technique, we demonstrate efficient removal of gDNA even in highly contaminated samples. This method can be used to enrich liquid biological samples for improved detection of rare genetic events such as microsatellite instability and mutations in key oncogenes. Using plasma from three individuals with colorectal cancer tumors harboring known mismatch repair gene mutations, we compare detection of somatic mutations in ccfDNA before and after this gDNA clean up method. Microsatellite instability profiles were obtained from ccfDNA and compared to normal and tumor profiles to determine if evidence of mismatch repair abnormalities could be detected. Targeted amplicon sequencing was then performed to detect tumor associated mutations. DNA isolated from matched adjacent normal and tumor tissues were used as controls in these experiments to confirm mutations were of tumor not germline mutations.
Effectively removing gDNA contamination from ccfDNA samples can improve biomarker detection consistency from liquid biological samples. We demonstrate a magnetic bead-based method for ccfDNA clean-up, which can be used prior to microsatellite instability detection by fragment analysis or rare variant detection by next generation sequencing.
Citation Format: Samantha R. Lewis, Charles Cowles, Kathryn Oostdik, Curtis Knox, Brad A. Hook. Circulating DNA clean up and enrichment from liquid biological samples for rare biomarker detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 561.
Abstract 5614: Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment
Authors: Singh Abhay , Kapoor Vaishali , Dadey David , Thotala Dinesh , Hallahan Dennis 
Published: August 2018

Abstract
Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities worldwide. NSCLC immunotherapy has not been successful in the past. Although lung cancer is not typically believed to be an immunogenic malignancy, more and more evidence suggests that immune responses to lung cancer may be important. The objective of this research was to address a critical barrier and develop a new paradigm in the treatment of NSCLC. Development of anticancer antibodies is limited by the scarcity of antigens that are specifically overexpressed in lung cancer, resulting in too few molecular targets and small percentages of patients who can be treated with the therapeutic antibody. We established a platform technology to develop antibodies to radiation-inducible neoantigens. Several radiation-inducible antigens have been identified by our group. Glucose-regulated protein 78 (GRP78), a multifunctional protein folding chaperone and co-receptor that is highly expressed on the surface of NSCLC, holds significant promise as a cancer-specific target. Although the potential of targeting GRP78 has been demonstrated in prostate cancer, melanoma, and breast cancer, there are limited data on the impact of targeting cell surface-associated GRP78 in NSCLC. We show that GRP78 undergoes radiation-induced translocation to the surface of NSCLC cells. We developed several GRP78-targeting monoclonal antibodies. NSCLC-specific antibody binding is achieved for several days by anti-GRP78 monoclonal antibodies after irradiation. Optical imaging and immunohistochemical staining indicated that the GRP78-specific antibodies achieve specific binding to irradiated NSCLC in mouse models. The anti-GRP78 antibodies also have a direct cytotoxic effect on NSCLC cells. The combination of anti-GRP78 antibodies and radiation showed an additive effect. Overall, this study suggests that GRP78 is a promising therapeutic target for the treatment of lung cancer. We propose to harness the physiologic response of cancer to radiotherapy and evolve it for immunotherapy of lung cancer using specific targeting antibodies.
Citation Format: Abhay Singh, Vaishali Kapoor, David Dadey, Dinesh Thotala, Dennis Hallahan. Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5614.