bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2191: Imaging the kinetics of targeted nanoparticles to pancreatic cancer
Authors: Moreno Jonathan , Fei Qin qin , Lambros Maria P. 
Published: July 2016

Abstract
Purpose: The purpose of this work is to image the kinetics of targeted lipid nanoparticles to an SCL transporter of pancreatic cancer using a near infrared (NIR) fluorescent dye DyLight® 747 and a mouse orthotopic model of fluorescent pancreatic cancer.
Methods: Initially and before the in vivo experiments, the uptake of nanoparticles by human pancreatic cancer cells was evaluated in vitro using fluorescent microscopy and flow cytometry. A quantity of 1.5 x105 PANC-1, MIA PaCa, or BxPC-3 cells/ml was placed in each well of a six-well plate and incubated for 5 hours with different formulations of fluorescent lipid targeted and non-targeted nanoparticles encapsulation daunorubicin which has natural fluorescence. After incubation, the growth media were removed and the cells were washed with PBS. The uptake of the fluorescent lipid nanoparticles by the cancer cells was evaluated an EVOS® microscope. All the in vitro experiments were done in triplicate. For the in vivo targeting studies, nude mice (Balb/c Ola Hsd-Fox1 nu) were implanted orthotopically (in the tail of the pancreas) with 3 x106 PANC-1 cells expressing GFP. The injection volume for the implantation was 50 microliters and contained 3 x106 PANC-1-GFP cells mixed with serum free media and HC Matrigel (1:1). One month after the orthotopic implantation, the implanted pancreatic tumor was visualized in live, anesthetized animals using UVP Scientia (UVP, Upland, CA). The animals were separated into three groups (three animals in each group) and injected via the tail vein as follows: Group A, was injected with only the fluorescent dye, Dylight 747; group B was injected with fluorescent non-targeted nanoparticles; and group C was injected with fluorescent targeted nanoparticles.
Results: Both the flow cytometry and fluorescence microscopy data show a significantly higher uptake of the targeted lipid nanoparticles compared to the non-targeted ones. The imaging of the fluorescent lipid nanoparticles in live mice shows that both targeted and nontargeted nanoparticles reach the pancreatic tumor. The nontargeted nanoparticles reside less than 48 hours on the tumor, whereas the targeted nanoparticles can reside for 96 hours on the tumor. The non-encapsulated fluorescent dye did not reach the tumor and was excreted in the urine.
Conclusion: The results show that Dylight® 747 can be used to image the kinetics of a drug delivery system in a live animal. Furthermore while both lipid nanoparticles reach the tumor, the targeted lipid nanoparticles reside significantly longer on the tumor and this may translate to a better therapeutic outcome.
Citation Format: Jonathan Moreno, Qin qin Fei, Maria P. Lambros. Imaging the kinetics of targeted nanoparticles to pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2191.
Abstract 2199: TLR3-induced immune response using PLGA nanoparticles for dendritic cell-based cancer immunotherapy
Authors: HAN. HEEDONG 
Published: July 2016

Abstract
Dendritic cells (DCs) are potent professional antigen presenting cells (APCs) capable of initiating a primary immune response and activating T cells, and they play a pivotal role in host immune responses to cancer. Prior to antigen presentation, efficient antigen and adjuvant uptake by DCs is necessary to induce their maturation and cytokine generation. Nanoparticles (NPs) are capable of intracellular delivery of both antigen and adjuvant to DCs. Here, we developed an advanced poly(lactic-co-glycolic acid) (PLGA)-NP encapsulating both ovalbumin (OVA) as model antigen and poly I:C as adjuvant to increase intracellular delivery, and promote DC maturation. These NPs were taken up by mouse primary DCs and their uptake greatly facilitated MHC class I antigen presentation in vitro. Moreover, vaccination with PLGA-NP treated DCs led to the generation of OVA-specific CD8+ T cells, and the resulting antitumor efficacy was significantly increased in EG.7 tumor-bearing mice compared to control (p &lt; 0.01). Taken together, we demonstrate that this PLGA-NP platform may be an effective method for delivering tumor-specific antigens or adjuvant to DCs.
Citation Format: HEEDONG HAN. TLR3-induced immune response using PLGA nanoparticles for dendritic cell-based cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2199.
Abstract 2215: Pembrolizumab and ipilimumab reduce human RKO colon carcinoma tumor growth in HLA matched CD34-NSG humanized mice
Authors: Lasaro Marcio , Davis Jason M. , Ellison Mark , Graf Martin R. , Mahajan Vivek , Synnott Aidan , Mullin Robert J. , Miliani De Marval. Paula L. 
Published: July 2016

Abstract
Over the past decade there has been an increasing demand for preclinical models useful for evaluating the efficacy of checkpoint inhibition-based cancer immunotherapies. The recently developed humanized mouse models composed of various types of human immune cells has the potential to recapitulate the human anti-tumor response modulated by checkpoint inhibitors. Tumor cells may develop multiple mechanisms to evade immune surveillance, including PD-L1 upregulation which suppresses T-cell effector responses towards the tumor. In the present study, we evaluated the efficacy of the checkpoint inhibitors pembrolizumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in the human RKO colon carcinoma xenograft model in CD34-NSG humanized mice. These mice were engrafted with human hematopoietic stem cells (HSC) that matched the HLA haplotype of the RKO cells (HLA-A*01). Flow cytometry analysis confirmed high level of expression of PD-L1 in RKO colon carcinoma cells. The results from this study revealed that pembrolizumab and ipilimumab monotherapies significantly inhibited tumor growth. Surprisingly, combination therapy did not provide additive or synergistic effects and resulted in the same level of efficacy as the individual regimens. In order to understand the impact of these therapies on distinct immune cell populations, we analyzed the distribution of CD4 and CD8 T lymphocytes, Treg cells, NK cells and B cells in peripheral blood, spleen and tumor samples from tumor bearing humanized mice, via flow cytometry. We found that these checkpoint inhibitors can enhance effector functions of CD4+ and CD8+ T cells associated with increased expression of IFN-Γ. A parallel study with these checkpoint inhibitors carried out with humanized mice engrafted with HSC of the same haplotype as the RKO cells but from a different donor resulted in identical anti-tumor efficacy. In summary, these studies validate the use of humanized mouse models to test the tumor response to immune-checkpoint based therapies as it shows significant anti-tumor growth as a result of pembrolizumab and ipilimumab monotherapies associated with activation of T lymphocytes.
Citation Format: Marcio Lasaro, Jason M. Davis, Mark Ellison, Martin R. Graf, Vivek Mahajan, Aidan Synnott, Robert J. Mullin, Paula L. Miliani De Marval. Pembrolizumab and ipilimumab reduce human RKO colon carcinoma tumor growth in HLA matched CD34-NSG humanized mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2215.
Abstract 2226: Anti-human PD-1 antibody BGB-A317 exhibits potent immune cell activation
Authors: Zhang Tong , Song Jing , Li Yucheng , Ma Jie , Shi Yingdi , Wu Xiaoran , Xu Lanlan , Liu Qi , Cao Yanping , Wang Yali , Peng Hao , Hou Hongjia , Zhao Xu , Song Xiaomin , Wang Lai , Wei Min , Luo Lusong , Li Kang 
Published: July 2016

Abstract
Background: PD-1 is a “check point” inhibitory receptor, which is primarily expressed in activated and/or exhausted T cells. Engagement of PD-1 receptor by its ligand PD-L1 or PD-L2 (expressed on APCs and some tumor cells), leads to negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A317 is a novel humanized IgG4 anti-PD-1 antibody under clinical development. The immunomodulatory activity of BGB-A317 was evaluated in in vitro assays and reported here.
Materials and methods: BGB-A317 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc and hinge regions of BGB-A317 were engineered to remove Fc gamma receptor (FcγR) binding and to stabilize the hinge region. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A317 were evaluated using both T-cell lines and primary immune cells.
Results: BGB-A317 binds to the extracellular domain of human PD-1 with high affinity (KD = 0.15nM) and specificity. In competition assays, BGB-A317 efficiently blocks the interactions between PD-1 and its ligands. In vitro cell-based assays, BGB-A317 significantly enhances cytokine (IL-2 and IFN-γ) production using T-cell line or primary T cells cocultured with signal-sending cells in a dose-dependent manner. BGB-A317 also potently increases NK cell-mediated IFN-γ production and cytotoxicity against PD-L1+ tumor cells. As an important functional attribute, BGB-A317 exhibits no binding to any of FcγRs, including FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA. Therefore, no antibody-dependent cell-mediated (ADCC) or complement-dependent cytotoxicity (CDC) has been observed in activated T cells treated with high concentration of BGB-A317 up to 100 μg/ml. BGB-A317 is stable as bivalent antibody unlike the wild type human IgG4 going through dynamic conformational change, forming bispecific antibody by Fab-arm exchange.
Conclusions: BGB-A317 demonstrated potent immune cell activation in in vitro assays, supporting its clinical development for the treatment of human cancers.
Keywords: Anti-PD-1, immunotherapy, functional assays
Citation Format: Tong Zhang, Jing Song, Yucheng Li, Jie Ma, Yingdi Shi, Xiaoran Wu, Lanlan Xu, Qi Liu, Yanping Cao, Yali Wang, Hao Peng, Hongjia Hou, Xu Zhao, Xiaomin Song, Lai Wang, Min Wei, Lusong Luo, Kang Li. Anti-human PD-1 antibody BGB-A317 exhibits potent immune cell activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2226.
Abstract 223: Comparison of human-specific versus cross-reactive Complex I inhibitor for in vivo tumor efficacy
Authors: Christian Sven , Algire Carolyn , Schwede Wolfgang , Mowat Jeffrey S. , Ehrmann Alexander , Menz Stephan , Bauser Marcus , Haegebarth Andrea 
Published: July 2016

Abstract
Mitochondria are both key regulators of energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC (Complex I to IV) pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, compared to cells that do not have these mutations. We have identified an optimized human/mouse cross-reactive Complex I inhibitor that allows profiling of Complex I inhibitors in pharmacological models. We have pursued different approaches based on the literature, an unbiased screen and in-house results generated with the human-specific Complex I inhibitor BAY 872243 to identify sensitive in vivo tumor models. However, using the cross-reactive Complex I inhibitor we were unable to identify sensitive models apart from weakly sensitive LKB1-deficient tumors (A549, G361) when animals were treated at maximum tolerated dose (MTD). In addition, all approaches for combination therapy failed to improve efficacy in vivo. Direct comparison of human-specific Complex I inhibitor BAY 87-2243 and cross-reactive inhibitor BAY179 in a sensitive LKB1-deficient melanoma model, G361, demonstrated that inhibition of Complex I specifically in the tumor is a valid approach as it results in tumor growth inhibition of ∼50%. However, cross-reactive compounds do not reach exposures at MTD to generate comparable effects.
Citation Format: Sven Christian, Carolyn Algire, Wolfgang Schwede, Jeffrey S. Mowat, Alexander Ehrmann, Stephan Menz, Marcus Bauser, Andrea Haegebarth. Comparison of human-specific versus cross-reactive Complex I inhibitor for in vivo tumor efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 223.
Abstract 2230: Evaluation of PD-L1 expression in ovarian carcinosarcoma by immunohistochemistry and RNAscope in-situ hybridization
Authors: Liang Li , Chen Jun-Song , Jiang Yi , Niu Na , Zhang Connie , Park Emily , Ma Xiao-Jun , Liu Jinsong 
Published: July 2016

Abstract
Ovarian carcinosarcoma, also called malignant Müllerian mixed tumor, is a rare, but very aggressive biphasic tumor with both malignant epithelial and stromal components. PD-L1 is one of the ligands of immune inhibitory receptor PD-1. PD-L1/PD-1 pathway suppresses T cell immune response, increases programmed cell death of activated T cells and plays an important role in tumor immune escape. Anti-PD-L1 immunotherapy has shown promising results in certain malignancies, such as melanoma and lung cancer. Therefore, we performed PD-L1 immunohistochemical staining on 30 specimens of ovarian carcinosarcoma collected from patients that underwent surgeries at our institution between 2002 and 2015. In addition, we performed RNAscope in-situ hybridization to examine PD-L1 mRNA expression in 16 specimens that were collected within past 5 years (2010-2015). Our result demonstrated focally membranous expression of PD-L1 protein in 23 of 30 cases (77%). PD-L1 mRNA expression correlated with membranous, but not cytoplasmic expression of PD-L1 protein. In conclusion, PD-L1 protein and mRNA are frequently expressed in ovarian carcinosarcoma, suggesting anti-PD-L1 immunotherapy may be helpful in these patients.
Citation Format: Li Liang, Jun-Song Chen, Yi Jiang, Na Niu, Connie Zhang, Emily Park, Xiao-Jun Ma, Jinsong Liu. Evaluation of PD-L1 expression in ovarian carcinosarcoma by immunohistochemistry and RNAscope in-situ hybridization. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2230.
Abstract 2231: IO125 is a potent inducer of tumor immunogenicity
Authors: Mylavarapu Sanghamitra , Kaushik Shelly , Yadav Yashpal , Roy Monideepa , Sengupta Aniruddha , Sengupta Shiladitya 
Published: July 2016

Abstract
Combinatorial treatments with chemotherapeutics and immunotherapies are currently being investigated in several cancers. Chemotherapeutics can increase the immunogenicity of tumors besides modulating the immune system. Here we describe the development of a novel platinum-based therapeutic, IO-125, which assembles into stable nanoscale supramolecular structures. IO125 demonstrates enhanced activity compared with standard Pt drug across cancer lines. IO-125 preferentially targets tumors in vivo, and demonstrated improved efficacy in triple negative breast cancer (4T1), Lewis lung carcinoma (LLC) and melanoma (B16/F10) tumor models. Treatment with IO-125 elevates expression of immune-markers (including IGKC, PD-L1, PD-1, CD8A), which are associated with good prognosis. In addition, combinatorial treatment with IO-125 and antibody against immune checkpoint inhibitor(s) resulted in superior antitumor efficacy compared to treatment with antibody alone. This study shows that supramolecular therapeutics, especially IO125, can emerge as a novel approach to focally modulate the tumor immune contexture.
Citation Format: Sanghamitra Mylavarapu, Shelly Kaushik, Yashpal Yadav, Monideepa Roy, Aniruddha Sengupta, Shiladitya Sengupta. IO125 is a potent inducer of tumor immunogenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2231.
Abstract 2238: Understanding immune phenotypes and their spatial relationships to breast adenocarcinoma in FFPE tissues
Authors: Zheng Yi , Thuse Pallavi , Liu Linying , Stack Edward C. , Campisano Michael , Johnson Kent , Unfricht Darryn , Narayanan Nara , Hoyt Clifford , Rajopadhye Milind 
Published: July 2016

Abstract
The relationship between elements of the immune system and breast tumors in situ requires an approach that leverages multiplexed immunohistochemistry (mIHC) with multispectral imaging to facilitate precise image analyses. To achieve this, we developed a novel 7-color mIHC assay, based on tyramide signal amplification, that allowed us to reliably interrogate CD3, CD4, CD8, FoxP3, CD68, and cytokeratin, in formalin-fixed, paraffin-embedded (FFPE) samples of human breast cancer. Imaging was performed using the multispectral Mantra system and inForm image analysis software. Using this specific mIHC panel and the cell segmenting and phenotyping tools in inForm, we were able to reliably identify cytotoxic T cells (CD3+ CD8+), helper T cells (CD3+ CD4+), regulatory T cells (CD3+ CD4+ FoxP3+), tumor associated macrophages (CD68+) and breast tumor cells (CK+). With cell phenotypes within the tumor microenvironment determined based on specific colocalized staining combinations, we then employed spatial point pattern analyses to examine spatial relationships between specific phenotypes. With this analysis, we were able to describe distances between cytotoxic T cells and regulatory T cells, cytotoxic T cells and tumor associated macrophages, as well as cytotoxic T cells and breast tumor cells. With this combined mIHC, multispectral imaging and advanced image analysis, we demonstrate a novel method that allows for unique tumor microenvironment assessments within in breast cancer. Through the preservation of tumor architecture available in archival FFPE tissues, these methods can advance our understanding of unique tumor microenvironment interactions, and could provide the ability to stratify responses to immunotherapies.
Citation Format: Yi Zheng, Pallavi Thuse, Linying Liu, Edward C. Stack, Michael Campisano, Kent Johnson, Darryn Unfricht, Nara Narayanan, Clifford Hoyt, Milind Rajopadhye. Understanding immune phenotypes and their spatial relationships to breast adenocarcinoma in FFPE tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2238.
Abstract 224: The role of the microphthalmia associated transcription factor in autophagy regulation in melanoma
Authors: Moller Katrin , Sigurbjornsdottir Sara , Dilixiati Remina , Brynjolfsdottir Solveig H. , Larue Lionel , Thorsson Vesteinn , Steingrimsson Eirikur , Ogmundsdottir Margret H. 
Published: July 2016

Abstract
Autophagy is considered a therapeutic target in various cancer types, including melanoma. The transcription factors TFEB and TFE3 have been shown to play a key role in autophagy regulation in various cell types by affecting gene expression required for this process. A close relative to these factors is the transcription factor MITF; often termed the master regulator of melanocyte development and function. MITF activity has also been shown to be important for various stages of melanoma formation and progression.
Analysis of The Cancer Genome Atlas expression data from melanoma tumors reveals that MITF expression correlates with lysosomal and autophagy gene expression in metastatic tumors. Furthermore, analysis of expression data from 23 melanoma cell lines shows that MITF expression correlates with lysosomal and autophagy gene expression, and the analysis of available MITF ChIP sequencing data shows that MITF binds the promoters of lysosomal and autophagy genes. This binding was experimentally verified by ChIP experiments in 501Mel melanoma cells. MITF over-expression and knock down experiments show effects of MITF on lysosomal and autophagy gene expression, as well as an effect on the autophagy activity.
Autophagy is high in melanoma and has been linked to tolerance against cancer treatment. We have found that MITF regulates autophagy genes and activity in melanoma cell lines. In light of both MITF and autophagy being considered a therapeutic target in melanoma, this relationship needs to be taken into consideration.
Citation Format: Katrin Moller, Sara Sigurbjornsdottir, Remina Dilixiati, Solveig H. Brynjolfsdottir, Lionel Larue, Vesteinn Thorsson, Eirikur Steingrimsson, Margret H. Ogmundsdottir. The role of the microphthalmia associated transcription factor in autophagy regulation in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 224.