bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B66: Tumor-specific differences in virus-induced inflammation may determine therapeutic response to HSV virotherapy in sarcoma models
Authors: Chen Chun-Yu , Hutzen Brian J. , Wang Pin-Yi , Leddon Jennifer L. , Currier Mark A. , Denton Nicholas , Eubank Timothy , Cripe Timothy P. 
Published: October 2015

Abstract
Ewing's Sarcoma (EWS) is the second most common childhood bone cancer with high rate of metastasis (25%) and tumor recurrence (30~40%). Despite tremendous advances in the five-year survival rate of localized disease (70~80%), overall survival for patients with relapse or metastasis remains poor (&lt;30%). Oncolytic virotherapy is an emerging anticancer treatment that utilizes attenuated viruses to selectively target and destroy tumor cells. Promotion of systemic anti-tumor immune responses by virotherapy holds great promise, as it has the potential to target distant metastasis and provide immunologic protection from tumor relapse. We tested the oncolytic herpes simplex virus (oHSV) rRp450 as a novel therapy for sarcomas using two human EWS cell lines 5838 and A673 in vitro and in mouse xenografts. Interestingly, our data showed a significant disconnect between the susceptibility of the EWS cell lines 5838 and A673 grown in vitro and the virus-induced antitumor efficacy in vivo. Although 5838 displayed much less virus replication and substantially weaker susceptibility to rRp450 in vitro, it displayed a superior in vivo therapeutic response to intratumoral rRp450 injection compared to tumors derived from the more susceptible A673 cell line. Analysis of these two tumor types demonstrated significant differences on baseline and virus-induced tumor microenvironment characteristics, including differences in cytokines, chemokines, and immune cell infiltrates. In the 5838 model, rRp450 treatment triggered higher inflammatory immune responses, including inductions of interferon-gamma (IFN-γ), Natural Killer (NK) cell chemokine CXCL10 and increased infiltration of NK cells and neutrophils in tumors. In addition, the number of pro-tumorigenic CD206+ M2-type macrophages also significantly decreased in rRp450-treated 5838 tumors. Blockade of NK cells or neutrophils alone had no effect on oHSV-induced antitumor efficacy, suggesting neither of these cell populations alone is crucial for virus-induced antitumor efficacy. Efforts to identify key mediator(s) to oHSV-induced antitumor efficacy are currently under investigation. Taken together, our study suggests that, rather than the persistence of virus replication, the oHSV-induced immune inflammatory response might determine the outcome of the oncolytic virotherapy in these models.
Citation Format: Chun-Yu Chen, Brian J. Hutzen, Pin-Yi Wang, Jennifer L. Leddon, Mark A. Currier, Nicholas Denton, Timothy Eubank, Timothy P. Cripe. Tumor-specific differences in virus-induced inflammation may determine therapeutic response to HSV virotherapy in sarcoma models. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B66.
Abstract B73: Ketogenic diet enhances immunity to glioblastoma
Authors: Johnson John L. , Woolf Eric , Lussier Danielle M. , Brooks Ken S. , Blattman Joseph N. , Scheck Adrienne C. 
Published: October 2015

Abstract
Glioblastomas are the most common and malignant brain tumor in adults and account for over 50% of all gliomas. Current standard of care combines surgical resection with temozolomide chemotherapy and radiotherapy, but 5 year survival rates remain less than 20%. There is a critical need for new therapies that increase efficacy without increasing toxicity. One therapeutic target can be found in the aberrant metabolism that is a hallmark of cancer. We have previously used an intracranial syngeneic immunocompetent mouse model of malignant glioma to demonstrate that targeting metabolism using a ketogenic diet reduced tumor burden and increased survival. The ketogenic diet is a high fat, low carbohydrate plus protein diet used for the treatment of refractory pediatric epilepsy. Mice maintained on a ketogenic diet (KetoCal®, Nutricia North America, Gaithersburg, MD) had a reduction in inflammation and peri-tumoral edema, prompting us to question the effects of the ketogenic diet on the infiltration and the functionality of glioblastoma-reactive immune cells. Immune cells were isolated from malignant gliomas from mice treated with either the ketogenic diet or a standard diet. Glioblastoma-specific immune cells were tested for functionality via cytokine production, capacity for cytotoxicity, and amount of infiltration. We found the ketogenic diet significantly decreased expression of the inhibitory receptors CTLA4 and PD-1 on tumor-infiltrating T cells, and coincided with a reduction in inhibitory ligand expression on the tumor. Moreover, this reduced T cell tolerance at the tumor site allowed CD8+ T cells to produce IFNγ and IL-2, and regain cytotoxic functions. Additionally, the ketogenic diet caused a reduction in immunosuppressive cytokine production via regulatory T cells. Innate immune responses to the tumor were also altered in mice maintained on the ketogenic diet, as natural killer cells infiltrating the tumor were able to produce more IFNγ and TNF in response to GL261-luc2 cells in vitro. Overall, the ketogenic diet may be an attractive adjuvant therapy to overcome several immune escape mechanisms in gliomas by decreasing regulatory T cell suppression of effector T cells and increasing CD8+ T cell killing and cytokine production, ultimately leading to increased tumor immune mediated rejection.
Citation Format: John L. Johnson, Eric Woolf, Danielle M. Lussier, Ken S. Brooks, Joseph N. Blattman, Adrienne C. Scheck. Ketogenic diet enhances immunity to glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B73.
Abstract B74: PTEN-deficiency in myeloid cells alters tumor immune surveillance in a murine model of inflammation driven colon cancer
Authors: Kuttke Mario , Pisoni Julia , Sahin Emine , Percig Sophie , Vogel Andrea , Kraemmer Daniel , Hanzl Leslie , Schmid Johannes , Schabbauer Gernot 
Published: October 2015

Abstract
Macrophages and antigen-presenting cells are important parts of the innate immune system as they fend off invading microbes, produce cytokines, activate other leukocytes and are implicated in the resolution of inflammatory processes and tissue remodeling. They have been found to contribute to tumor progression as they undergo phenotypic conversion from a ‘classical’ inflammatory state (M1) into an ‘alternatively’ activated, tumor tolerating state (M2). In our previous work we could show that the PI3K/PTEN signaling pathway plays a role in this fate decision process. Deletion of PTEN in myeloid cells leading to sustained PI3K activation results in an M2-like phenotype characterized by an increased release of anti-inflammatory factors.
Alternative activation of myeloid cells is beneficial in acute models of infection and inflammation, but a diminished innate immune response could be detrimental in tumor development since tumor-associated macrophages show an immune-suppressive, M2-like phenotype. To address the question whether myeloid PTEN plays a role in tumor immune surveillance, we applied a model of colitis associated colon cancer (CAC) in myeloid cell specific PTEN-deficient mice.
PTENfl/fl LysM cre conditional knock-out (KO) mice showed an increased tumor burden and increased mortality in this model of inflammation driven CAC. Isolated myeloid cells from these mice exhibited an up-regulation of M2-marker genes and a down-regulation of pro-inflammatory cytokines. Moreover we found an increase in immune-regulatory innate cells of the secondary lymphoid organs. T-cells isolated from PTEN KO-mice had decreased cytokine production as well as a reduced proliferative potential ex vivo. Therefore we suggest that myeloid PTEN deficiency leads to reduced T-cell stimulation thereby promoting intestinal tumor growth.
Taken together this study highlights the importance of the PI3K/PTEN signaling axis in myeloid cells to control tumor immune surveillance and supports the idea that PI3K inhibitors currently used in clinical settings may have additional functions beyond tumor cell targeting.
Citation Format: Mario Kuttke, Julia Pisoni, Emine Sahin, Sophie Percig, Andrea Vogel, Daniel Kraemmer, Leslie Hanzl, Johannes Schmid, Gernot Schabbauer. PTEN-deficiency in myeloid cells alters tumor immune surveillance in a murine model of inflammation driven colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B74.
Abstract B77: Targeted nano-immune conjugates to melanoma: Preclinical testing of bevacizumab targeted nab-paclitaxel
Authors: Nevala Wendy K. , Markovic Svetomir N. 
Published: October 2015

Abstract
Background: Phase 3 clinical results demonstrate that nab-paclitaxel (ABX) exhibits single agent activity in patients with metastatic melanoma relative to dacarbazine. Additionally, phase 2 clinical data suggest that ABX combined with bevacizumab (BEV) with/without carboplatin exhibits greater clinical efficacy than ABX alone. We hypothesized that the latter may be due to a pharmacokinetic, non-covalent interaction between bevacizumab (BEV) and nab-paclitaxel (ABX) allowing for greater localization of ABX to sites of VEGF overproduction (metastases). Herein we present pre-clinical data describing the utility of experimentally created ABX/BEV complex nanoparticles used to deliver ABX to VEGF producing cancer targets.
Methods and Results: To test whether BEV binds to ABX we employed flow cytometry and discovered that the BEV does bind to ABX while preserving the ability of BEV to bind its ligand, VEGF. To measure binding affinity we used Biolayer Interferometry (BLItz) to measure association and dissociation constants. Results of BLItz experiments demonstrate that the binding affinity of BEV to ABX is pH and temperature dependent. The size and stability of the nanoparticle formed by binding BEV and ABX was determined using light refraction (Mastersizer) and Brownian motion (Nanosight). Results of these experiments suggest that a range of nanoparticles can be produced and stability of the BEV particle is increased relative to ABX particles alone. Finally the tumor efficacy of the BEV/ABX complex relative to ABX and BEV as well as sequential administration of the two drugs was tested in a xenograft model of A375 human melanoma cell line. Pharmacokinetic studies in these mice suggest that more ABX is deposited in the tumor site when treated with the complexes relative to ABX alone.
Conclusions: The therapeutic antibody BEV has the capability to bind to the chemotherapy drug ABX while still binding its ligand, VEGF. The resulting nanoparticle is more stable than the original ABX particle. In a preclinical model of human A375 xenografts in nude mice, AB160 treatment offers significantly improved antitumor activity beyond that of ABX, BEV or ABX+BEV with no additional toxicity. Initial results indicate that the improved efficacy of the ABX/BEV nanoparticle relative to ABX alone is primarily due to the ability of the anti-VEGF antibody (BEV) to target the chemotherapy agent to the tumor where local VEGF concentration is very high. Clinical translation of the safety of a 160nm AB particle (AB160) in patients with metastatic melanoma is in progress.
Citation Format: Wendy K. Nevala, Svetomir N. Markovic. Targeted nano-immune conjugates to melanoma: Preclinical testing of bevacizumab targeted nab-paclitaxel. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B77.
Abstract IA16: Designing cancer vaccines that mimic viral infections
Authors: Celis Esteban 
Published: October 2015

Abstract
Numerous CD8 T cell epitopes have been identified allowing the development of epitope-based cancer immunotherapy such as the use of synthetic peptide-based vaccines. However, peptide vaccines have been notoriously poorly immunogenic and provide suboptimal therapeutic effects. In contrast, as a response to viral and bacterial infections, the immune system has the capacity to produce huge numbers of antigen-specific T cells that eliminate disease and provide memory responses to prevent future infections. Our strategy to optimize peptide vaccines is to design immunization strategies that mimic these infections by providing the necessary immune activation signals together with the appropriate immunogenic peptide. Furthermore, it has been proposed that minimal peptide epitopes are poorly immunogenic because they are presented to T cells by non-professional APCs. Therefore, it is suggested that using long peptides vaccines will improve immunogenicity by forcing antigen presentation by professional APCs. Using several mouse tumor models, we observe that peptide composition (hydrophobicity, amphipathicity), adjuvant and route of vaccine administration are more critical than peptide size for generating strong CD8 T cell responses that limit tumor growth. Two separate events are required for peptides to generate massive CD8 T cell responses, similar to those observed during acute viral infections: 1) Peptide priming mediated professional APCs, where CD40 activation and TLR signals are critical; 2) T cell expansion, which can be mediated by either professional and non-professional APCs and where type-I interferon induced by retinoic acid-inducible (RIG-I)-like receptor stimulation by poly-IC plays a critical role. Effective anti-tumor CD8 T cell responses were accomplished by 2 systemic injections (iv or im 5-7 days apart) of peptide/poly-IC.
Citation Format: Esteban Celis. Designing cancer vaccines that mimic viral infections. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA16.
Abstract IA26: Vaccines: The igniters of antitumor immunity
Authors: Zheng Lei 
Published: October 2015

Abstract
Pancreatic cancer is one of a number of malignancies that typically lack tumor infiltrating effector lymphocytes and are considered “non-immunogenic” neoplasms. This situation has drastically slowed the development and application of immune-based therapies for these cancers. In this study, we tested the hypothesis that vaccine based immunotherapy can convert pancreatic cancer, a “non-immunogenic” tumor, into an “immunogenic” tumor with infiltrating effector lymphocytes. We recently completed a novel neo-adjuvant and adjuvant study designed to evaluate post-immunotherapy changes within the tumor microenvironment (TME) of primary pancreatic tumors following treatment with the GM-CSF-secreting pancreatic cancer vaccine, given either alone or with immune modulating doses of cyclophosphamide to deplete regulatory T cells. Pathological examination of tumor tissue resected just two weeks following vaccination identified the formation of novel immunotherapy-induced tertiary lymphoid aggregates, organized lymphoid structures that are not observed in tumors resected from unvaccinated patients. This study shows for the first time that treatment with a vaccine-based immunotherapy directly alters the pancreatic cancer TME, allowing infiltration of organized and functional immune structures that convert an immunologically quiescent tumor into an immunologically active tumor. This study also demonstrates that the formation of these immune regulatory structures within the TME is just the first step toward establishing optimal anticancer immune responses within the TME since these lymphoid aggregates can express both effector activating and effector down-regulatory immune signatures. These data support combination immunotherapies that include vaccines that induce T cells and facilitate T cell trafficking into the TME given together with agents that modulate vaccine induced regulatory signals. In addition, these data suggest a new model for developing more effective immunotherapy for traditionally “non-immunogenic” tumors like pancreatic cancer. Finally, the intratumoral signatures identified in this study provide potential targets for developing strategies for modulating the TME and promoting more robust antitumor immune responses in future studies.
Citation Format: Lei Zheng. Vaccines: The igniters of antitumor immunity. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA26.
Parques lineares do Tremembé: o uso de infraestruturas verdes na criação de um sistema de espaços livres
Authors: Lima Gerson Amaral , Pellegrino Paulo Renato Mesquita 
Published: October 2015

Este trabalho consiste na elaboração de uma proposta de intervenção paisagística numa porção da Subprefeitura Jaçanã/Tremembé no município de São Paulo. A região compõe a zona de amortecimento do Parque Estadual da Cantareira, e o adensamento construtivo do bairro constitui uma ameaça à preservação do meio ambiente local. O projeto toma como diretriz o tratamento das águas urbanas, especialmente na requalificação dos fundos de vales, introduzindo novos conceitos de manejo das águas urbanas que se baseiam na ideia de Desenvolvimento de Baixo Impacto (Low Impact Development – LID). A proposta deste trabalho busca, também, estabelecer novas relações entre a cidade e os seus recursos naturais, tecendo novas costuras entre a floresta e a cidade.
Os córregos ocultos e seus resquícios nos espaços livres urbanos: os afluentes do córrego Mandaqui
Authors: Cabral Arthur Simões Caetano 
Published: October 2015

O presente artigo visa a contextualizar, enquanto testemunhos das características geomorfológicas originais do sítio, cursos d’água da bacia do córrego Mandaqui, canalizados e tamponados no decorrer da consolidação urbana da zona norte paulistana. Tal contextualização, no entanto, mostra-se reveladora não apenas de elementos naturais historicamente negados enquanto paisagem, mas também de relações afetivas diversas estabelecidas entre o homem e as águas. A experiência dos espaços associados aos afluentes do Mandaqui demonstra a possibilidade de retomar a consciência sobre a existência de pequenos córregos tamponados em São Paulo. Por meio de vestígios, os córregos ocultos insinuam-se à superfície. Pouco a pouco, o olhar de quem se encontra em tais espaços é inevitavelmente conduzido, entre becos e vielas, a percorrer o trajeto esculpido pelas águas. Estas, ainda que apartadas da superfície, por meio de seus vestígios demonstram a impossibilidade do fazer humano em apagar por completo certos traços da natureza primitiva. O trabalho do qual resulta o presente artigo integra os estudos de caso da margem direita do Tietê, realizados no âmbito da pesquisa acerca dos Córregos Ocultos, coordenada pelo Prof. Dr. Vladimir Bartalini junto ao Laboratório da Paisagem, Arte e Cultura da Faculdade de Arquitetura e Urbanismo da Universidade de São Paulo.
Ensemble Prediction of the Dispersion of Volcanic Ash from the 13 February 2014 Eruption of Kelut, Indonesia
Authors: Dare Richard A. , Smith David H. , Naughton Michael J. 
Published: October 2015

AbstractA meteorological ensemble prediction system that represents uncertainties in both initial conditions and model formulations is coupled with a modified version of the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model. This coupled dispersion ensemble prediction system (DEPS) is used to generate a 24-member ensemble forecast of the dispersion of the volcanic ash cloud produced by the 13 February 2014 eruption of Kelut, Indonesia. Uncertainties in the volcanic ash source are not represented. For predictions up to 12 h from the start of the eruption, forecasts from the deterministic control member and from the DEPS both show very good qualitative agreement with satellite observations. By 18–24 h the DEPS forecast shows better qualitative agreement with observations than does the deterministic forecast. Although composited fields such as the ensemble mean and probability present information concisely, experiments here show that it is very important to also consider results from individual member forecasts in order to identify features that may be underrepresented. For example, an area of relatively high ash concentration that was forecast by most of the members was not particularly evident in the composited fields because the location of this feature was highly variable between member forecasts. To fully understand a DEPS forecast, it is necessary to consider both atmospheric column load and concentration fields, individual member forecasts, and a range of thresholds in computing and interpreting probabilities.
Nearest Neighbor–Genetic Algorithm for Downscaling of Climate Change Data from GCMs
Authors: Kim Soojun , Kwak Jaewon , Kim Hung Soo , Jung Younghun , Kim Gilho 
Published: October 2015

AbstractThe spatial and temporal resolution of readily available climate change projections from general circulation models (GCM) has limited applicability. Consequently, several downscaling methods have been developed. These methods predominantly focus on a single meteorological series at specific sites. Spatial and temporal correlation of the precipitation and temperature fields is important for hydrologic applications. This research uses a nearest neighbor–genetic algorithm (NN–GA) method to analyze the Namhan River basin in the Korean Peninsula. Using the simulation results of the CNRM-CM for the RCP 8.5 climate change scenario, archived in the fifth phase of the Coupled Model Intercomparison Project (CMIP5), the GCM projections are downscaled through the NN–GA. The NN–GA simulations reproduce the features of the observed series in terms of site statistics as well as across variables and sites.