bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1345: Automated capture and analysis of circulating tumor cells across different types of tumors in pediatric cancer patients
Authors: Batth Izhar S. , Zaky Wafik , Khatua Soumen , Daw Najat C. , Mahadeo Kris M. , Khazal Sajad , Albert Aisha , Huang Wilber , Chen Diva , Gill Jonathan B. , Kleinerman Eugenie , Gorlick Richard , Li Shulin 
Published: August 2019

Abstract
The clinical utility of blood analysis such as circulating tumor cells (CTCs) has garnered increasing interest in recent years. However very few studies were conducted in pediatric cancer patients especially in brain tumor, osteosarcoma, and leukemia patients due to the lack of an effective tool to isolate/capture CTC from these patients. For example, only three independent studies were published to investigate CTC capture from adult brain tumor patients but zero studies were conducted with pediatric brain cancer patients. Our previous studies showed the high specificity of using cell surface vimentin (CSV) to identify and capture CTCs from various types of adult tumor patients using a manual isolation method. Here we present the first automated system for capturing CTCs across different types of pediatric tumors. This automated system utilizes the Abnova CytoQuest system loaded with the CSV antibody 84-1-coated microfluidic cassette for capturing CTCs from peripheral blood samples. This automated assay was very sensitive because as few as one tumor cell can be captured out from one million normal cells. Based on our preliminary study, our success rate for non-DIPG brain tumor, ALL, and AML patients is 100%. This success provides a potential opportunity for analyzing brain tumor genetic properties using blood samples instead of the invasive tumor biopsy; likewise, this high sensitivity assay opens up clinical opportunities to use this assay for transplant and treatment decision making.
Note: This abstract was not presented at the meeting.
Citation Format: Izhar S. Batth, Wafik Zaky, Soumen Khatua, Najat C. Daw, Kris M. Mahadeo, Sajad Khazal, Aisha Albert, Wilber Huang, Diva Chen, Jonathan B. Gill, Eugenie Kleinerman, Richard Gorlick, Shulin Li. Automated capture and analysis of circulating tumor cells across different types of tumors in pediatric cancer patients [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 1345.
Abstract 1349: Personalized circulating tumor DNA profiling in malignant pleural mesothelioma
Authors: Martinson Luke J. , Sharkey Annabel J. , Dawson Alan G. , Hastings Robert K. , Wilson Gareth , Waller David , Nakas Apostolos , Swanton Charles , Shaw Jacqui A. , Fennell Dean A. 
Published: August 2019

Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with exposure to asbestos and is rising in incidence worldwide. A lack of early detection methods and treatment successes have maintained a dismal prognosis of just 12 - 16 months. Circulating tumor DNA (ctDNA) is emerging as an important stratification biomarker in other thoracic malignancies, however research in this area has been lacking in MPM. Homozygous deletion of CDKN2A is one of the few established negatively prognostic molecular markers in MPM.
Methods and Results:
We conducted multiregional whole exome sequencing (m-WES) on tumor tissue (4 or 5 regions) and matched germline DNA from 11 patients with MPM that received surgery (extended pleurectomy decortication) as their primary treatment modality. Using a validated bioinformatics pipeline (developed as part of the TRACERx study), clonal single nucleotide variants (SNVs) and/or indels (present within all tumor regions) were selected from m-WES data for patient-specific assay design. Variants were prioritized for selection based on tumor driver status and higher mean variant allele frequencies (VAFs) amongst tumor regions. A minimum of 10 ng cfDNA isolated from pre-surgical blood was analyzed for ctDNA detection using Droplet Digital PCR (ddPCR), with positivity being defined as ≥ 3 mutant droplets and a plasma VAF ≥ 0.1%. Four out of eleven (36.4%) patients were ctDNA-positive using this patient-specific approach with VAFs ranging between 0.16% and 2.96%. Two additional patients had one or two positive mutant droplets, but these were excluded as potential false positives. In this pilot study, ctDNA-positive patients had significantly shorter survival than ctDNA-negative patients (P = 0.047), although this failed to reach significance by Cox regression analysis, likely due to a small sample size. Furthermore, in this cohort ctDNA status was a stronger prognostic biomarker than CDKN2A deletion status.
Conclusions:
Considering the short survival of patients with MPM despite surgery, we consider ctDNA-based analyses could be used to stratify patients regarding surgery, where risk-benefit would be marginal for those ctDNA-positive. This study provides proof-of-principle that the detection of tumor DNA from minimally invasive sources is possible in MPM and has alluded to how this could potentially impact clinical decision-making.
Citation Format: Luke J. Martinson, Annabel J. Sharkey, Alan G. Dawson, Robert K. Hastings, Gareth Wilson, David Waller, Apostolos Nakas, Charles Swanton, Jacqui A. Shaw, Dean A. Fennell. Personalized circulating tumor DNA profiling in malignant pleural mesothelioma [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 1349.
Abstract 1358: Tumor-derived extracellular vesicles as kidney cancer biomarkers
Authors: Zieren Richard C. , Dong Liang , Amend Sarah R. , Pierorazio Philip M. , Reijke Theo M. de , Pienta Kenneth J. 
Published: August 2019

Abstract
Renal cell carcinoma (RCC) is a fairly common and lethal cancer. The wide variety of RCC histological subtypes constitutes a challenge in treatment decision-making. Exosomes are extracellular membrane vesicles that are produced by all cell types in physiological conditions. Extracellular vesicles (EVs) are now accepted as a mode of intercellular communication and transport proteins, RNAs, DNA, and lipids to surrounding and distant cells. The lipid bilayer membrane of the EVs helps to protect these cargos. EVs are involved in many pathological processes, such as cancer, and can be easily obtained through liquid biopsy. Currently, EVs are rarely considered as candidate biomarkers for kidney cancer. However, improvements in the characterization of tumor-derived EVs could lead to the implementation of blood- and urine-derived EVs as biomarkers in the management of oncologic patients. Since all organs, not just the tumor, contribute to EV population, the thoughtful discrimination of tumor-derived EVs remains an unmet need for the clinical application of this kind of liquid biopsy technology. To determine the contribution of the tumor to blood- and urine-derived EVs, we utilize a novel approach to isolate tissue-derived EVs in parallel with liquid biopsy-derived EVs. To our knowledge, only a handful of studies (only one in RCC) have studied EVs directly derived from tissue. We propose the use tissue-derived EVs to screen for candidate EV biomarkers in plasma and/or urine. We hypothesize that using tissue-derived EVs would increase the tumor specificity for the characterization of EVs as liquid biopsy biomarkers. We optimized a protocol in which we used tissue of RCC patients (normal kidney or tumor) to condition media and isolate tumor-derived EVs alone by ultracentrifugation. Additionally, we isolated plasma- and urine EVs by ultracentrifugation using standard protocols. Nanoparticle Tracking Analysis (NTA) showed normalized concentrations of &gt;2 x 109 particles/mL with a size distribution in the small EV-range. Transmission Electron Microscopy (TEM) images showed typical exosome morphology, with the characteristic cup-shaped membrane vesicles. Western Blot (WB) confirmed the presence of exosome markers. We successfully isolated EVs from human RCC and healthy kidney tissue. We will proceed with screening the EV-samples for candidate miRNA-biomarkers by multiplexed gene expression analysis, followed by confirmation of the candidate markers by RT-qPCR.
Citation Format: Richard C. Zieren, Liang Dong, Sarah R. Amend, Philip M. Pierorazio, Theo M. de Reijke, Kenneth J. Pienta. Tumor-derived extracellular vesicles as kidney cancer biomarkers [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 1358.
Abstract 1363: Identifying blood exosomal miRNAs as biomarkers in the diagnosis and prognosis of pancreatic ductal adenocarcinoma
Authors: Guo Shiwei , Wang Huan , Qin Hao , Zhang Dadong , Shao Zhuo , Zhang Yanan , Song Bin , Xu Xiaoya , Shen Jing , Chen Zishuo , Shi Xiaohan , Gao Suizhi , Pan Yaqi , Li Fugen , Jin Gang 
Published: August 2019

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is of high mortality with a shortage of effective non-invasive biomarkers in the diagnosis and prognosis. Without a proper method to identify reasonable target molecules and their references for normalization, robust and accurate blood miRNA biomarkers have not been reported. We aim to explore the exosomal miRNAs as biomarkers for the diagnosis and prognosis of PDAC with sufficient biological insights and robustness.
Materials and Methods: miRNA-seq was performed on miRNAs extracted from blood exosomes. 16 non-metastatic PDAC, 11 metastatic PDAC and 15 pancreatitis patients were enrolled in 2017 as the training set. Another 18 non-metastatic PDAC, 12 metastatic PDAC and 18 pancreatitis patients were enrolled in 2018 as the testing set. Bayesian network was built on the levels of miRNAs to identify candidate biomarkers with biological insights. The area under the curve (AUC) of receiver operating characteristic (ROC) was used to measure the accuracy of each pair of miRNAs.
Results: The exosomal miRNA from the plasma of these patients with PDAC or pancreatitis has been successfully extracted and sequenced. The Bayesian network consisted of 337 nodes and 713 edges. The quotient of miR-95-3p (a “consequence” of “cancer”) over miR-26-5p (a “cause” of “pancreatitis”) performed 81.5% sensitivity and 93.3% specificity in the training cohort, and 86.7% sensitivity and 100% specificity in the testing cohort respectively. Furthermore, considering either high serum level of CA19-9 or the quotient of miR-95-3p/miR-26-5p as PDAC, the sensitivity increased to 96.5%, and the specificity was maintained at 96.9%. In addition, miR-335-5p level in blood exosome could predict metastasis with a mean accuracy of 77.2%, and showed strong relation with overall survival after surgeries.
Conclusions: MiRNAs biomarkers from blood exosomes in differential diagnostics and prognosis are identified and rationale by Bayesian network. Integration of biomarkers of various molecular types could enhance the diagnostic accuracy beyond single molecular types. Blood exosomal miRNAs could be applied to monitor the development of PDAC.
Citation Format: Shiwei Guo, Huan Wang, Hao Qin, Dadong Zhang, Zhuo Shao, Yanan Zhang, Bin Song, Xiaoya Xu, Jing Shen, Zishuo Chen, Xiaohan Shi, Suizhi Gao, Yaqi Pan, Fugen Li, Gang Jin. Identifying blood exosomal miRNAs as biomarkers in the diagnosis and prognosis of pancreatic ductal adenocarcinoma [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 1363.
Abstract 1407: Histone marks interplay at LIFR enhancer determines the response to HDAC inhibitors in breast cancer
Authors: Wang Xiaomin , Xu Jun , Ding Jian , Geng Meiyu , Huang Min 
Published: August 2019

Abstract
The dynamic crosstalk of epigenetic modifications is believed to impose a strong impact on epigenetically-targeted therapies, such as histone deacetylase (HDAC) inhibitors, but current understanding in this regard is extremely limited.Our previous work has revealed that the transcriptional feedback activation of leukemia inhibitory factor receptor (LIFR) limits the response to HDAC inhibitors in breast cancer. However, LIFR transcriptional response appears highly heterogeneous in breast cancer and the reason behind is unclear. This study takes LIFR as a representative to dissect how histone marks interplay determines the transcriptional outcome of epigenetically-targeted therapies. We herein discover that the H3K27 methylation specifically at LIFR enhancer restricts the H3K27 acetylation upon HDAC inhibition and prevents the upregulation of LIFR. The intrinsic level of H3K27 methylation at LIFR enhancer stratifies the responsive subset to HDAC-targeted therapies in a panel of patient-derived breast cancer models. This study provides strong evidence showing how existing histone marks and their specific localization together determine the transcriptional output and the outcome of epigenetically-targeted therapies, highlighting the significance of histone marks crosstalk in epigenetic therapeutics.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaomin Wang, Jun Xu, Jian Ding, Meiyu Geng, Min Huang. Histone marks interplay at LIFR enhancer determines the response to HDAC inhibitors in 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 1407.
Abstract 1419: Metastasis and cancer stem cell markers identify two colorectal cancer subtypes with different molecular and clinical features
Authors: Alsaihati Burair , Zhao Shaying 
Published: August 2019

Abstract
Introduction Colorectal cancer (CRC) falls among the top prevalent cancer types with lethal outcome both in the United States and worldwide. The heterogeneity of CRC highlights the importance of identifying molecular markers for meaningful classification and prognosis. The recently published Consensus Molecular Subtypes (CMS) represent a widely-used molecular subtyping of CRC. However, our analyses indicate that clear heterogeneity still exists in some CMSs. To better classify CRC, we performed the following study.
Methods We collected from literature 19 gene markers classified as metastasis or cancer stem cell (CSC) markers in CRC. We then examined their expression in 622 CRC samples by The Cancer Genome Atlas (TCGA), and validated the findings using another published dataset, GSE39582, with 566 CRC samples.
Results We found among the 19 gene markers examined, 9 genes cluster into two oppositely co-expressed groups (VEGFC, SMAD4, TNIK, ITGB1, CD44 and ALCAM in group 1 and VEGFB, OTUB1 and DLL4 in group 2). Principal component analysis and hierarchical sample clustering of theses 9 genes identify two subtypes among the samples of each CMS, particularly CMS2 and CMS4. We named the two subtypes S1, which corresponds to increased expression in group 1 genes, and S2, which corresponds to higher expression of group 2 genes. Analysis of cancer hallmarks indicates a strong enrichment of six pathways (androgen response, protein secretion, mitotic spindle, UV response down, PI3K and TGF-β signaling), a common and defining feature of the S1 subtype in all CMSs. Immune activation pathways and most immune cells are strongly enriched in the S1 subtype of CMS4 samples only. Conversely, S2 is the subtype that exhibits immune activation across CMS2 samples. Tumor microenvironment signatures indicate more lymph vessels and stromal invasion in S1 samples within CMS4. However, within CMS2, a higher leukocyte fraction and invasive signature feature the S2 subtype. The epithelial and proliferative signatures are associated with the S1 subtype in general, but more prominently within CMS2. Consistent with the invasive signature of S2 samples in CMS2, the analysis of TCGA clinical data indicates increased lymphatic invasion, metastasized tumors and worse overall survival for them. On the other hand, GSE39582 clinical data show that worse overall survival is associated with the S1 subtype in CMS4.
Conclusion Each of CMS2 and CMS4 can be further divided into two subtypes, S1 and S2. While S2 may define more aggressive CMS2 cancers, S1 can be linked to worse prognosis in CMS4 patients.
Citation Format: Burair Alsaihati, Shaying Zhao. Metastasis and cancer stem cell markers identify two colorectal cancer subtypes with different molecular and clinical features [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 1419.
Abstract 1424: Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies
Authors: Helsen Christopher W. , Hayes Danielle , Hammill Joanne , Aarts Criag , Bader Andreas , Rill Donna , Bramson Jonathan 
Published: August 2019

Abstract
Background: The T cell antigen coupler (TAC) is a chimeric receptor co-opting the natural TCR receptor signaling complex to target tumor antigens in an MHC-independent manner (Helsen et. al., Nat. Comm. 2018). TAC engineered T cells mediate biological effects that are distinct from conventional chimeric antigen receptors (CARs) and may offer safety advantages due to greater target selectivity and no detectable off-target toxicity. Here, we present preclinical data of TAC01-CD19, an autologous CD19-specific TAC-T cell product candidate for clinical testing in patients with CD19-positive B cell malignancies
Materials and Methods: T cells from healthy donors and lymphoma patients were engineered with a CD19-specific TAC using lentivirus. Anti-tumor activity, T cell expansion and persistence were measured in the CD19-positive NALM-6 and Jeko-1 mouse tumor xenograft models. We used flow cytometry to determine surface expression of CD19-TAC, cytokine production and in vitro T cell proliferation. Cytotoxicity was evaluated in vitro using luciferase-based killing assay.
Results: Cytotoxicity was measured against multiple CD19 positive tumors cells (NALM6/Jeko-1/Raji) showing strong cytotoxicity in all cases. Treatment of established NALM-6 (acute lymphoblastic leukemia) and Jeko-1 xenografts (mantle cell lymphoma) with CD19 TAC-T cells resulted in clearance of tumors within a few weeks of T cell infusion. In vivo efficacy was tested across multiple donors, establishing consistent and reproducible anti-tumor efficacy. Monitoring of TAC T cells post-infusion revealed robust expansion that peaked in the peripheral blood 1-2 weeks post-infusion. Mice that cleared tumors following TAC-T cell treatment were resistant to subsequent challenge with fresh tumor cells demonstrating persistence of TAC-T cells. In contrast, treatment with control TAC-T had no impact on tumor growth. A histological examination of normal mouse tissues failed to detect TAC-T cell induced toxicity.
Conclusion: The pre-clinical evaluation of TAC01-CD19 has demonstrated specific anti-tumor responses without signs of toxicity. Results were reproducible across multiple donors demonstrating the robustness of the CD19 TAC system. TAC01-CD19 is expected to enter clinical testing in patients with CD19-positive hematological malignancies in Q2 2019.
Citation Format: Christopher W. Helsen, Danielle Hayes, Joanne Hammill, Criag Aarts, Andreas Bader, Donna Rill, Jonathan Bramson. Preclinical development of TAC01-CD19, a CD19 specific T-cell Antigen Coupler (TAC) therapy for the treatment of CD19-positive B cell malignancies [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 1424.
Abstract 1427: IL6 trans-signaling robustly promotes the expansion and antitumor activity of CAR T cells
Authors: Li Peng , Jiang Zhiwu , Liao Rui , Tang Zhaoyang 
Published: August 2019

Abstract
Chimeric antigen receptor T (CAR T) cell immunotherapy targeting CD19 positive B cells malignancies induces promising clinical remissions. However, the treatments are often accompanied with high levels of IL-6 characterized cytokine release syndrome (CRS). Previous studies had shown that sIL-6R are constitutively present in high concentrations in serum. Therefore, when the level of IL-6 is elevated (above nomogram per ml), sIL-6R combines with IL6 to form the IL-6/sIL-6R complex (trans-signaling). The IL-6 trans-signaling plays important roles in regulating immune responses, cell survival, apoptosis, and proliferation. To our knowledge, comprehensive assessment of the IL-6 signaling in biologic functions of CAR T has not been well addressed. We thus tested whether the IL-6 trans-signaling promotes expansion and anti-tumor activity of CAR T. We found that the levels of serum IL-6 and IL-6/sIL-6R complex were positively correlated with anti-CD19 CAR T cell expansion and anti-leukemia response in patients. To simulate the IL-6 trans-signaling, we next constructed a constitutively expression of Hyper IL-6 (HIL-6) with various CAR T cells. Anti-tumor efficacy of HIL-6-CAR T cells were confirmed in leukemia (anti-CD19) and solid tumors (anti-MUC1 and anit-GPC3 CAR T cells targeting lung cancer and hepatocellular carcinoma, respectively). Our results demonstrate that HIL-6-CAR T cells are more effective for suppressing tumor growth and more persistent in xenograft models. Transcriptomic profiling analysis revealed that the expression of genes that facilitate T-cell migration, early memory differentiation and the IL-6/GP130/STAT3 signaling was upregulated in HIL-6 simulated CAR T cells compared to the ones without HIL-6 overexpression. Because IL-6 trans-signaling activates downstream signaling via GP130, we also generated a novel CAR vector with constituted GP130 activation and demonstrated the CAR T cells were superior in anti-tumor activity with delayed xGVHD in xenograft models of leukemia, lung cancer and liver cancer. Taken together, these results showed that IL-6 trans-signaling can significantly enhanced the expansion anti-tumor activity of CAR T cells via GP130/STAT3 activation and GP130/CAR T may have the potential to promote anti-tumor effects with reduced toxicity in vivo.
Keywords: Chimeric antigen receptor T, cytokine release syndrome, IL-6 trans-signaling, GP130
Citation Format: Peng Li, Zhiwu Jiang, Rui Liao, Zhaoyang Tang. IL6 trans-signaling robustly promotes the expansion and antitumor activity of CAR T 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 1427.