bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4550: IODNE: an integrated optimization method for identifying the deregulated sub-network for precision medicine in cancer
Authors: Cheng Lijun , Inavolu Sai Mounika , Radovich Milan , Vasudevaraja Varshini 
Published: July 2017

Abstract
Background and Purpose: Sub-network analysis can explore complex patterns of the entire molecular pathways and networks for the drug target identification, and therefore drug selection. Computational algorithms are needed to optimize the sub-network search for molecular pathways and networks under certain conditions.
Materials and Methods: In the paper, the gene expression profile of a cohort breast cancer patients and protein-protein interaction (PPI) network are integrated with edge score and node score simultaneously. A novel optimization algorithm, IODNE, is developed to search for the optimal de-regulated subnetwork of merging gene and protein network. The application of IODNE is demonstrated for a sub-network of drug target selection in breast cancer subtypes Luminal-A/Luminal-B data from Cancer Genome Atlas (TCGA). Where, the PPI networks data selected from Pathway Commons.
Results: IODNE selects sub-networks, which contain ER1/PR and HER2, the well-known targets in clinic Luminal-A/Luminal-B breast cancer subtypes. This validates the utility of IODNE. When applying IODNE to the triple-negative breast cancer subtype data, we identify sub-networks that contain genes such as ERBB2, HRAS, PGR, CAD, POLE and SLC2A1.
Conclusion: Using the known drug targets in breast cancer subtypes, we demonstrate that IODNE is a robust and powerful algorithm to identify sub-networks for drug target identification. Based on the gene expression profiles and protein interaction networks, it detects the optimum deregulated subnetwork for the candidate drug target selection. The IODNE is promising tool for the precision medicine.
Citation Format: Lijun Cheng, Sai Mounika Inavolu, Milan Radovich, Varshini Vasudevaraja. IODNE: an integrated optimization method for identifying the deregulated sub-network for precision medicine in 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 4550. doi:10.1158/1538-7445.AM2017-4550
Abstract 4554: Unified theoretical algorithms for graphics dynamic multiple transformations of dose-effect relationships with computer simulation
Authors: Chou Ting-Chao 
Published: July 2017

Abstract
Based on physico-chemical principle of the mass-action law, bio-system analysis (arrangement & combinatorial) several hundred rate equations have been derived and published. Mathematical induction allows the deduction of them into the unified general median-effect equation (MEE) that makes dose & effect “interchangeable” for the 1st order and higher order dynamics. Based on the MEE plot, all dose-effect curves can be “linealized” which allows the quantitative determination of x-intercept (log Dm which signifies potency) and slope (m which signifies shape or dynamic order). Extension of MEE to multi-drug combinations resulted the combination index (CI) theorem which quantifies synergism (CI&lt;1), additive effect (CI=1), and antagonism (CI&gt;1). This unprecedented approach and multi-step logics have been summarized in [Chou TC. Pharmacol Rev 58: 621-681, 2006] which has been cited 1,261 times in 485 bio-medical journals (http://www.researcherid.com/rid/B4111-2009 as of 10.19.2016). Dose-effect curves (single & multi-drugs) can be quantitatively transformed into the MEE plot, Fa-CI plot, isobologram, Fa-DRI Plot for dose-reduction index, and when n&gt;2, the polygonogram. This presentation will illustrate of combinations (1:5) of docetaxel (TXT) with T-compound against HCT-116 colon carcinoma xenograft in nude mice. In all, only 66 nude mice have been used, i.e. TXT 3 doses, T 3 doses and TXT+T 4 doses, plus a control group, each N=6. The MEE “Linearization” allows the “Econo-Green Bio-research”, with small experimental size and small number of data points, using small number of animals. The algorithms based computer simulation using CompuSyn software can be completed within one second after the dose and effect data entries. The CompuSyn has been offered for free download upon registration via www.combosyn.com.
Note: This abstract was not presented at the meeting.
Citation Format: Ting-Chao Chou. Unified theoretical algorithms for graphics dynamic multiple transformations of dose-effect relationships with computer simulation [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 4554. doi:10.1158/1538-7445.AM2017-4554
Abstract 4563: Local and abscopal effects in oncolytic virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade
Authors: Fend Laetitia , Yamazaki Takahiro , Préville Xavier , Quéméneur Eric , Kepp Oliver , Adam Julien , Marabelle Aurélien , Pitt Jonathan , Kroemer Guido , Zitvogel Laurence 
Published: July 2017

Abstract
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We here report that an engineered oncolytic Vaccinia Virus, VVWR-TK-RR--Fcu1, is able to induce an immunogenic cell death and thus to generate a systemic immune response. Effect on tumor growth and survival is largely driven by CD8+ T-cells, and we could demonstrate that the immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T-cells to regulatory CD4+ T-cells. The key role of the type 1-IFN pathway in oncolytic virotherapy was also highlighted, and we could show a strong abscopal response in Ifnar-/- tumors. In this model, the single administration of the virus directly into the tumors, on one flank, led to regression in the contralateral flank (i.e. opposite to the virus injection site). Moreover, we observed that these effects are further enhanced when the oncolytic treatment is combined with either immunogenic chemotherapy such as oxaliplatin, or with immune checkpoint blockers such as anti-PD-1 or anti-CTLA-4. Altogether, these data suggest that local oncolytic virotherapy in patients with tumors altered in IFNAR signaling could increase immune-mediated abscopal regression of distant metastases.
Citation Format: Laetitia Fend, Takahiro Yamazaki, Xavier Préville, Eric Quéméneur, Oliver Kepp, Julien Adam, Aurélien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel. Local and abscopal effects in oncolytic virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade [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 4563. doi:10.1158/1538-7445.AM2017-4563
Abstract 4567: Immunoclassification of gastric cancer in the context of clinical outcome
Authors: Wang Weili , Liao Ping , Xie Shangchen , Shen Dongya , Zhou Chengfang , Mcleod Howard , He Yijing 
Published: July 2017

Abstract
Background: Gastric cancer (GC) plays a leading role in all cancer deaths especially in Eastern Asia. Current classifications including WHO, Lauren, and TCGA defined molecular classification have illuminated the clinicopathological characteristics or genetic profile of GC. However, these classifications were lack of association with clinical outcome and guidance for medication selection.
Objective: We aimed to identify a new immunoclassification for GC to predict patient’s prognosis and provide evidence for choosing proper medication.
Methods: Formalin-fixed and paraffin-embedded (FFPE) samples of GC were obtained along with the clinical outcome of the patient. Epstein-Barr virus (EBV) infection was measured by RT-PCR. Immune markers including CD3, CD8 and PD-L1 were measured by immunohistochemistry (IHC) at tumor infiltration area (TI) and invasive margin area (IM). The expression of PD-L1 in tumor microenvironment (TME) was assessed by immune reactive score (IRS) system. For immunoclassification, patients were classified into two subgroups: strong immunoreaction (SIR) and weak immunoreaction (WIR) defined by the number of CD8+ T cells and PD-L1 expression at TI.
Results: EBV infection was associated with the number of CD3+T cells and PD-L1 expression in TME. EBV+ patients also showed a poor overall survival (OS) compared with EBV- patients. Importantly, WIR patients lived significantly shorter than SIR patients. Moreover, patients who were treated by taxanes in WIR group had a shorter OS compared with those not using taxanes.
Conclusion: In this study, we suggest a new immunoclassification for gastric cancer which is associated with patients’ outcome and may provide a way to guide chemotherapy.
Citation Format: Weili Wang, Ping Liao, Shangchen Xie, Dongya Shen, Chengfang Zhou, Howard Mcleod, Yijing He. Immunoclassification of gastric cancer in the context of clinical outcome [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 4567. doi:10.1158/1538-7445.AM2017-4567
Abstract 4578: Does poor prognosis in African Americans with MSI-H colorectal cancer associate with altered immune markers
Authors: Golconda Umamaheshwari , Sokol Lena , Shokrani Babak , Lee Edward , Hansel Donna , Fadare Oluwole , Patel Sandip , Nouraie Mehdi , Soleimani Hooman , Sharif Zaki , Afsari Ali , Daremipouran Fareed , Brim Hassan , Ashktorab Hassan 
Published: July 2017

Abstract
BACKGROUND: Microsatellite instability high (MSI-H) of sporadic colorectal carcinomas (CRC) is usually associated with improved prognosis and a high density of tumor-infiltrating lymphocytes. However, African Americans with MSI-H have poor prognosis.
AIM: To evaluate whether or not expression of different immune and tumor markers individually or in combination in African American MSI-H CRC associate with the prognosis status.
METHODS: Tissues Microarray (TMA) were prepared by microdissection from FFPE (Formalin Fixed Paraffin Embedded) blocks of 15 MSI-H patients. Immune markers (CD8+, Granzymes, Perforins, CD4+, STAT1, IRF1 and IRF5) and PD-L1 status were analyzed by immunohistochemistry (IHC). Demography and clinical data including TNM, tumor grading (WHO standard), histological type of the tumor, date of diagnosis, date of the last follow-up examination, treatment, comorbidities, metastasis, recurrence, 5-year disease-free survival and death were collected. RESULTS: There were 4 patients with improved prognosis (27%) with relatively high CD4 density (2 with &gt;50% and 2 with 11-50%) regardless of PD-L1 status (3+/1-), stage (II,III), and other immune markers (CD8, CD4, Granzymes, Perforins, IRF1, IRF5 and STAT1). One of the improved prognosis patients with KRAS mutation has elevated expression of all considered immune markers besides CD4. There were 9 patients (6 dead, 3 alive) with poor prognosis, with different immune and tumor markers level (3 were PD-L1+ and 5 have relatively high CD4 count; but with low level of STAT1. There were also 2 patients with expected improved prognosis based on their immune markers level (stage II), however, they died within the 5 year period post-diagnosis, due to their age (98 and 87 years old).
Conclusion: MSI-H Colorectal cancer from African American patients has poor prognosis which may correlate with the nature of tumor-associated immune response. Other factors such as MSH3 defects might cancel the positive prognosis of MSI-H status. Nonetheless, low STAT1 and low CD4 may be indicators of poorer prognosis.
Citation Format: Umamaheshwari Golconda, Lena Sokol, Babak Shokrani, Edward Lee, Donna Hansel, Oluwole Fadare, Sandip Patel, Mehdi Nouraie, Hooman Soleimani, Zaki Sharif, Ali Afsari, Fareed Daremipouran, Hassan Brim, Hassan Ashktorab. Does poor prognosis in African Americans with MSI-H colorectal cancer associate with altered immune markers [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 4578. doi:10.1158/1538-7445.AM2017-4578
Abstract 458: Choline metabolism in cancer cells modifies PD-L1 expression
Authors: Krishnamachary Balaji , Penet Marie-France , Mironchik Yelena , Bhujwalla Zaver M. 
Published: July 2017

Abstract
Increased expression of choline kinase-α (Chk-α), the enzyme that converts choline to phosphocholine has been observed in most cancer cells including breast (1). This increase of choline kinase results in increased production of phosphocholine that is used in the synthesis of membrane phosphatidylcholine. We investigated the relationship between Chk-α and the programmed death ligand-1 (PD-L1) expression in triple negative MDA-MB-231 human breast cancer cells. Expression of PD-L1 in response to the secretion of interferon gamma (IFNγ) by cytotoxic T cells and its binding to the immune checkpoint PD-1 on T cells results in cancer cells escaping destruction by the immune system (2). Quantitative real-time PCR analysis (q-RT-PCR) did not reveal any change in PD-L1 mRNA expression between MDA-MB-231 expressing an empty vector control plasmid (231-EV) and MDA-MB-23 stably expressing shRNA against Chk (231-Chk). However, there was a difference in the mean intensity fluorescence (MIF) between 231-EV (325 ±11.5, n=2) and 231-Chk (527±18.5, n=2) in the FACS analysis. Upon induction with IFNγ (10ng/ml) for 24h, there was 1.23 fold increase in PD-L1 mRNA in 231-Chk compared to 231-EV. Interestingly, the MIP for cell surface expression of PD-L1 was 600±21 (n=2) for 231-EV compared to 872±16 (n=2) for 231-Chk cells. Values represent mean + SE. These data suggest that the cell surface increase of PD-L1 in 231-Chk cells could be due to translocation. Increased PD-L1 expression creates an opportunity to deliver PD-L1 targeted nanoparticles carrying therapeutic cargo. Since most conventional treatments result in a decrease of Chk-α and phosphocholine, our data suggest that these treatments may also result in cancer cells escaping immune surveillance through expression of PD-L1.
Acknowledgements: This work was supported by NIH R01CA136576 and P50 CA103175.
Reference: 1) Glunde K et al, Cancer Res 65, 11034 (2005)., 2) Zou W, Chen L, Nat Rev Immunol 8(6), 467-77 (2008).
Citation Format: Balaji Krishnamachary, Marie-France Penet, Yelena Mironchik, Zaver M. Bhujwalla. Choline metabolism in cancer cells modifies PD-L1 expression [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 458. doi:10.1158/1538-7445.AM2017-458
Abstract 4606: Preclinical characterization of a novel fully human IgG1 anti-PD-L1 mAb CK-301
Authors: Gorelik Leonid , Avgerinos George , Kunes Yune , Marasco Wayne A. 
Published: July 2017

Abstract
Antibodies targeting Programmed Death-1 (PD-1), or its ligand, PD-L1, have demonstrated remarkable efficacy in subsets of cancer patients, with inhibition of the interaction between PD-1 on T-cells and PD-L1 on tumor cells leading to the recovery of anti-tumor immune response and immune-mediated eradication of tumors. However, not all patients respond to existing PD-1 and PD-L1 targeting agents and relapses to therapy still occur. Therefore, there exists a need to identify additional therapeutics and approaches to engage the immune system to enhance the efficacy of current anticancer therapies. Using phage and yeast display approaches, we have discovered and optimized a novel, fully human, PD-L1 specific IgG1 antibody, CK-301, which exhibits subnanomolar binding affinity for PD-L1. CK-301 blocks binding of PD-L1 to both PD-1 and B7-1 in enzyme-linked immunosorbent assays (ELISA) and cell-based competition assays. Using an assay measuring inhibition of a nuclear factor of activated T-cells (NFAT) reporter caused by PD-L1 binding to PD-1, we demonstrate that CK-301 completely reverses reporter inhibition at concentration of less than 1 µg/ml, IC50 of the dose response curve is 80ng/ml. CK-301 enhances IFN-gamma secretion in allogeneic mixed lymphocyte reaction (MLR) using primary human T-cells and immature dendritic cells. CK-301 can also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) mediated killing of PD-L1+ cell lines, including lymphoma cells. CK-301 has similar subnanomolar affinity for cynomolgus monkey PD-L1 as for human PD-L1, hence we chose Macaca fascicularis for pre-clinical toxicology and safety pharmacology studies. Single-dose administration of CK-301 to monkeys up to the highest tested dose of 100 mg/kg was shown to be safe and demonstrated linear dose-dependent pharmacokinetic (PK) properties over the dose range from 1 to 100 mg/kg with a half-life of 15 days at 100 mg/kg. A first-in-human Phase 1 study of CK-301 is planned to commence in mid-2017.
Citation Format: Leonid Gorelik, George Avgerinos, Yune Kunes, Wayne A. Marasco. Preclinical characterization of a novel fully human IgG1 anti-PD-L1 mAb CK-301 [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 4606. doi:10.1158/1538-7445.AM2017-4606
Abstract 4612: Development and validation of a screening platform for the identification of novel immuno-oncology targets
Authors: Scoumanne Ariane , Rabolli Virginie , Legrand Lea , Martini Murielle , Letellier marie-claire , Crosignani Stefano , Quéva Christophe , Detheux Michel , Cauwenberghs Sandra , Swiercz Jakub 
Published: July 2017

Abstract
Although immune therapy of cancer, including immune-checkpoint blockade have demonstrated therapeutic benefit in patients with various advanced cancers, further understanding of human immune pathology triggered by the tumor microenvironment, is essential to improve these therapeutic approaches.
In order to shed light on novel immune suppressive mechanisms in tumor, iTeos Therapeutics developed a target discovery and drug repurposing platform based on phenotypic screening assays. We established a co-culture assay combining tumor immune suppressive cells and T-cells. This assay is flexible to allow the screening of chemicogenomics, shRNA and cDNA libraries. Multi-parameter readouts are combined to assess both T cell activation and proliferation, through high content imaging of T cell clusters formation, complemented with detection of IFNγ secretion and tumor cell death, as assessed using a cytotoxicity assay. The 96-well format of the assay allows medium-throughput testing of up to 3000 samples/screen. From the technical point of view we were able to adapt the assay to low level of automation, making it affordable to the biotech start-ups and academic laboratories.
As a proof-of-concept we evaluated the assay for its ability to detect metabolic immune-oncology targets in A549 cells, a lung cancer immune suppressive cell line. A549 express indoleamine-2,3-dioxygenase 1 (IDO1), an enzyme expressed in many cancers that mediates local T-cell suppression through depleting the essential amino acid tryptophan. The assay conditions were validated with an IDO1 inhibitor as positive control and subsequently scaled up for automation. A commercially available small molecule library of 1900 compounds, with a high percentage of clinically tested drugs was screened. The library was tested at two different concentrations (0.3μM and 3μM), with two independent T-cell donors and spiked with IDO1 inhibitor as control. Combined analysis of T-cell activity and tumor killing led to the identification of 42 compounds with activity on multiple, potential immune suppressive pathways, including metabolism, epigenetics, autophagy, TGFβ, Wnt/β-catenin and TNFα/NF-κB signaling.
Citation Format: Ariane Scoumanne, Virginie Rabolli, Lea Legrand, Murielle Martini, marie-claire Letellier, Stefano Crosignani, Christophe Quéva, Michel Detheux, Sandra Cauwenberghs, Jakub Swiercz. Development and validation of a screening platform for the identification of novel immuno-oncology targets [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 4612. doi:10.1158/1538-7445.AM2017-4612
Abstract 4613: Cytotoxicity of selenium trastuzumab and bevacizumab immunoconjugates against triple negative breast cancer cells
Authors: Khandelwal Soni , Gollahon Lauren , Spallholz Julian , Boylan Mallory , Garcia-Hernandez Maria Del Mar 
Published: July 2017

Abstract
Breast cancer (BC) is the second leading cause of death among women with an estimated 246,660 new cases of invasive breast cancer expected to be diagnosed this year. Of the different subtypes, 15-20% are classified as triple negative breast cancer (TNBC) because they lack three key receptors; progesterone, estrogen and HER2. These receptors are considered essential for “targeted therapies”. Thus, systemic chemotherapy is the only TNBC drug treatment option. In this study, two clinical monoclonal antibodies; Herceptin® and Avastin® were covalently labeled with redox selenium and used to treat two TNBC cell lines (MDA-MB-231 and MDA-MB-468) in culture. TNBC cell lines were treated with vehicle control, increasing concentrations of selenium as Selenite (ranging from 2 to 20 µg); Se-Herceptin® or Se-Avastin® and compared to native antibodies with equal concentrations of protein. Cell counts and viability were analyzed using Beckman ViCell Counter and Trypan Blue exclusion over a seven day period. Selenite, Se-Avastin® and Se-Herceptin® were observed to be more cytotoxic over dose and time to both TNBC cell lines in comparison to control cells and cells treated with native antibodies alone. Morphological changes were observed under phase contrast microscopy in all selenium treated cell lines. In contrast, visible alterations in morphology were absent in native Herceptin® and Avastin® treated cells compared to control cells. We believe this is the first report of selenium Antibody-Drug Conjugates (ADCs) being demonstrated as cytotoxic to these TNBC cell lines, suggesting a potential strategy to design more effective treatments of TNBC resistant to chemotherapy.
Citation Format: Soni Khandelwal, Lauren Gollahon, Julian Spallholz, Mallory Boylan, Maria Del Mar Garcia-Hernandez. Cytotoxicity of selenium trastuzumab and bevacizumab immunoconjugates against triple negative breast cancer cells [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 4613. doi:10.1158/1538-7445.AM2017-4613