bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5460: Detecting somatic DNA copy number differences with cyclic shift testing
Authors: Walter Vonn , Choi Hyo Young , Zhao Xiaobei , Zevallos Jose , Hayes D. Neil 
Published: September 2020

Abstract
The most basic differential expression analysis involves the identification of genes that exhibit distinct expression patterns in two cohorts. Surprisingly, even though there are numerous computational methods for detecting and assessing the statistical significance of somatic DNA copy number (CN) gains and losses in a single cohort, there are no tools for detecting and assessing the statistical significance of CN differences between two cohorts. Instead, typically each cohort is analyzed separately and distinct findings are presented as evidence of CN differences.
Cyclic shift testing was originally introduced as a method to identify and assess the statistical significance of recurrent somatic CN gains and losses. Subsequent work explored theoretical statistical underpinnings of cyclic shift testing. Here we extend the previous results by showing that cyclic shift testing can be applied to detect and assess the statistical significance of CN differences between two cohorts.
Human papilloma virus (HPV) infection is a risk factor for head and neck squamous cell carcinoma (HNSC), and it is known that HPV+ and HPV- HNSC have distinct mutational and gene expression profiles. We apply cyclic shift testing to detect and assess the statistical significance of CN differences between HPV+ and HPV- HNSC using data from The Cancer Genome Atlas HNSC cohort. Our approach detects statistically significant CN differences in regions that are known to contain HNSC drivers (7p, 9p21, 11q13, 11q14-qter), as well as regions of chr14, chr16, and others that are less well characterized.
Citation Format: Vonn Walter, Hyo Young Choi, Xiaobei Zhao, Jose Zevallos, D. Neil Hayes. Detecting somatic DNA copy number differences with cyclic shift testing [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 5460.
Abstract 5493: Mathematical modeling of antibody nanoconjugates transport quantifies the impact of the tumor microenvironment on drug penetration
Authors: Vaghi Cristina , Rodallec Anne , Sicard Guillaume , Correard Florian , Fanciullino Raphaelle , Ciccolini Joseph , Poignard Clair , Benzekry Sebastien 
Published: September 2020

Abstract
One of the major challenges in breast cancer treatment is the high toxicity associated with cytotoxic agents. To overcome this issue, we developed nanoparticles conjugated with cancer cell specific antibodies (trastuzumab) to improve drug delivery to the tumor, while sparing healthy tissues. These antibody nano-conjugates (ANCs) consist in docetaxel-encapsulated liposomes engrafted with trastuzumab on the surface. Intra-tumor penetration properties of these ANCs are not fully understood and could be improved. To this end, mathematical modeling can provide quantitative tools to obtain a description of the ANCs transport inside a tumor. Few models in literature characterize the nanoparticle penetration in tumors. We derived a multi-scale model to obtain a description of the fluid flow and nanoparticle transport in the tumor interstitium and vessels. Moreover, there is a lack of studies that integrate spatial data to theoretical models. Here, we aim at filling this gap.
Experimental data - carried on human MDA-MB-231 xenografts - included ex-vivo microscopy images of tumor sections obtained from different regions of the tumor (central and peripheral) using fluorescence imaging. This data allowed to recover the tumor microstucture. Our multi-scale model consisted of two Darcy equations for the fluid flow and two convection-diffusion equations governing the ANCs penetration, including the porosity of the medium. Eventually, our model was calibrated with the ex-vivo imaging data.
Simulations confirmed that the tumor microsctructure influences the macroscale flow dynamics and ANC delivery in the tumor interstitium. The model also provides quantitative predictions of the impact of the tumor microenvironment (e.g., heterogeneity, vessel leakage and interstitium permeability) on the accumulation and penetration of ANCs. This methodology could be further applied to personalize the dose of injected nanoparticles according to a patient's specific tumor histology.
Citation Format: Cristina Vaghi, Anne Rodallec, Guillaume Sicard, Florian Correard, Raphaelle Fanciullino, Joseph Ciccolini, Clair Poignard, Sebastien Benzekry. Mathematical modeling of antibody nanoconjugates transport quantifies the impact of the tumor microenvironment on drug penetration [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 5493.
Abstract 5544: Newcastle Disease Virus in human derived tumors: Understanding immune recruitment and activation via virally delivered IL-12
Authors: Durham Nicholas M. , McGlinchey Kelly , Burke Shannon , Creasy Todd , Rath Nicola , Monks Noel , Tammali Ravinder , Schifferli Kevin , Holoweckyj Nick , Hayes Susie , Jones Emma , Kelly Elizabeth J. , Carroll Danielle , Harper James , Streicher Katie 
Published: September 2020

Abstract
Oncolytic viruses (OV) are defined by their intrinsic or engineered tropism for tumor cells. Understanding the drivers of susceptibility to infection as well as the downstream intracellular signaling and immune activation profile is critical in identifying the patients that will respond to OV therapy. Newcastle Disease Virus (NDV) is a negative stranded RNA avian paramyxovirus, here modified to encode human GM-CSF or IL-12. Patient derived xenografts (PDX) can more accurately reflect the genetic, epigenetic, and architectural heterogeneity of human tumors and were therefore selected to model the in vivo activity of NDV:GM-CSF. Eighty-nine independent models derived from patients with Bladder, Colorectal, Head and Neck, Kidney, Liver, Lung, Ovarian, Pancreatic, and Breast tumors were studied. Mice were dosed intravenously with NDV:GM-CSF, monitored for pharmacodynamic and pharmacokinetic changes 48 hours after the first dose, and followed for tumor growth inhibition. Objective response was observed in 68% of treated mice, with responses observed in all indications. Using total stranded RNAseq, we were able to assess changes in human tumor, murine immune infiltrate, and viral RNA. Results showed that NDV:GM-CSF treatment leads to increases in transcripts of inflammatory chemokines and cytokines such as RANTES and CXCL9, with induction directly correlated to level of viral replication. Additionally, we saw increases in NKp46 and IL-12R, markers of NK cells. To assess if IL-12 would augment immune activation, we treated surgically resected human tumors with NDV:IL-12. NDV:IL-12 was capable of infecting tumor cells, generating IL-12 protein, and driving a strong IFNγ response. Here we show that NDV can infect a wide variety of human tumors across multiple indications and drive a potent immune activation which can be modulated by transgenes. This data provides insight into what types of tumors could be treated with NDV:GM-CSF or NDV:IL-12.
Citation Format: Nicholas M. Durham, Kelly McGlinchey, Shannon Burke, Todd Creasy, Nicola Rath, Noel Monks, Ravinder Tammali, Kevin Schifferli, Nick Holoweckyj, Susie Hayes, Emma Jones, Elizabeth J. Kelly, Danielle Carroll, James Harper, Katie Streicher. Newcastle Disease Virus in human derived tumors: Understanding immune recruitment and activation via virally delivered IL-12 [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 5544.
Abstract 5545: Neutralization of interleukin-10 by genetically engineered macrophages increase cancer cell death in metastatic colorectal cancer
Authors: Labadie Kevin P. , Kreuser Shannon A. , Brempelis Katherine J. , Jiang Xiuyun , Daniel Sara K. , Crane Courtney A. , Pillarisetty Venu G. 
Published: September 2020

Abstract
Background
Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits innate and adaptive antitumor immune responses in the tumor microenvironment (TME). Antibody neutralization of IL-10 in organotypic tumor slice cultures (TSC) in colorectal cancer liver metastases (CRCLM) leads to cancer cell death through. To target IL-10 blockade to the TME, we genetically engineered macrophages (GEM) to produce an IL-10 neutralizing antibody which we hypothesized would reactivate tumor infiltrating immune cells and increase cancer cell death in TSC.
Methods
We created a lentiviral construct to transduce GEMs with a publicly available neutralizing IL-10 antibody sequence (BT-063). CD14+ monocytes were isolated from healthy donor peripheral blood mononuclear cells and differentiated into macrophages, which were transduced with lentivirus to create control (cGEMs) and anti-IL-10 GEMs (αIL10 GEMs). To test the efficacy of αIL10 GEMs, punch biopsies (6 mm) were obtained from resected CRCLM, sliced to 250 um thickness with a vibratome and placed in individual culture wells. Slices were treated in triplicates with either 20ug/mL of human monoclonal αIL10 (αIL10), 1e5 cGEMs or αIL10 GEMs + 20ug/mL αIL10. GEMs and tumor cells were visualized with a Leica SP8X confocal microscope and apoptosis was measured with SR-FLICA fluorescent poly-caspase assay kit. Supernatant interferon-gamma (IFN-γ) levels were measured with Bioplex immunoassay and IL-10 neutralizing antibody was quantified with an enzyme-linked immunosorbent assay.
Results
Allogenic GEMs were transduced with BT-063-T2A-CD19t at 31% efficiency. cGEMs and αIL10 GEMs persisted in tumor slice culture for at least 6 days. αIL10 GEM-treated slice cultures contained 6.6ng/mL and 6.5ng/mL of αIL10 antibody after 3 and 6 days, respectively. At day 6 in culture, cancer cell apoptosis was increased in the αIL10 treated groups with 7%, 15%, 25%, 31% and 39% of cells were apoptotic in the no treatment control, cGEM, αIL10, cGEM + αIL10 and αIL10 GEM groups, respectively (One-way ANOVA, p = 0.0004). Elevation in IFN-γ was observed on day 6 in slices treated cGEMs (7.2ng/mL+4.3) and αIL10 GEMs (9.2ng/mL+5) compared to isotype control.
Conclusion
GEMs transduced with lentivirus encoding IL-10 neutralizing antibody maintain its production and are associated with increased cancer cell apoptosis.
Citation Format: Kevin P. Labadie, Shannon A. Kreuser, Katherine J. Brempelis, Xiuyun Jiang, Sara K. Daniel, Courtney A. Crane, Venu G. Pillarisetty. Neutralization of interleukin-10 by genetically engineered macrophages increase cancer cell death in metastatic colorectal 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 5545.
Abstract 5565: Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 therapy
Authors: Falo Louis D. 
Published: September 2020

Abstract
Despite the remarkable treatment benefits associated with interventional checkpoint blockade for solid tumors, many patients ultimately progress on therapy. The development of novel strategies that can overcome resistance to checkpoint therapy remains a considerable unmet clinical need. In this context, we developed a novel tumor immunization strategy that is multifunctional and combines co-delivery of plasmid DNA encoding antigen and molecules driving immunostimulatory function and antigen targeting. Specifically, we targeted expression of plasmid DNA encoding the stress response transcription factor XBP1 and the melanoma-associated antigen TRP2 fused to heat shock protein HSP70. Transient skin-localized expression promotes a pro-immunogenic skin microenvironment and the induction, recruitment, and maintenance of Type-1 cytotoxic CD8 T cells (Tc1), including Tc1 T-cell infiltrates within the tumor microenvironment (TME), and tumor regression in a PD1-resistant mouse melanoma model. These data suggest a novel therapeutic strategy in which combined effects of localized XBP1 and HSP70 antigen conjugation establishes a PD1-responsive TME for effective and durable treatment of PD1-resistant cancers.
Citation Format: Louis D. Falo. Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 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 5565.
Abstract 5591: Differential profiles of pro-inflammatory chemokines identified in patients with prostate cancer and benign prostatic hyperplasia
Authors: Reyes Niradiz , Tiwari Raj , Geliebter Jan 
Published: September 2020

Abstract
Background: Prostate cancer (PCa) is the most frequently diagnosed malignant disease and the second leading cause of cancer-related deaths of men in the United States. The development of PCa has been linked to inflammation; thus, systemic inflammatory biomarkers may be useful to differentiate PCa from other prostatic disorders, such as benign prostatic hyperplasia (BPH). Proinflammatory chemokines are among the factors that regulate inflammatory processes through the recruitment of leukocytes to the sites of infection or injury. The aim of the present study was to compare the serum profiles of pro-inflammatory chemokines of patients newly diagnosed either with PCa or BPH.
Methods: Serum was prepared from blood samples collected at the time of diagnosis from a cohort of patients newly diagnosed with PCa or BPH. Protein concentrations of chemokines were measured in each group of samples with a multiplex ELISA kit specific for the quantification of 12 proinflammatory chemokines: CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL22, CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11. Results were further validated for selected chemokines using single analyte ELISA kits. This work was approved by the Institutional Review Board of the University of Cartagena.
Results: Our study showed that PCa patients had a significantly different proinflammatory chemokine profile compared to BPH patients. Serum samples in the PCa group had significant higher levels of CXCL8, CCL2, CCL3, CCL4, CXCL11 and CXCL1 compared with the BPH group.
Conclusion: Our study showed that PCa patients had a high proinflammatory chemokine profile. Additional studies are required to determine whether proinflammatory chemokine profiles can serve as a diagnostic signature to differentiate between PCa and BPH, and whether proinflammatory chemokine profiles are correlated with clinical outcomes of PCa patients.
Keywords: Prostate cancer, chemokine, inflammation, Benign Prostatic Hyperplasia
Citation Format: Niradiz Reyes, Raj Tiwari, Jan Geliebter. Differential profiles of pro-inflammatory chemokines identified in patients with prostate cancer and benign prostatic hyperplasia [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 5591.
Abstract 5592: MOSPD2 a novel target for bi-specific antibody mediated solid tumor cells immune death
Authors: Salem Yaniv , Yacov Niva , Propheta-Meiran Oshrat , Kafri Pinhas , Mendel Itzhak , Breitbart Eyal 
Published: September 2020

Abstract
Introduction: We have previously identified motile sperm domain-containing protein 2 (MOSPD2) as key regulator of monocyte motility. While MOSPD2 is normally expressed by myeloid cells with low/undetectable levels in healthy tissues, high expression of MOSPD2 is detected in multiple solid tumors and cancer cell lines. MOSPD2 expression was highly elevated in invasive and metastatic breast cancer but not in in-situ tumors, and our data indicate that it is essential for breast cancer cell metastasis in vitro and in-vivo. Based on its abundant-and specific solid tumor expression profile, MOSPD2 may serve as a target for immune-mediated targeting of tumor cells.
Experimental procedure: We have developed CD3xMOSPD2 bi-specific IgG antibodies (BsAb) for killing of MOSPD2+ cancer cells. Binding of the BsAbs to cancer cells and T-cells was validated by flow cytometry. For efficacy, cancer cell lines were co-cultured with effector CD8 T-cells in the presence of CD3xMOSPD2 BsAb or a control IgG. Cancer cell survival and T-cell activation was determined by flow-cytometry and ELISA for IFN-gamma.
Results: Flow-cytometry confirmed surface binding of BsAbs to cancer cell lines and CD8 T-cells. Employing CD3xMOSPD2 IgG BsAb on cancer cell lines induced T-cell activation and yielded profound death of target tumor cells.
Conclusions: CD3xMOSPD2 bi-specific antibodies potentially offer a new immuno-oncology therapeutic tool for treatment of various MOSPD2-positive solid tumors.
Citation Format: Yaniv Salem, Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Itzhak Mendel, Eyal Breitbart. MOSPD2 a novel target for bi-specific antibody mediated solid tumor cells immune death [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 5592.
Abstract 5596: Dynamic monitoring of plasma DAMP proteins during multimodal anticancer treatment in advanced lung cancer patients
Authors: Inoue Hiroyuki , Tsutsumi Hirono , Shiraishi Yoshimasa , Okamura Koji , Nakanishi Yoichi , Okamoto Isamu 
Published: September 2020

Abstract
Immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells is a potential contributor to the synergistic antitumor effects of the combination of cytotoxic chemotherapy with immune checkpoint blockade. However, little information on the kinetics of circulating DAMP levels in cancer patients has been available. We evaluated the possible effects of various anticancer treatment modalities on the kinetics of plasma DAMP proteins in lung cancer patients. In a prospective observational study, plasma concentrations of three representative DAMP proteins–high-mobility group box 1 (HMGB1), calreticulin (CRT), and histone H3–in 50 patients with advanced lung cancer were measured at five time points during the first cycle of anticancer therapy by ELISA assay. The plasma levels of HMGB1 and CRT increased during the first treatment cycle in 42 (84%) and 35 (70%) patients, respectively, with these increases being detectable as early as day 3. The maximum fold changes in HMGB1 and CRT concentrations was associated with clinical response. Among the various treatment modalities, cytotoxic chemotherapy induced the greatest increases in the concentrations of these DAMPs. There was no correlation between the maximum fold changes in the plasma levels of HMGB1 and CRT. Meanwhile, histone H3 was essentially undetectable in most patients. In conclusion, serial monitoring of plasma revealed that anticancer treatment modalities increased the circulating levels of DAMPs with their association with clinical response, suggesting that agents capable of increasing the release of DAMPs into plasma might induce immunogenic cell death in advanced lung cancer patients.
Citation Format: Hiroyuki Inoue, Hirono Tsutsumi, Yoshimasa Shiraishi, Koji Okamura, Yoichi Nakanishi, Isamu Okamoto. Dynamic monitoring of plasma DAMP proteins during multimodal anticancer treatment in advanced lung cancer patients [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 5596.
Abstract 5618: Evaluating anti-IL-2Ra in vivo efficacy on humanized knock-in mice
Authors: Guo Yanan , Zhou Xiaofei , Su Youhong , Ng Gary , Guo Chaoshe 
Published: September 2020

Abstract
Interleukin-2 receptor alpha chain (also called as CD25) is a 55 kD glycoprotein, also known as IL-2Ra, Ly-43, p55, or Tac. It is expressed on activated T and B cells, thymocyte subset, pre-B cells, and T regulatory cells. IL-2Ra and IL-2Rβ (CD122), together with the common gamma chain (IL2Rg)(CD132), form the high affinity signaling IL-2 receptor. Its affinity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of IL-2Ra on the surface of many different haematological tumor cells is now well established and, apart from its prognostic significance, IL-2Ra may be present on leukemic stem cells and enable oncogenic signaling pathways in leukemic cells. Additionally, high IL-2Ra expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumors and autoimmune disease. The relative clinical safety and efficacy of administering anti- IL-2Ra radioimmunoconjugates and immunotoxins in various haematological tumor indications has been established and clinical trials of a novel IL-2Ra-directed antibody drug conjugate are underway.
Biocytogen has generated IL-2Ra humanized mouse for both in vitro functional validation of signaling pathway and in vivo efficacy evaluation of IL-2Ra antibodies. The targeting strategy is that the genomic DNA covering exons 2~6 of mouse IL-2Ra gene which encode the extracellular domain are replaced by the counterpart of human IL-2Ra genomic DNA covering exons 2~6. Human IL-2Ra is mainly detectable on the T cells in spleen of the IL-2Ra humanized mice. The humanized mice are highly similar to the wild-type mice in basal leukocyte subpopulations, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. STAT-5 phosphorylation induced by mouse IL2 protein is blocked by anti-human IL-2Ra antibodies, suggesting that the functional pathways in IL-2Ra humanized mice work well. The colon cancer model established in IL-2Ra humanized mice is undergoing, anti-human IL-2Ra antibodies showed good efficacy in inhibiting tumor growth.
Taken together, IL-2Ra humanized mice are a useful tool for in vivo efficacy evaluation of human IL-2Ra antibodies that can be advanced to human clinical trials.
Citation Format: Yanan Guo, Xiaofei Zhou, Youhong Su, Gary Ng, Chaoshe Guo. Evaluating anti-IL-2Ra in vivo efficacy on humanized knock-in mice [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 5618.