bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4206: EUD-GK-001 is a novel kinase inhibitor with in vitro anti-lymphoma activity
Authors: Scalise Lorenzo , Tarantelli Chiara , Zuccotto Fabio , Spriano Filippo , Mascia Michele , Cascione Luciano , Gaudio Eugenio , Angiolini Mauro , Bertoni Francesco 
Published: September 2020

Abstract
Introduction. EUD-GK compounds, and in particular EUD-GK-91, show selectivity for a restricted number of kinases (ALK, RET, TRK, DDR2, ROS1) and have shown anti-tumor activity in specific solid tumor models (Zuccotto et al, EORTC-NCI-AACR 2016). Here, we have assessed a novel derivative of this class of compounds, EUD-GK-001, in a panel of lymphoma models.
Methods. Lymphoma cell lines, including both B- and T-cells lymphomas, were exposed to a large range of concentrations of EUD-GK-001 as single agent for 72h, followed by MTT proliferation assay and IC50 calculation. Cell cycle were assessed in four cell lines (FARAGE, DOHH2, TMD8, OCI-LY-10) treated with 500 nM of EUD-GK-001 for 72h. Baseline protein expression was assessed by mass spectrometry. Baseline gene expression was obtained by using the Illumina HumanHT 12 Expression BeadChips.
Results. EUD-GK-001 presented a median IC50 of 1.65 μM and 3.75 μM across 14 B- and 4 T- cell lines, respectively. Five out of 14 DLBCL cells lines, including both ABC- and GCB- subtypes, presented IC50 values lower than 1 μM, A dose-depended increase of the cells in the sub-G0 phase (15-55%) was observed in two GCB-DLBCL and two ABC-DLBCL cell lines after EUD-GK-001 exposure for 72h.
Taking advantage of available omics data for the tested cell lines (Cascione at al, AACR 2019), functional annotation of RNA and protein levels showed that TNF/NFKB, inflammation, IL6/JAK/STAT3, IL2/STAT5 signatures were enriched among the transcripts more expressed in the sensitive cell lines, while E2F, DNA repair, MYC signatures were enriched in the resistant cell lines. No genes coding for kinases were more expressed in both GCB (n.=2) and ABC (n=2) sensitive than in resistant DLBCL cell lines (GCB, n=2; ABC, n=3 R). However, three kinases, namely SRC, JAK2 and LCK, were significantly more expressed in EUD-GK-001 GCB-DLBCL sensitive cell lines (DOHH2, FARAGE) than in EUD-GK-001 resistant cells (SU-DHL-8, TOLEDO) and merging the top-50 mRNA and top-50 proteins identified by limma, SRC appeared as a central hub of the top genes associated with sensitivity to EUD-GK-001. The pattern of activity of EUD-GK-001 was however different from what reported for the SRC inhibitor dasatinib in the same lymphoma models (Scuoppo et al, PNAS 2019).
Conclusion. EUD-GK-001 is a novel small molecule with in vitro anti-tumor activity in subsets of lymphoma models, which needs to be further explored.
Citation Format: Lorenzo Scalise, Chiara Tarantelli, Fabio Zuccotto, Filippo Spriano, Michele Mascia, Luciano Cascione, Eugenio Gaudio, Mauro Angiolini, Francesco Bertoni. EUD-GK-001 is a novel kinase inhibitor with in vitro anti-lymphoma activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4206.
Abstract 4234: Machine learning-driven label-free cell sorting for cell therapy
Authors: Ochiai Hiroshi , Sugimoto Keiki 
Published: September 2020

Abstract
Ghost cytometry (GC) is a recently realized approach for machine learning-driven analysis of image information without image production and enabled high throughput cell sorting through its integration with a microfluidic sorting technology. When a supervised machine learning is adopted in GC, a classifier model is first trained using a data set comprising of simultaneously measured imaging waveform signals and cell specific (ground truth) labels indicating cell types and functions. This trained model, in turn, is able to infer the cell specific label directly from the imaging waveforms at a speed of several orders of magnitude faster than the other methods, thus enabling subsequent cell sorting at high speed. Here, we investigate the applicability of label-free GC to manufacture and isolate the effective therapeutic cells.First, we tested classification of live T cells from dead cells to understand the potential of GC for monitoring the healthiness of live cells in cell manufacturing processes. A model for classifying the label-free information was trained using labels based on the positivity of annexin V and PI staining and applied to test data. Next, we assessed classification of T cells from live blood samples after hemolysis process. In this experiment, labels of a CD3 marker was used to construct a training data set to develop the T cell classifier. Finally, we applied the label-free GC to identify cells with low glycolytic activity because the cell metabolic status has a big impact on their therapeutic potency and persistency. Selection of the low glycolytic T cell may address current challenges on CAR-T cell therapy such as sustained tumor elimination. As a result, GC was found to classify not only live and dead cells but also apoptotic cells. Moreover, GC was able to discriminate CD3 positive T cells from PBMC with a good accuracy. These results indicate that our label-free GC can detect the healthy live cells without using any surface markers and could be beneficial for monitoring the quality of T cell products. Furthermore, the label-free GC may have a potential to classify the cells based on their phenotypic properties such as metabolic status. We would like to share our recent data at the meeting and discuss the potential of label-free GC for delivering sophisticated therapeutic cells, especially CAR-T cells, with good efficacy and persistency.
Citation Format: Hiroshi Ochiai, Keiki Sugimoto. Machine learning-driven label-free cell sorting for cell therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4234.
Abstract 4244: The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas
Authors: Yang Jilong 
Published: September 2020

Abstract
Sarcomas are a group of rare and malignant tumors originating from mesenchymal tissue with a variety of cellular subtypes. Although several major standard treatments, including neo-adjuvant and adjuvant chemotherapy, surgery and radiation, have made breakthroughs to improve overall survival, there are few additional effective treatments for metastatic sarcomas that have failed traditional therapy. With the encouraging efficacy of PD-1 monoclonal antibodies in nonresectable or metastatic malignant melanomas and lung cancers, immunosuppressive agents provide new hope for the treatment of sarcomas. We retrospectively collected information from 15 patients with stage IV sarcomas who were treated with a PD-1 inhibitor with or without angiogenesis inhibitor after the failure of traditional treatments, from June 15, 2016 to September 30, 2019. The primary observation endpoint was median progression-free survival (mPFS), and the objective response rate (ORR) and the disease control rate (DCR) were secondary endpoints. Treatment-related adverse events (AEs) were evaluated. Patients were observed until death, loss to follow-up, or the end of the PD-1 inhibitor therapy. The average follow-uptime was 8.47 months (1.97-28.12 months). At 12 weeks, the ORR was 23.1% (3/13) and the DCR was 84.6% (11/13). Finally the overall median PFS was 5.06 months, the ORR was 15.4% (2/13) and the DCR was 61.5% (8/13). Common AEs (occurring with 15 patients) included grade 4 hypertension (n=1, 2.6%), grade 3 leukopenia (n=1,2.6%), grade 2 hand and foot syndrome(HFSR) (n=2, 5.1%), grade 1 reactive capillary hyperplasia (RCCEP) (n=7,17.9%), fatigue and weakness (n=5, 12.8%), digestive dysfunction (n=3,7.7%) and fever (n=3,7.7%). The results indicate that PD-1 inhibitors based therapies are effective, safe and well tolerated in patients with advanced sarcomas. The PD-1 inhibitor combined with anti-angiogenesis agents might provide a new and effective strategy to treat metastatic sarcomas.
Citation Format: Jilong Yang. The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4244.
Abstract 4255: Reliable identification of both known and novel gene fusions using a high-efficiency amplicon-based NGS panel
Authors: LI Chenyu 
Published: September 2020

Abstract
Gene fusions and RNA splicing errors are important events frequently involved in tumorigenesis, and often represent clinically addressable targets for various cancers. The reliable detection of such mutations via NGS requires the development of cutting-edge technologies capable of overcoming many challenges. These include detecting fusion mutations regardless of the complexity of fusion structures, removing the length and quantity constraints of FFPE RNA, reducing ribosomal RNA interference, eliminating false negatives and positives, revealing the existing copies of mutations, and improving the reproducibility and ease of workflow. Here we describe the development and validation of a fast and user-friendly RNA-based fusion detection technology - CleanPlex® Fusion. Adding a universal primer at the 3' end of single-stranded cDNA via template switching allows us to eliminate the constraint of template length, and hence amplify damaged RNA fragments, such as FFPE RNA. The presence of a target-specific primer on one side enables the detection of any mutations on the RNA fragments, including novel ones. With a panel of 61 primers (covering most of fusion mutations of NSCLC) annealing to the 3' end portion of RNA, we demonstrated the high on-target rate, mapping rate, and low rRNA rate and primer-dimer rate. We validated the amplification of each amplicon by using fragmented total RNA. Additionally, we also made a dual-primer multiplex PCR panel covering the same set of fusion mutations as defined by the single-primer panel, confirmed its coverage of all fusion mutations using a synthetic pool of fusion targets, and detected all commercial reference fusion mutations targeted by the panel. We again demonstrated the detection of such reference fusion mutations using the single-primer mPCR panel, and demonstrated that the single-primer method even detected fusion mutations outside the boundary of the dual primers. Moreover, we showed that the detected fusion reads significantly correlate with copy numbers determined by digital PCR. Lastly, we validated detection of fusion mutations in cell lines and FFPE RNA. CleanPlex® Fusion therefore represent a robust and efficient NGS method for detecting fusion mutations.
Citation Format: Chenyu LI. Reliable identification of both known and novel gene fusions using a high-efficiency amplicon-based NGS panel [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4255.
Abstract 4266: Proteomics for precision oncology: Profiling the proteome of matching tumor and adjacent normal tissue using data-independent acquisition
Authors: Vowinckel Jakob , Novy Karel , Corwin Thomas , Treiber Tobias , Bruderer Roland , Reiter Lukas , von Leitner Eike , Rinner Oliver , Escher Claudia 
Published: September 2020

Abstract
Precision oncology requires a deep understanding of the molecular mechanism in cancer biology. The predominant approach today focuses on genome structure and gene expression data, which have become available with the rise of next-gen sequencing technology. On a phenotypic level, however, protein expression and activation are arguably more directly related to cellular function. The availability of combined genome and proteome level data from the same tumor is therefore expected to provide a much more complete picture of a tumor in a particular state. Until recently, proteomics technology could not match the scale of next-gen sequencing and consequently, precision medicine research has almost exclusively been based on gene-level data. Here we show the first truly large-scale data set for protein expression and protein phosphorylation for a large collection of biospecimens derived from the IndivuType cohort of Indivumed, Germany. Matching fresh-frozen tumor and adjacent normal tissue samples from thousands of patients including various cancer entities were obtained from Indivumed's network of partner hospitals Enabled by the novel data-independent acquisition (DIA) workflow, a mass spectrometric method that obtains peptide fragmentation data in a highly parallelized way with high reproducibility and sensitivity, more than 7,000 proteins in the whole proteome (WP) and 20,000 phospho-peptides in the phospho-proteome (PP) workflow were analyzed. Sample processing from 5 mg of tissue per sample was performed on 96-well plates with the help of a liquid handling robot. Phospho-peptide enrichment was carried out using a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads (ReSyn Biosciences). Data-independent acquisition (DIA) LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (WP) and 60 min (PP) gradients. With a throughput of 850 WP and 650 PP samples per month, thousands of samples were analyzed to date. The resulting proteome data is integrated into Indivumed's IndivuType multi-omics database, supporting the identification and validation of new molecular cancer drug targets and biomarkers.
Citation Format: Jakob Vowinckel, Karel Novy, Thomas Corwin, Tobias Treiber, Roland Bruderer, Lukas Reiter, Eike von Leitner, Oliver Rinner, Claudia Escher. Proteomics for precision oncology: Profiling the proteome of matching tumor and adjacent normal tissue using data-independent acquisition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4266.
Abstract 427: A mouse model for studying oncogenesis of HPV-associated oropharyngeal cancer
Authors: McGhee Eva , Lin Yi-Ling , Vadgama Jay , Lang Khadijah , Okoro Judith , Vidal Victoria , Long Naomi , Li Mengtao 
Published: September 2020

Abstract
The human papillomavirus (HPV) causes 70% of oropharyngeal cancers in the United States. While the molecular and cellular mechanisms and the stepwise progression of HPV-related cervical cancer have been well studied, oropharyngeal HPV carcinogenesis remains to be unraveled since an equivalent HPV premalignant stage has never been identified in clinical oropharyngeal tissues. In this study, a series of keratinocyte cell lines derived from the base of the tongue of C3H mice were established. These cells formed varying degrees of malignancy in the syngenetic mice and are used to study the biology of HPV-related oropharyngeal cancer in an immunocompetent host. Keratinocytes from the base of the tongue were isolated from C3H newborns and were subsequently retrovirally immortalized with TERT or HPV16 E6E7 oncoproteins, with or without oncogene H-ras. They are designated MOKT1 (TERT), MOKT1/H-ras (TERT/H-ras), MOKE2 (E6E7), or MOKE2/H-ras (E6E7/H-ras). These cells were injected in the masseter muscle of syngeneic mice and the developing lesions were harvested for histological analysis over a time course of 1 month. E6E7 transformed MOKE2 cells exhibited features of HPV associated cancer cells. We found that p63 and phosphorylated STAT3 were upregulated in MOKE2 cells in comparison to MOKT1 cells. MOKE2 cells obtained growth advantages with increased cell proliferation and decreased apoptosis. In addition, MOKE2 cells showed increased cell migration activity in wound healing assays. While all cell lines grew indefinitely in vitro, MOKT1 and MOKT1/H-ras failed to show any sign of malignancy when implanted in vivo. MOKE2 demonstrated features of malignancy, but the phenotype was transient. Host immunity does not appear to be the determining factor for suppressing tumor growth as MOKE2 regressing also occurred when implanted in immunodeficient NSG mice. Only MOKE2/H-ras cells were capable of progressing and establishing permanent cancer. Ourdata suggest that differentiation induced cell growth arrest may contribute to tumor regression and a second hit is required to overcome such arrest. The MOKE2 cells can be used in syngeneic mice to study secondary oncogenic factors in the development of HPV-related oropharyngeal cancer.
Citation Format: Eva McGhee, Yi-Ling Lin, Jay Vadgama, Khadijah Lang, Judith Okoro, Victoria Vidal, Naomi Long, Mengtao Li. A mouse model for studying oncogenesis of HPV-associated oropharyngeal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 427.
Abstract 4304: Radio-chemotherapy efficacy is predicted by intra-tumor CD8+FoxP3+ double positive T cell density in locally advanced non-small cell lung carcinoma
Authors: Velut Yoan , Boulle Geoffroy , Lupo Audrey Mansuet , Gibault Laure , Blons Hélène , Tredaniel Jean , Fournel Ludovic , Boni Aurélie , Cremer Isabelle , Wislez Marie , Duchatelle Veronique , Hammond Scott , Alifano Marco , Giraud Philippe , Damotte Diane 
Published: September 2020

Abstract
Background: radiotherapy is a standard of care for locally advanced stage III (N2) non-small cell lung cancer (NSCLC) combined with surgery and/or chemotherapy. Radiotherapy is hypothesized to induce intra-tumoral immune infiltration via neoantigen release from dying tumor cells sometimes resulting in an abscopal effect. However, intra-tumoral immune cell characteristics that predict radiotherapy efficacy have not been identified.
Patients and Methods: we retrospectively analyzed tumor samples and clinical data from 113 patients, 89 resected) and 24 non-resected stage III (N2) NSCLC treated within the same radiotherapy department (2002 to 2015). We performed multiplex staining (CD8, FoxP3, PD-L1, pan-keratin) in order to correlate immune environment (density and location) to overall survival (OS) and disease free survival (DFS).
Results: high density of CD8+ T cells was associated with DFS (p=0.0036, HR=2.42 [1.31 - 4.47]) and OS (p=0.049, HR=1.93 [0.99 - 3.78]) in resected group only. High density of CD8+/FoxP3+ double positive T cells was associated with OS (p=0.017, HR= 1.97 [1.11 - 3.48]) in the global population; and in resected group for OS (p=0.05, HR=1.92 [0.98 - 3.74]) and PFS (p=0.03, HR=1.83 [1.03 - 3.23]), with a trend of significance for OS and PFS in the non-resected group (p=0.06, HR=2.84 [0.88 - 9.13] and p=0.05, HR=3.03 [0.91 - 10.10], respectively). Intermediate PD-L1 expression in tumor cells (TPS=1-49%) was associated with a higher survival in the resected group.
Conclusions: we demonstrated that intra-tumoral CD8+ T cell and particularly the CD8+/FoxP3+ cell density predict radiotherapy efficacy and survival in stage III N2 NSCLC. Thus, it suggests that radiotherapy rather improves than promotes tumor immunogenicity.
Citation Format: Yoan Velut, Geoffroy Boulle, Audrey Mansuet Lupo, Laure Gibault, Hélène Blons, Jean Tredaniel, Ludovic Fournel, Aurélie Boni, Isabelle Cremer, Marie Wislez, Veronique Duchatelle, Scott Hammond, Marco Alifano, Philippe Giraud, Diane Damotte. Radio-chemotherapy efficacy is predicted by intra-tumor CD8+FoxP3+ double positive T cell density in locally advanced non-small cell lung carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4304.
Abstract 4345: Environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan: A Multi-media analysis
Authors: Uppala Padma P. Tadi , Wong Brian , Berman Laurel , Caudill Motria , Cadet Jean 
Published: September 2020

Abstract
Environmental risk factors such as air, water, soil pollution, chemical exposures, climate change, and radiation contribute to more than 100 diseases. Understanding the connection of the environment to health is a critical pathway to address health disparities and poor health outcomes in communities. Purpose: This study investigates environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan. Methods: We examined environmental contaminants in the land, air, and water. Environmental data was obtained from toxic release Inventories (TRI) and brownfields from the US EPA's TRI databases, My Environment, Environmental justice SCREEN websites, ATSDR public health assessment information for contaminated sites in Berrien County and ATSDR Toxicological Profiles and ToxFAQs for common environmental contaminants and associated health concerns. We created GIS maps overlaid with all-cause mortality data. Using the TOXMAP database, we generated Environmental Health Toxmaps for cancer mortality in Berrien County and overlaid with TRI facilities. Results: Age-adjusted mortality among black males for all malignant cancers (208.90) and cancer of the lung and bronchus (110.70) were high compared to national data. An important observation from this analysis indicated that cancer of the lung and bronchus was 110.70 among black males and was 60.20 among white males in Benton Harbor. According to the overlaid GIS maps, zip codes surrounding the Benton harbor area seems to have the highest number of contaminated sites and high mortality rates. Benton Harbor in Berrien County had the second-highest level of summer Action Days (10 days) in the state. We reviewed the Action Days reported on the Michigan Department of Environmental Quality website (2019) and found that Benton Harbor typically was in the "top" tier for Action Days for several years. Although health disparities were observed among Black and White males for lung cancer, smoking rates were not elevated among black males as compared to the general population. In conclusion, we suggest that in addition to smoking, environmental, and socioeconomic factors may contribute to high lung cancer rates among Black men in Benton Harbor in Berrien County.
Citation Format: Padma P. Tadi Uppala, Brian Wong, Laurel Berman, Motria Caudill, Jean Cadet. Environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan: A Multi-media analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4345.