bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4568: A novel TGF-beta receptor I kinase inhibitor demonstrated to be an effective immuno-therapy for cancer
Authors: Xu Zusheng , Lou Yangtong , Chen Li , Zeng Kun , Sun Qingrui , Qu Yingying , Wang Wei , Wu Xiaodong , Ge Xiaomei , Gu Ying , Zhang Yingjia , Zhou He 
Published: July 2017

Abstract
TGF-beta (TGF-β) pathways, despite serving as tumor suppressor in early stage of carcinogenesis, have shown be one of the key tumor-promoting factors in later-stage tumor progression. TGF-β receptor I kinase (TGF-βR1) inhibitors have shown great potentials in their anti-tumor and anti-metastasis efficacy in preclinical studies and some of them are being tested in the clinical settings. A specific TGF-βR1 inhibitor YL-13027 was developed at Yingli Pharmaceutical. YL-13027 possesses good ADME and PK properties and shows potent inhibition of the TGF-β and receptor interaction both in cell-free and cell-based assays. Functionally, in vitro Treg differentiation assay demonstrated the significant inhibition of the induction of FoxP3 expressing cells as well as inhibiting the secretion of IL-10 by YL-13027. In murine colon cancer CT26 model, YL-13027 was well tolerated and significantly inhibited tumor progression with dose dependency. More mechanistic studies are on-going. These data suggest that YL-13027, a novel TGF-βR1 inhibitor, represents a promising and safe immune modulator and shows great potential as a cancer immuno-therapeutics.
Citation Format: Zusheng Xu, Yangtong Lou, Li Chen, Kun Zeng, Qingrui Sun, Yingying Qu, Wei Wang, Xiaodong Wu, Xiaomei Ge, Ying Gu, Yingjia Zhang, He Zhou. A novel TGF-beta receptor I kinase inhibitor demonstrated to be an effective immuno-therapy for cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2017-4568
Abstract 4576: Targeted human cytolytic fusion proteins: an update
Authors: Barth Stefan 
Published: July 2017

Abstract
Targeted immunotherapeutics, such as antibody drug conjugates (ADCs) or immunotoxins (ITs) represent promising agents for treatment of cancer. Despite their encouraging performance in clinical trials, both ADCs and ITs suffer from disadvantages like stoichiometrically undefined chemical linkage of the cytotoxic payload and potential immunogenicity of bacteria- or plant-derived toxins in humans, respectively. Therefore, in contrast to depleting B cell epitopes from bacterial toxins, we designed a number of targeted recombinant cytolytic fusion proteins, replacing bacterial toxins like Pseudomonas exotoxin A by human enzymes like proteases, kinases, RNases or microtubuli-associated proteins. Binding and biological activities were shown in vitro, ex vivo and in different in vivo models. This presentation will summarize the latest results on the hCFPs generated and demonstrate the efficacy of treatment of CD64-, CSPG4-, and EpCAM-targeting constructs in direct comparison to the corresponding Pseudomonas exotoxin-based immunotoxins. The presentation will conclude with an outlook on future perspective and applications of the next generation of targeted fully human recombinant cytolytic fusion proteins.
Citation Format: Stefan Barth. Targeted human cytolytic fusion proteins: an update [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4576. doi:10.1158/1538-7445.AM2017-4576
Abstract 4591: Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL
Authors: Boshuizen Julia , Koopman Louise A. , Breij Esther C. , Satijn David , Peeper Daniel , Parren Paul W. 
Published: July 2017

Abstract
Upon therapeutic pressure, cancers commonly select for drug-resistant, invasive subpopulations with elevated expression of the receptor tyrosine kinase AXL. Besides the correlation between high AXL expression and induction of epithelial-to-mesenchymal transition, a process known to support metastasis, ample evidence also links AXL to resistance against a variety of targeted therapies, including inhibitors of the MAPK pathway in malignant melanoma and the EGFR pathway in lung cancer.
AXL-107-MMAE (HuMax-AXL-ADC) is a therapeutic antibody-drug conjugate specific for AXL, containing the microtubule disrupting agent monomethyl auristatin E as the cytotoxic payload. AXL-107-MMAE was previously shown to induce potent cytotoxicity in vitro and in vivo, which was dependent expression of AXL on the cell surface.
We evaluated the capacity of AXL-107-MMAE to target AXL-positive MAPK pathway inhibitor resistant tumor cells, using malignant melanoma as a clinically relevant example. First, AXL-107-MMAE was shown to induce cytotoxicity in BRAF-mutant tumor cell lines that showed AXL expression upon acquired resistance to BRAF-inhibitors. In contrast, no cytotoxicity was observed in the BRAF-inhibitor-sensitive, AXL-negative parental cell lines. In heterogeneous tumor cell cultures, treatment with a BRAF-inhibitor selected for AXL-high, MAPK pathway inhibitor-insensitive melanoma cells, which was prevented by combined BRAF-inhibitor and AXL-107-MMAE treatment. Interestingly, we observed marked AXL upregulation in biopsies obtained from patients after they developed resistance to MAPK pathway inhibitors compared to paired pre-treatment biopsies.
The in vivo potential of AXL-107-MMAE in malignant melanoma was demonstrated using BRAFV600E-mutated xenograft model derived from a patient who developed resistance to the BRAF inhibitor vemurafenib in the clinic. This indicates that AXL expression levels in treatment-resistant malignant melanoma are sufficient to induce tumor regression with AXL-107-MMAE, at least in this model system.
These findings merit clinical validation of the targeting of both treatment-naïve and drug-resistant cancers with AXL-107-MMAE, either alone or in combination with other targeted therapies.
Citation Format: Julia Boshuizen, Louise A. Koopman, Esther C. Breij, David Satijn, Daniel Peeper, Paul W. Parren. Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4591. doi:10.1158/1538-7445.AM2017-4591
Abstract 4593: Glycoengineered antibodies for click chemistry applications
Authors: Sehgal Drishti , Kalscheuer Stephen , Sadhukha Tanmoy , Panyam Jayanth 
Published: July 2017

Abstract
Antibody-drug conjugates (ADC) hold considerable promise as anticancer agents. A critical determinant of the effectiveness of ADCs is the chemistry that is used to conjugate the payload. Currently used approaches include primarily conjugation to either side-chain amine or carboxylic acid groups or conjugation to thiols. Because these reactions are not site specific and not easily controlled, these chemistries can result in reduced affinity for the target antigen. Further, these conjugation reactions lack selectivity and can result in heterogeneous mixtures of products that differ in the sites and stoichiometry of modification. We investigated a glycoengineering strategy that enables the introduction of artificial azide groups in the antibody without affecting their antigen affinity. This is based on the observation that glycosyltransferases can incorporate non-natural sugars (e.g., azido mannose) at different sites on an IgG molecule. The azide groups inthese artificial sugars are then available to react with alkynes through copper-catalyzed ‘click’ chemistry or with strained alkynes such as dibenzyl cyclooctyne (DBCO) allowing for biorthogonal, copper-free ‘click’ chemistry. Because the sugars are added reproducibly and at asite that does not affect antigen binding, the glycoengineering technology would overcome problems associated with traditional conjugation strategies. Using this approach, azide groups were introduced in anti-CD133 and anti-perlecan antibodies. Further, the azide groups were available to react with various DBCO conjugates including fluorophores, drug molecules and nanoparticles. Importantly, the addition of artificial sugar and subsequent azide-alkyne reactiondid not affect the affinity of the antibody for the target antigen. Conjugation of nanoparticles to antibodies using this approach resulted in enhanced cellular uptake of the nanoparticles. Similarly, conjugation of a cytotoxin to the antibody resulted in enhanced cell kill in vitro. Weexpect that this glycoengineering strategy will prove to be a unique platform technology that will have a significant impact on antibody-based therapeutics.
Citation Format: Drishti Sehgal, Stephen Kalscheuer, Tanmoy Sadhukha, Jayanth Panyam. Glycoengineered antibodies for click chemistry applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2017-4593
Abstract 4628: Selection of Smad2 for TGF-β to suppress dendritic cells by STAT3/c-Ski-induced repression of Smad3
Authors: Yoon Jeong-Hwan , Bae Eunjin , Sudo Katsuko , Takanashi Masakatsu , Han Jin Soo , Park Seok Hee , Weinstein Michael , Nakae Susumu , Yamashita Tadashi , Lee In-Kyu , Ju Ji Hyeon , Sumida Takayuki , Kuroda Masahiko , Miyazawa Keiji , Kato Mitsuyasu , Mamura Mizuko 
Published: July 2017

Abstract
The mechanisms how Smad-mediated transforming growth factor-β (TGF-β) signalling regulates dendritic cells (DCs) remain largely unknown, despite its crucial regulatory roles in the differentiation and activation of DCs. Here, we show that STAT3/c-Ski-induced downregulation of Smad3 during differentiation selects Smad2 as the specific TGF-β receptor-regulated Smad (R-Smad) to suppress the immunogenicity of DCs. Smad3 transcribed by unphosphorylated Smad2/3 prevented the progenitor cells from DC differentiation with repression of Flt3, IRF4 and STAT3. Repression of Smad3 by synergy of phosphorylated STAT3 and c-Ski was essential for DC differentiation. TGF-β suppressed DC activation via Smad2, hence DC-specific Smad2 deletion enhanced anti-lymphoma effector functions of cytotoxic T lymphocytes (CTLs) and type 1 helper T (Th1) cells in a mouse EL4 lymphoma model. Our findings reveal stepwise regulatory roles of R-Smads in DC regulation: Smad3 inhibits differentiation and Smad2 suppresses immunogenicity.
Citation Format: Jeong-Hwan Yoon, Eunjin Bae, Katsuko Sudo, Masakatsu Takanashi, Jin Soo Han, Seok Hee Park, Michael Weinstein, Susumu Nakae, Tadashi Yamashita, In-Kyu Lee, Ji Hyeon Ju, Takayuki Sumida, Masahiko Kuroda, Keiji Miyazawa, Mitsuyasu Kato, Mizuko Mamura. Selection of Smad2 for TGF-β to suppress dendritic cells by STAT3/c-Ski-induced repression of Smad3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4628. doi:10.1158/1538-7445.AM2017-4628
Abstract 4633: Crosstalk between MDSCs and Th17
Authors: Singh Brijendra 
Published: July 2017

Abstract
Expansion of myeloid-derived suppressor cells (MDSCs) within the tumor is a known barrier to successful cancer immunotherapy. MDSCs are heterogeneous population of immature myeloid cells with potent immunosuppressive activity. Emerging evidences in the recent years define the role of immunosuppressive activity of MDSCs on different subsets of CD4+ T cells, however the exact effect of MDSCs on inflammatory Th17 cells during tumor progression is not clear. Here we demonstrate the immunosuppressive effect of MDSCs on Th17 cells. We further show that the interaction between MDSCs and Th17 is not unilateral and reveal that Th17 cells can promote the immunosuppressive effect of MDSCs. MDSCs, either isolated from tumor bearing mice or generated in vitro from bone marrow (BM-derived MDSCs), can both suppress IL-17A expression. Our data also demonstrate that IFNg, produced by Th17 cells is essential for the immunosuppressive activity of BM-derived MDSCs on IL-17A expression and further that the IFNgR1-driven signaling is important for Nos2-mediated immunosuppressive effect of BM-derived MDSCs on IL-17A expression. Understanding the molecular mechanism of the interplay between MDSCs and Th17 cells may help to develop more specific targeted therapy for cancer immunotherapy and improve therapeutic efficacy of the existing therapies against cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Brijendra Singh. Crosstalk between MDSCs and Th17 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4633. doi:10.1158/1538-7445.AM2017-4633
Abstract 4639: HLA and NKG2D ligand abnormalities and IFN-γ unnresponsiveness in human colorectal carcinoma cell lines
Authors: Liang Yi-Hsin , Lin Yen-Cheng , Chen Kuo-Hsin , Kao Chiu-Hwa , Cheng Ann-Lii , Yeh Kun-Huei , Chang Chien-Chung 
Published: July 2017

Abstract
Background: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has shown promising efficacy on wild-type RAS metastatic colorectal cancer (CRC) patients. Cetuximab demonstrates anti-cancer effect via NK cells and subsequent immunogenic cell death. Chemotherapy or targeted therapy may change immune surface markers.
Methods: We characterized a panel of 6 CRC cell lines with different genetic features. The impacts of interferon-γ (IFN-γ) on cell surface expressions of major histocompatibility complex (MHC) class I (including subtypes), MHC class II (including subtypes), MHC class 1 related molecule A (MICA, the NK cell ligand), Intercellular Adhesion Molecule 1 (ICAM-1, the immunoglobulin superfamily), EGFR, and Chondroitin Sulfate Proteoglycan 4 (CSPG-4, pericyte attaching marker) before and after treatment with IFN-γ (100 U/ml, 48 h) were explored in selected cell lines
Results:
Among six human colon cancer cell lines analyzed, DLD-1, HCT15, and LoVo
exhibited no expression of HLA-A and HLA-B,C. Colo-320 demonstrated both low HLA-A and HLA-B,C expression and irresponsive to IFN-γ stimulation. In contrast, both HT-29 and SW-480 showed low HLA-A and HLA-B,C expression, but the expression of both HLA-A and HLA-B,C was corrected after IFN-γ stimulation. All six cell lines possessed low MHC class II expression and irresponsive to IFN-γ stimulation. All six cell lines possessed low MIC expression and irresponsive to IFN-γ stimulation. All six cell lines showed low ICAM-1 expression, but only HT-29 and SW-480 were responsive to IFN-γ stimulation. LOVO and SW-480 demonstrated high EGFR expression and irresponsive to IFN-γ stimulation. Only HT-29 possessed high CSPG-4 expression.
Conclusion:
These findings reveal that regardless of their genetic features, all six CRC cell lines possess a phenotype that may allow them to escape cytotoxic T and NK cell attack.
Table
Cell LineMSICIMPKRASBRAFPI3KCATP53DLD-1MSI+G13DWTE545KS241FHCT-15MSI+G13DWTE545KS241FLOVOMSI-G13DWTWTWTCOLO-320MSS-WTWTWTR248WHT-29MSS+WTV600EP449TR273HSW-480MSS-G12VWTWTR273H
Citation Format: Yi-Hsin Liang, Yen-Cheng Lin, Kuo-Hsin Chen, Chiu-Hwa Kao, Ann-Lii Cheng, Kun-Huei Yeh, Chien-Chung Chang. HLA and NKG2D ligand abnormalities and IFN-γ unnresponsiveness in human colorectal carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4639. doi:10.1158/1538-7445.AM2017-4639
Abstract 4643: Plasma thioredoxin reductase 1 as a diagnostic marker for non-small cell lung cancer
Authors: Kang Xiaozheng , Dong Chaoran , Shen Bocun , Yan Wanpu , Dai Liang , Yang Yongbo , Yin Hanwei , Xu Guobing , Zeng Huihui , Chen Ke-Neng 
Published: July 2017

Abstract
Non-invasive diagnostic markers for patients with suspicious non-small cell lung cancer (NSCLC) may provide needed guidance on invasive diagnostic and therapeutic decisions. Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme, and plays an important part in tumor growth, progression, metastasis, and chemotherapy resistance. The goal of this study is to test the feasibility of developing plasma TrxR1 as a novel diagnostic marker for NSCLC. The plasma TrxR1 activity was determined spectrophotometrically by monitoring the NADPH-dependent production of 2-nitro-5-thiobenzoate at 412nm and at 37°C. All detection kits and automatic analyzer possess independent intellectual property rights, and have been widely used in breast cancer screening. In this study, the plasma levels of TrxR1 were measured in 45 treatment-naïve NSCLC patients and 10 individuals with benign tumor-like pulmonary diseases. Taking plasma TrxR1 activity of 4 as reference, the overall concordance rate was 73.3%, while those of CEA, CA199, CA125, NSE, CYFRA21-1 and SCC were 19.0%, 7.1%, 16.7%, 35.7%, 24.4% and 2.5%, respectively. Furthermore, using TNM staging (AJCC 7th ed.) as classifier, the concordance rates of TrxR1 in local, local regional and advanced stage subgroups were 66.7% (20/30), 77.8% (7/9) and 100% (4/4), respectively. A multipoint linear fitting correlation model was created, and the equation was TrxR1 = 5.821 + 0.396*Stage. Besides, the concordance rates of TrxR1 in benign tumor-like pulmonary diseases was 60% (6/10). Our data suggest that plasma TrxR1 activity is a useful non-invasive diagnostic marker for NSCLC, and there may be a linear correlation between TrxR1 activity and pathological stage.
Citation Format: Xiaozheng Kang, Chaoran Dong, Bocun Shen, Wanpu Yan, Liang Dai, Yongbo Yang, Hanwei Yin, Guobing Xu, Huihui Zeng, Ke-Neng Chen. Plasma thioredoxin reductase 1 as a diagnostic marker for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4643. doi:10.1158/1538-7445.AM2017-4643
Abstract 4644: A cell-line based TP53 expression pattern control panel with interobserver variability and next-generation sequencing analysis
Authors: Zhou Yaling , Raiciulescu Sorana , Syed Viqar , Malafronte Patrick , Wells Justin , Grantham Mica , Allgaeuer Michael , Gong Heping , Moncur Joel , Xing Deyin , Andersen John D. 
Published: July 2017

Abstract
Introduction: TP53 gene mutation status is known to be manifested through distinct p53 immunohistochemical staining patterns; diffuse, wild-type and null. This stratified staining pattern is routinely utilized in subtyping ovarian and endometrial cancer subtypes and distinguishing low- and high-grade serous carcinoma.
Experimental Procedure: Three ovarian cancer cell lines were used in the construction of an immunohistochemical control panel slide that highlights each respective TP53 expression pattern. Cell lines were expanded, harvested and resuspended in agarose gel and subsequently sectioned onto a microscope slide. Procured tissue specimens were submitted along with either standard control tissue or the TP53 cell line control panel to pathologists of varying experience. Next-generation sequencing analysis was performed on cases in which there was discordance in expression pattern interpretation.
Results: Interobserver variability was assessed on 44 samples between five raters of varying experience. The results were similar with the use of the TP53 expression panel (Fleiss kappa= 0.6 vs 0.53). Next-generation sequencing analysis demonstrated low-frequency variant mutations in cases in which there was reviewer discordance.
Conclusion: This study suggests the addition of a TP53 cell line expression pattern control panel could potentially increase diagnostic accuracy for ovarian and endometrial cancer subtypes and distinguishing ovarian low-grade and high-grade serous carcinoma. The cell line control has refined quality assurance potential for antibody optimization.This cell line control panel has the potential to be utilized in routine immunohistochemical staining with difficult to interpret p53 expression patterns directed to submission for next-generation sequencing.
Citation Format: Yaling Zhou, Sorana Raiciulescu, Viqar Syed, Patrick Malafronte, Justin Wells, Mica Grantham, Michael Allgaeuer, Heping Gong, Joel Moncur, Deyin Xing, John D. Andersen. A cell-line based TP53 expression pattern control panel with interobserver variability and next-generation sequencing analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4644. doi:10.1158/1538-7445.AM2017-4644
Abstract 4657: LOX and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma
Authors: Kim Minkyu , Kim Hyun-Won , Jung Soon-Hee , Oh Sung Soo , Jeong Yangsik , Choi Jong-Whan 
Published: July 2017

Abstract
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer being developed on outlayer of lung tissues and caused by mostly occupational exposure to asbestos. Poor prognosis needs to develop therapeutic drug as well as early diagnostic biomarker. Currently, mesothelin (MSLN), osteopontin (OPN), and fibulin 3 (FBLN3) have been reported as potential diagnostic biomarkers for MPM. In this study, we first performed bioinformatics analysis for public database to find diagnostic biomarkers for MPM. From the analysis using Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO) databases, included were 7 genes involving LOX, LOXL1, LOXL2, ZFPM2, THBS2, SULF1, CDH11 identified as potential diagnostic biomarkers. These genes showed a similar diagnostic ability to FBLN3 or MSLN as MPM biomarker candidates. Further molecular approach using quantitative real-time polymerase chain reaction (QPCR) confirmed the higher mRNA expression of these candidates in MPM cell lines and patient samples. Moreover, two particular genes, LOX and ZFPM, showed MPM specific patterns of mRNA expression that were further confirmed in protein level by western blot assay. Together with biological approach, biostatistical analysis of receiver operating characteristic (ROC) analysis using the GEO database revealed significantly higher diagnostic potential of LOX and ZFPM2 genes compared to the FBLN3, one of the best diagnostic biomarkers currently reported. From this study, we believe these genes together with FBLN3 and MSLN would become novel potential biomarker candidates for MPM diagnosis.
Citation Format: Minkyu Kim, Hyun-Won Kim, Soon-Hee Jung, Sung Soo Oh, Yangsik Jeong, Jong-Whan Choi. LOX and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2017-4657