bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5654: Fully automated tissue classification by imaging mass spectrometry, moving towards a hundred samples a day
Authors: Jones Emrys A. , Chapman Richard , Hoyes Emmy , Migas Lukasz , Henderson Fiona , Pringle Steven , Langridge James , McMahon Adam 
Published: August 2018

Abstract
Desorption electrospray ionisation mass spectrometry is a surface analysis technique that can rapidly analyse the lipid and metabolite composition of a tissue section. By moving the tissue under the analysis probe, a chemical map of the sample can be generated in a matter of minutes. As has been shown in the literature 1,2, each tissue type or disease state has its own characteristic molecular fingerprint, therefore, using histologically annotated databases of these molecular profiles these maps can be classified using machine learning approaches. With the increased rate of analysis made possible by recent technological advances, the timeframes of a single sample makes automation an attractive proposition. With a slide loading system and a range of software solutions, up to two hundred slides can be queued for analysis. Each will be loaded in turn onto the analysis stage, the location of the tissue section determined with optically directed object detection algorithms, and the analysis started. During the analysis the information from each pixel is projected into the classification model and colour coded by designated tissue type. Applications of this approach that have been demonstrated from a research perspective are the analysis of serial sections of drug dosed spheroids and tumour xenografts for studying the chemical heterogeneity of these systems in three dimensions, in the latter case allowing comparison with other imaging modalities such as MRI and PET. Initial studies will also be presented which will investigate the use of the system for the classification of large cohorts of unknown tissues with subsequent comparison to histological classification by conventional methodologies.l 1. Calligaris, D.Caragacianu, D.Liu, et al; PNAS, 2014, 111, 15185-15189 2. Guenther, S., Muirhead, L.J., et al, Cancer Res, 2015, 75, 1828-1837
Citation Format: Emrys A. Jones, Richard Chapman, Emmy Hoyes, Lukasz Migas, Fiona Henderson, Steven Pringle, James Langridge, Adam McMahon. Fully automated tissue classification by imaging mass spectrometry, moving towards a hundred samples a day [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 5654.
Abstract 566: High dimensional single cell analysis predicts response to anti-PD-1 immunotherapy
Authors: Krieg Carsten , Nowicka Malgorzata , Guglietta Silvia , Schindler Sabrina , Hartmann Felix J. , Weber Lukas M. , Dummer Reinhard , Robinson Mark D. , Levesque Mitchell P. , Becher Burkhard 
Published: August 2018

Abstract
Checkpoint inhibition of programmed cell death protein 1 (PD-1) has revolutionized cancer therapy. As more and more patients with metastatic melanoma but also other cancers show a dramatic increase in progression-free survival, still a large proportion of patients do not show durable response. As options for monotherapies, as well as combination immunotherapies, increase in the clinics, predictive biomarkers of clinical response are urgently needed. We employed high-dimensional single cell mass cytometry and a machine-learning bioinformatics pipeline for the in-depth characterization of all immune cells in the peripheral blood of stage IV melanoma patients before and at 12 weeks of anti-PD-1 immunotherapy. We observed a clear treatment response of patients under immunotherapy. However, a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy before therapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent, blinded validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. We further present a high dimensional analysis workflow to analyze predictive and prognostic immune biomarkers during future clinical trials.
Citation Format: Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J. Hartmann, Lukas M. Weber, Reinhard Dummer, Mark D. Robinson, Mitchell P. Levesque, Burkhard Becher. High dimensional single cell analysis predicts response to anti-PD-1 immunotherapy [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 566.
Abstract 5664: Chemical proteomic platforms to probe metabolic heterogeneity in the tumor microenvironment
Authors: Moellering Raymond E. 
Published: August 2018

Abstract
Proteomic platforms provide quantitative snapshots of the proteins present in a biological sample. Despite widespread use, these methods typically require homogenization of samples, signal-averaging over thousands-to-millions of cells and provide no information on protein function. This talk will focus on several novel technologies to circumvent these limitations and to interrogate protein activity within the complex architecture of biological samples, and on spatial scales ranging from single cells to whole organisms. At the single cell level we have developed a chemical proteomic technology, activity-dependent proximity ligation, which enables multiplexed quantification of enzyme activity with high spatial resolution in cellular co-culture and in patient tissue samples. Application of this platform has enabled detection of several metastasis-associated biomarker activities in primary patient samples, as well as simultaneous detection of activity and mRNA expression profiles. These data provide insight into the progression lineage of metastatic ovarian cancers. On the other end of the spectrum, we have recently developed a first-in-class activity-dependent PET imaging probe that specifically and irreversibly labels one of these enzyme biomarkers in vivo. This provides an opportunity to detect aggressive tumor populations, both at sites of primary occurrence and metastasis, with this novel PET radiotracer. Together, these approaches offer new paradigms for studying protein function in basic and translational biology and medicine, ideally providing new tools and biological hypotheses to understand and target tumor malignancy.
Citation Format: Raymond E. Moellering. Chemical proteomic platforms to probe metabolic heterogeneity in the tumor microenvironment [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 5664.
Abstract 5671: Humanized mouse models for evaluation of cancer therapies
Authors: Mirjolet Jean-Francois , Caradec Josselin , Duchamp Olivier , Bichat Francis , Mignard Caroline 
Published: August 2018

Abstract
Mice with a humanized immune system, so called “humanized” mouse models, can be used to study the complex interactions between the human immune system and tumor cells. In order to assess compounds efficiency in immune-oncology, the in vivo model should recapitulate the biological characteristics of the human tumor and the related immune microenvironment. The choice of mouse strain is the first critical factor as genetically engineered mouse strains differentially express cytokines and growth factors. Then the choice of human antigen/target to be assessed drives the choice of the tumor models and the immune population to be transferred into mice. We developed on different immunodeficient mouse strains multiple humanization strategies using either human PBMCs, Hematopoietic Stem Cells (HSCs), or specific human immune cells such as Dendritic Cells (DCs), T cells, subset of T cells (e.g. gamma9 delta2 T cells) and NK cells. We also developed mouse humanization models using combinations of immune subpopulations such as co-transfer of autologous T cells and DCs.Humanized models were then used for in vivo proof of concept studies with mice xenografted with cell lines (human disseminated lymphoma, orthotopic/subcutaneous solid tumors) or patient-derived xenografts. Tumor-bearing humanized mice were treated with cancer therapeutics such as bispecific antibodies, ADCC-inducing antibodies, Treg targeting antibodies, TLR agonists, vaccines and adoptive T cells transfer therapeutic antibodies. Therapeutics efficiency was assessed by following up mice survival and tumor growth. The impact of therapeutics on tumors and immune cells was also assessed by flow cytometry and immunohistochemistry analyses. In case of disseminated lymphoma and ovarian human tumor in mice reconstituted with human PBMCs, significant antitumor activity of bispecific antibodies were evidenced by an increase in survival, decrease in specific biomarkers (CA125 for ovary) and decrease of residual disease.
Citation Format: Jean-Francois Mirjolet, Josselin Caradec, Olivier Duchamp, Francis Bichat, Caroline Mignard. Humanized mouse models for evaluation of cancer therapies [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 5671.
Abstract 5683: Value of new spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for drug development of novel immune therapeutic approaches
Authors: Beshay Janette , Jantscheff Peter , Obodozie Cynthia , Schaechtele Christoph , Weber Holger 
Published: August 2018

Abstract
Checkpoint inhibitor treatment has already become a common therapy of various cancer types. However, there is still a growing need for well-characterized preclinical mouse models, as clinical data indicate that patients only partially respond to this regiment. Currently, cell lines cultured from the 1970s are used frequently to evaluate novel therapies. In a research development program, new mouse-derived isografts (MDI) were established from spontaneously occurring and carcinogen-induced tumors. These tumors are transplanted as tissue pieces in a PDX-like manner and tested for their solid growth. Furthermore, the efficacy of immune checkpoint inhibitor treatment is evaluated and the presence of different immune cell populations in the tumor is characterized by FACS analysis. In addition, RNA-seq data complete the first characterization of these models and will give insights into the expression level and genetic modification of genes in these models. Here, the spontaneous MDI model JA-0009 and two carcinogen-induced MDI models JA-2042 and JA-2011 are presented. Whereas JA-0009 and JA-2011 tumors are only partially affected by immune checkpoint inhibitor treatment, JA-2042 shows a significant response in a combined treatment of anti-PD-1/anti-CTLA-4. Characterization of the infiltrated immune populations revealed a high number of T cells, especially Treg cells. In contrast, the JA-0009 tumor is infiltrated mainly by macrophages of M2 type with a low number of CD8+ T cells and the JA-2011 tumor by neutrophils. Taken together, the new MDI models complement the existing GEMs and cell-line derived syngeneic tumor models by their new properties (low passage number, no tissue culture, conserved original tumor properties and intra-tumoral immune cell populations) to characterize novel immune-modulatory agents in drug development.
Citation Format: Janette Beshay, Peter Jantscheff, Cynthia Obodozie, Christoph Schaechtele, Holger Weber. Value of new spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for drug development of novel immune therapeutic approaches [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 5683.
Abstract 5686: Utilization of fluorescent multiplex IHC and digital image analysis for studying LAG-3, CD3 and CD8 positive TIL subsets in NSCLC tissue
Authors: Khenkhar Malik , Biljes Daniel , Winkler Nickels , Uhlig Philipp C. , Juhl Hartmut , Bigley Alison L. , Sherry Lorcan 
Published: August 2018

Abstract
Targeting checkpoint molecules expressed on immune cells has shown promising results in the treatment of non-small cell lung cancer (NSCLC). One interesting molecule that is frequently expressed on exhausted tumor-infiltrating lymphocytes (TIL) is lymphocyte activation gene-3 (LAG-3). We recently implemented chromogenic anti-LAG-3/CD3 dual immunohistochemistry (IHC) and digital image analysis to quantify LAG-3 positive T cells in NSCLC tissue. Here, we extended this work by establishing an anti-LAG-3/CD3/CD8/pan-Cytokeratin (pan-CK) fluorescent multiplex IHC (mIHC) assay followed by digital image analysis to examine the composition of T cells infiltrating NSCLC tissue in more detail. Tyramide signal amplification (TSA) based fluorescent 5-color mIHC (LAG-3/CD3/CD8/pan-CK + DAPI) was developed by Indivumed on the Leica BOND RX automated staining platform and applied to formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples. Image analysis was performed by OracleBio. Tumor and stroma regions of interest (ROI) were classified according to the pan-CK and DAPI signals. LAG-3, CD3 and CD8 single positive cells, as well as dual and triple positive cells, were then quantified in the tumor and stroma ROIs. Fluorescent mIHC allowed for a specific quantification of LAG-3, CD3 and CD8 single, LAG-3/CD3, LAG-3/CD8, CD3/CD8 dual and LAG-3/CD3/CD8 triple labeled cells in the tumor and stroma ROIs of the analyzed NSCLC samples. As part of the assay validation, similar ratios of the differently labeled cells, in particular LAG-3 positive T cells (LAG-3/CD3 dual positive), were observed with fluorescent mIHC and chromogenic IHC, demonstrating a good concordance between the two approaches. Among the analyzed NSCLC samples, different ratios of LAG-3 positive TILs in adeno- and non-adenocarcinoma samples were detected. Determining the ratios of dual or triple positive TIL subsets by mIHC in combination with digital image analysis allows for a clearer understanding of the lymphocyte composition within NSCLC tissue than a simple quantification of LAG-3, CD3 and CD8 single positive cells. Furthermore, such information will contribute to a deeper understanding of the role of LAG-3 positive immune cell sub-populations in the progression and treatment of NSCLC.
Citation Format: Malik Khenkhar, Daniel Biljes, Nickels Winkler, Philipp C. Uhlig, Hartmut Juhl, Alison L. Bigley, Lorcan Sherry. Utilization of fluorescent multiplex IHC and digital image analysis for studying LAG-3, CD3 and CD8 positive TIL subsets in NSCLC tissue [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 5686.
Abstract 5705: The key role of kynurenine in anti-PD-1 failure
Authors: Botticelli Andrea , Cerbelli Bruna , Lionetto Luana , Zizzari Ilaria , Pisano Annalina , Roberto Michela , Onesti Elisa , Pietro Francesca Romana DI , Napoletano Chiara , Pizzuti Laura , Vici Patrizia , D'Amati Giulia , Mazzuca Federica , Simmaco Maurizio , Nuti Marianna , Marchetti Paolo 
Published: August 2018

Abstract
Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of severe and often fatal disease, as metastatic lung cancer, demonstrating long-term tumor control and extended patient survival. Unfortunately, only 25-30% of patients have a long-term benefit from immunotherapy, while the remaining 70-75% demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) has been proposed as a possible mechanism of resistance to anti-PD1 treatment. Indeed, IDO catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn), which seems to enhance the activity of Treg, leading to an immunosuppressive microenvironment.
Methods: The serum concentrations of Trp and Kyn were measured by high-performance liquid chromatography tandem mass spectrometry in 26 patients affected by non-small cell lung cancer (NCLSC) before the start of the second-line therapy with nivolumab. The IDO activity was expressed with Kyn/Trp ratio. The associations between Kyn/Trip ratio and early progression, PS, age, sex, brain metastases and pleural effusion were analyzed using Spearman test and Mann Whitney test.
Results: 14 out of 26 patients (54%) presented early progression (defined as progression of the disease within 6 months from the beginning of nivolumab treatment). The median value of Kyn/Trp ratio was 0.073 (0.024-0.18). We found a significant association between Kyn/Trp ratio and early progression (p= 0.009), while no statistical associations were found between Kyn/Trp ratio and PS, age, sex, brain metastases and pleural effusion. Indeed, patients with early progressive disease presented a median value of Kyn/Trp ratio significantly higher than other patients (0.094 vs 0.052; p= 0.01).
Conclusion: The pretreatment evaluation of IDO activity, expressed as Kyn/Trp ratio, seems to be associated with response to immunotherapy. In particular, higher Kyn/Trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in patients with high level of Kyn/Trp ratio.
Citation Format: Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Annalina Pisano, Michela Roberto, Elisa Onesti, Francesca Romana DI Pietro, Chiara Napoletano, Laura Pizzuti, Patrizia Vici, Giulia D'Amati, Federica Mazzuca, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti. The key role of kynurenine in anti-PD-1 failure [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 5705.
Abstract 5707: On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC
Authors: Patil Namrata , Zou Wei , Mocci Simonetta , Gupta Vinita , Molinero Luciana , Sandler Alan , Ballinger Marcus , Flynn Susan , Kowanetz Marcin , Hegde Priti 
Published: August 2018

Abstract
Background: Overall survival (OS) is an optimal endpoint for evaluation of checkpoint inhibitors (CPI). Identification of early surrogates of OS is important to inform early clinical signals and treatment decisions. We evaluated C-reactive protein (CRP) in clinical trials with atezolizumab (anti-PD-L1 antibody). CRP is elevated in different inflammatory and malignant conditions and is often considered to be a marker of poor prognosis.
Materials and Methods: Serum from patients enrolled in the 2L+ NSCLC studies POPLAR and OAK (randomized phase 2 and phase 3 controlled trials of patients with non-small cell lung cancer (NSCLC) who progressed on post-platinum chemotherapy) was analyzed for CRP levels over time. Patients were binned by changes in CRP at 6 weeks post-treatment (C3D1; Cycle 3 Day 1) as compared to pre-treatment levels, by either greater than 1.5 fold, less than 1.5 fold or unchanged (within +1.5 fold).
Results: C3D1 decreases in serum CRP were associated with RECIST1.1 based responses to atezolizumab but not with docetaxel in the POPLAR study, and these findings were further validated in the OAK study. Patients with RECIST based disease progression (PD) demonstrated an increase in serum CRP as early as Cycle 2 (3 weeks post atezolizumab therapy). Notably, decrease in CRP levels was strongly associated with improved PFS and OS. Results from OAK are shown below (table). Furthermore, in patients with RECIST PD or stable disease (SD), decrease in on-treatment CRP also predicted long overall survival.
Conclusion: CRP is a soluble biomarker that is modulated post-atezolizumab treatment. This simple lab test may provide utility in informing OS benefit for CPIs and combinations.
C3D1 CRP fold change relative to pre-treatmentHRCIp valueHRCIp valueITT0.750.62-0.910.0040.740.6-0.910.0053CRP &lt;1.5 FC0.480.33-0.690.0000950.490.32-0.750.0011CRP +1.5 FC0.850.62-1.150.280.610.43-0.860.0049CRP&gt;=1.5 FC0.960.69-1.340.811.250.86-1.810.25
Citation Format: Namrata Patil, Wei Zou, Simonetta Mocci, Vinita Gupta, Luciana Molinero, Alan Sandler, Marcus Ballinger, Susan Flynn, Marcin Kowanetz, Priti Hegde. On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC [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 5707.
Abstract 5709: Effect of IL-18 on the expansion and phenotype of human natural killer cells
Authors: Senju Hiroaki , Kumagai Asuka , Nakamura Yoichi , Takemoto Shinnosuke , Fukuda Masaaki , Gyotoku Hiroshi , Nakatomi Katsumi , Fukuda Minoru , Mukae Hiroshi , Tanaka Yoshimasa 
Published: August 2018

Abstract
When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in the immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and the anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells, and the IL-2/IL-18-induced NK cells might serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.
Citation Format: Hiroaki Senju, Asuka Kumagai, Yoichi Nakamura, Shinnosuke Takemoto, Masaaki Fukuda, Hiroshi Gyotoku, Katsumi Nakatomi, Minoru Fukuda, Hiroshi Mukae, Yoshimasa Tanaka. Effect of IL-18 on the expansion and phenotype of human natural killer cells [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 5709.