bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B67: A big role in tumor immune microenvironment of a small non-coding RNA: microRNA-200
Authors: Chen Limo , Goswami Sangeeta , Yi Xiaohui , Byers Lauren , Diao Lixia , Roybal Jonathon , Ungewiss Christin , Peng David , Wang Jing , Wistuba Ignacio , Chen Lieping , Ullrich Stephen , Heymach John , Kurie Jonathan , Qin Xiao-Feng , Gibbons Don 
Published: October 2015

Abstract
Immunosuppression of tumor-infiltrating lymphocytes (TIL) is a common feature of advanced epithelial tumors, but its biological basis has remained obscure. In addition, anti-PD-1/PD-L1 treatment has produced encouraging clinical responses, but it is still unclear which patients are likely to benefit. Thus, successful therapeutic translation will require a thorough understanding of mechanisms of treatment resistance and predictive biomarkers to select patients.
Using multiple lung cancer mouse models (spontaneous and transplant models), we demonstrate a molecular link between epithelial-to-mesenchymal transition (EMT) and intra-tumoral CD8+ T cell immunosuppression, two key drivers of malignant tumor progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1, a checkpoint inhibitor of CD8+ T cell immunity. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumor cells, leading to CD8+TIL dysfunction and metastasis. These findings were further supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets: The Cancer Genome Atlas (TCGA) lung adenocarcinoma dataset and the Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (PROSPECT) project at MD Anderson Cancer Center.
In addition to revealing a link between EMT and T cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and they suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists. Our data also suggest that EMT represents an important biomarker to select the patients who may benefit from immune checkpoint blockade agents and other immunotherapies in lung cancer and possibly a broader range of other cancers.
Citation Format: Limo Chen, Sangeeta Goswami, Xiaohui Yi, Lauren Byers, Lixia Diao, Jonathon Roybal, Christin Ungewiss, David Peng, Jing Wang, Ignacio Wistuba, Lieping Chen, Stephen Ullrich, John Heymach, Jonathan Kurie, Xiao-Feng Qin, Don Gibbons. A big role in tumor immune microenvironment of a small non-coding RNA: microRNA-200. [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 B67.
Abstract B68: BAMLET in combination with the TLR7 agonist R848 protects against melanoma in a murine model
Authors: Dyck Lydia , Harte Níal , Mok Kenneth Hun , Mills Kingston H.G. 
Published: October 2015

Abstract
BAMLET, a bovine α-lactalbumin - oleic acid complex, is a novel and promising candidate for the treatment of cancer because of its capacity to specifically kill tumor cells while leaving normal cells and tissues relatively unharmed. While recent studies focused on direct tumoricidal effects of BAMLET, we investigated the potential of BAMLET to modulate anti-tumor immune responses, in combination with the TLR7 agonist R848, which stimulates innate and adaptive immunity.
Consistent with previous studies, BAMLET induced killing of B16 melanoma cells in vitro. Interestingly, we demonstrated for the first time that BAMLET also has immunostimulatory effects. BAMLET enhanced R848-induced dendritic cell (DC) maturation and IL-12, TNF and IL-6 production, which are crucial for the induction of adaptive immune responses against tumors. Moreover, DCs stimulated with BAMLET and R848 were capable of activating CD4 T cells in vitro. Treatment of tumor bearing mice with either BAMLET or R848 alone conferred some protection against tumor growth. However, treatment with a combination of BAMLET and R848 conferred a high level of protection, with 57% of mice completely rejecting the tumor. We found a higher frequency of DCs and IFNγ-secreting T cells in the tumor draining lymph nodes and spleens of mice treated with the combination of BAMLET and R848, compared with untreated mice or mice treated with either BAMLET or R848 alone.
Our data are consistent with a role for BAMLET in directly killing tumor cells, which release antigens that are taken up by DCs, but suggest that BAMLET can also promote maturation and secretion of T cell polarizing cytokines by DCs, especially when co-activated through a TLR. These activated DCs promote induction of IFNγ-secreting CD4 T cells that have anti-tumor activity. In conclusion, we demonstrated that BAMLET and R848 are a promising combination therapy against cancer as they target tumor cells directly, but also activate anti-tumor immune responses.
Citation Format: Lydia Dyck, Níal Harte, Kenneth Hun Mok, Kingston H.G. Mills. BAMLET in combination with the TLR7 agonist R848 protects against melanoma in a murine model. [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 B68.
Abstract B75: CCL2 promotes epithelial-mesenchymal transition (EMT) in prostate cancer cells via downregulation of dual-specificity phosphatase 22
Authors: Lin Wen-Jye , Izumi Kouji , Lin Showping , Ho Hui-Min 
Published: October 2015

Abstract
CCL2 is a member of the CC chemokine superfamily that plays a crucial role in mediating macrophage recruitment and prostate cancer (PCa) metastasis. We have discovered that inhibiting the function of androgen receptor (AR) in prostate cancer cells results in the upregulation CCL2 and promotes disease progression by recruiting macrophages, activating signal transducer and activator of transcription 3 (STAT3), and by favoring the epithelial-to-mesenchymal transition. However, the molecular switches controlling CCL2 downstream signaling in PCa cells are not well understood. Here, we established an in vitro cell migration screening system using transwell migration chambers, and identified a higher amount of CCL2 in migrating PCa cells, establishing a link between CCL2 and a subpopulation of PCa cells. Importantly, we found that CCL2 expression correlated with the EMT marker, N-cadherin in migrating PCa cells. Importantly, CCL2 stimulation in PCa cells enhanced the expression levels of several EMT markers and induced STAT3 activation. In addition, CCL2 stimulation in PCa cells induced the downregulation of dual-specificity phosphatase 22 (DUSP22), which has been shown to act as a negative regulator of the IL-6-induced STAT3 activation through a direct interaction with STAT3. This supports that CCL2-induced DUSP22 downregulation in PCa cells as a potential mechanism to promote EMT. Therefore, we believe CCL2 may promote PCa metastasis in an autocrine manner through promotion of EMT in PCa cells with more aggressive motility behaviors. Targeting of the CCL2-STAT3 axis may offer new approaches to suppress the multifaceted support (immunosuppression, macrophage recruitment, and angiogenesis) of CCL2 for PCa cells in complex tumor microenvironment.
Citation Format: Wen-Jye Lin, Kouji Izumi, Showping Lin, Hui-Min Ho. CCL2 promotes epithelial-mesenchymal transition (EMT) in prostate cancer cells via downregulation of dual-specificity phosphatase 22. [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 B75.
Abstract B84: Live imaging reveals hypoxia to be a limiting factor in CTL-mediated tumor rejection
Authors: Shakhar Guy , Feferman Tali , Manaster Yoav , Hutzler Anat 
Published: October 2015

Abstract
Background: One of the obstacles to successful immunotherapy by CTLs is thought to be poor vascularization of tumors that leads to sub-optimal tumor infiltration. In contrast, the effects of disrupted vascularization and the hypoxia it introduces on CTL migration and function within tumors have not been investigated.
Methods: To study whether tumor vascularity can shape anti-tumor CTL responses, we combined immunohistochemistry of human melanoma samples with dynamic two-photon imaging within B16-OVA tumors in live mice.
Results: In patients, CD8 T cells were twofold denser around peripheral vessels than around deep vessels, and fourfold denser than in avascular areas. This pattern was clearest in poorly-infiltrated tumors. Correspondingly, in mice, OT-I CTLs preferentially infiltrated B16-OVA tumors through peripheral ICAM1+ vessels. CTLs remained initially at their entry areas, crawling vigorously only within 50 µm of flowing blood vessels. Gradually, CTLs formed dense perivascular swarms, producing locally-high CTL-to-target ratios at their advancing front. These swarms advanced through the tumors, leading to patchy elimination of tumor cells. Target killing was antigen-specific, contact-dependent and perforin-mediated, and required several CTLs to engage one target cells to be effective. Several findings suggest that CTL confinement to perivascular areas is oxygen-dependent: occlusion of intratumoral blood vessels resulted in immediate arrest of CTLs. Immunohistology indicated that CTLs avoided hypoxic tumor areas. Hypoxia and mitochondrial uncoupling interfered with CTL migration in vitro and, finally, highly vascular tumors grown in a matrix containing pro-angiogenic factors were more easily rejected after CTL injection, displayed delayed growth in untreated mice but were not affected in immunodeficient mice.
Conclusions: We suggest that CTLs depend on oxygen for intratumoral locomotion and cytolysis. Incomplete vascularization promotes patchy infiltration and tumor escape; tumor immunotherapy may thus benefit from normal and extensive tumor angiogenesis
Citation Format: Guy Shakhar, Tali Feferman, Yoav Manaster, Anat Hutzler. Live imaging reveals hypoxia to be a limiting factor in CTL-mediated tumor rejection. [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 B84.
Abstract B86: The NF-κB p65 and p50 homodimer cooperate with pSTAT1 to synergistically activate iNOS transcription
Authors: Simon Priscilla , Sharman Sarah , Lu Chunwan , Yang Dafeng , Paschall Amy , Liu Kebin 
Published: October 2015

Abstract
Inducible nitric oxide synthase (iNOS) metabolizes L-arginine to produce NO that was originally identified in myeloid cells as a host defense mechanism against pathogens. Recent studies, however, have revealed that iNOS is often induced in both tumor and myeloid cells in the tumor microenvironment. More intriguingly, compelling experimental data have shown that iNOS promotes tumor development in certain cellular context and suppress tumor development under other cellular conditions. The molecular mechanisms underlying this contrasting function of iNOS is unknown. Because iNOS is often induced by inflammatory signals, it is therefore likely that the opposite functions of iNOS might be controlled by the inflammatory signaling pathways. We show here that proinflammatory IFN-γ and NF-κB signals synergistically induce iNOS expression in human colon cancer cells. We further demonstrated that NF-κB directly binds to the NOS2 promoter to regulate iNOS expression. Although the IFN-γ signaling pathway or the NF-κB signaling pathway alone is insufficient to induce iNOS expression in myeloid cells, IFN-γ and NF-κB synergistically induce iNOS expression in myeloid cells. Furthermore, we determined that IFN-γ up-regulates IRF8 expression to augment NF-κB induction of iNOS expression. More interestingly, we observed that the p65/p65 and p50/p50 homodimers, not the canonical p65/p50 heterodimer, directly binds to the nos2 promoter to regulate iNOS expression in myeloid cells. Our results thus determine that the IFN-γ-induced IRF8 acts in concert with the NF-κB p65/p65 and p50/p50 homodimers to regulate iNOS expression.
Citation Format: Priscilla Simon, Sarah Sharman, Chunwan Lu, Dafeng Yang, Amy Paschall, Kebin Liu. The NF-κB p65 and p50 homodimer cooperate with pSTAT1 to synergistically activate iNOS transcription. [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 B86.
Abstract B90: Poly (lactide)-based nanoparticles by free-radical dispersion polymerization: Fabrication, characterization and in vitro studies
Authors: Adesina Simeon K. , Akala Emmanuel O. 
Published: October 2015

Abstract
We have used the macromonomer method to prepare crosslinked, paclitaxel-loaded PLA-PEG (stealth) nanoparticles using free-radical dispersion polymerization. The nanoparticles were optimized using statistical D-optimal mixture design. Nanoparticle fabrication with poly(lactide) is mainly carried out by the dispersion of preformed polymers which makes it difficult to attach targeting moieties to the surface of the nanoparticle and to produce crosslinked networks; hence we designed a new approach based on dispersion polymerization. Confirmation of nanoparticle synthesis was by scanning electron microscopy. Particle size and size distribution and the zeta potential of the optimized formulation were determined using Zetasizer nano Zs. The release profile of paclitaxel-loaded nanoparticles was determined by high performance liquid chromatography and encapsulated drug was released over 7 days. In vitro cytotoxicity studies were carried out using the CellTiter®glo luminescent cell viability assay in MCF7, MDA-MB-231 (breast cancer) and SK-OV-3 (ovarian cancer) cell lines. The cytotoxicity assay shows that the blank nanoparticle is biocompatible with no toxicity for the duration of the assay compared to medium-only treated controls. Further, the paclitaxel-loaded nanoparticle formulation exhibits similar cytotoxicity compared to free drug in solution against the cancer cell lines tested. In vitro intracellular localization of nanoparticle by confocal microscopy also demonstrated that the nanoparticles are rapidly internalized by MCF-7 cancer cells within one hour probably by nonspecific endocytosis. The stealth nanoparticles are suitable for the design of controlled delivery systems for bioactive agents.
Citation Format: Simeon K. Adesina, Emmanuel O. Akala. Poly (lactide)-based nanoparticles by free-radical dispersion polymerization: Fabrication, characterization and in vitro studies. [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 B90.
Abstract IA01: Molecular basis of T cell exhaustion: Insights for immunotherapy
Authors: Wherry E. John 
Published: October 2015

Abstract
T cell exhaustion is common during chronic infections, cancer and prevents optimal immunity. Exhausted T cells are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity and poor survival following antigen stimulation. In addition, it has become clear that exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating exhausted T cells. Our work has recently defined transcriptional networks of T cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes) in controlling the sustainability and terminal differentiation of exhausted T cell populations. We have found a key role for T-bet in sustaining a progenitor pool of exhausted CD8 T cells during chronic infection, while the related transcription factor Eomes governs terminal differentiation. Our new data indicates that PD-1, the major current target of immunotherapy approaches dramatically regulates these subsets of exhausted T cells and modulating PD-1 signals may have long-term impact on lineage dynamics of exhausted T cell populations. One key observation from these studies is that a key surrogate of reivingoration of exhausted CD8 T cell responses is a population of EomesHi PD-1Hi exhausted CD8 T cells. The use of this subset of CD8 T cells as a biomarker is explored. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.
Citation Format: E. John Wherry. Molecular basis of T cell exhaustion: Insights for immunotherapy. [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 IA01.
Abstract IA19: Curative potential of T-cell immunotherapy for cancer
Authors: Rosenberg Steven A. 
Published: October 2015

Abstract
Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor infiltrating lymphocytes (TIL) mediated a 56% objective response rate including 20% of patients with durable complete regression ongoing from 6.7 to 10.3 years. Administration of autologous TIL to 9 patients with HPV induced metastatic cervical cancer mediated objective responses in 3 patients including 2 complete regressions that are ongoing beyond a year.
The ideal targets for ACT are the unique mutations that occur in cancers. Using deep exomic sequencing a technique has been developed to identify any cancer mutation, presented on any of the patient's MHC molecules, that gives rise to reactive T cells. We recently reported the successful application of this approach to treat a patient with a metastatic bile duct cancer. Since virtually all cancers contain mutations this approach is now being vigorously studied to expand the current reach of cancer immunotherapy to common epithelial cancers.
Genes encoding conventional alpha-beta T cell receptors (TCR) or chimeric antigen receptors (CAR) can be efficiently transduced into autologous lymphocytes though choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normal tissues. ACT using CARs to target the CD19 molecule present on normal B cells as well as on the great majority of B cell lymphomas and leukemias was first reported to successfully treat a patient with refractory lymphoma in 2010 in a patient who remains progression-free at five years. Durable complete and partial responses have been seen in patients with chemotherapy refractory indolent and aggressive large B cell lymphomas. Of 9 heavily pretreated patients with large cell lymphomas receiving ACT, 4 patients have had complete regressions, 3 ongoing from 9 to 22 months and 2 additional patients have had partial responses.
Cancer-testes antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10 to 80% of cancers from multiple tissues but are often not expressed in adult normal tissues. ACT targeting NY-ESO-1 resulted in a 67% response rate in 15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patients with melanoma including durable complete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for cell transfer immunotherapy and we are conducting a trial using a CAR targeting the EGFRvIII mutation expressed in about 40% of patients with high grade glioblastoma
Citation Format: Steven A. Rosenberg. Curative potential of T-cell immunotherapy for 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 IA19.
Lugares públicos como potencialidades: uma leitura urbana do centro histórico de São Paulo
Authors: Rupf Lilian Dazzi Braga , Queiroga Eugênio Fernandes 
Published: October 2015

Este trabalho propõe um ensaio de leitura urbana a fim de apreender relações entre o espaço urbano produzido e as vivências cotidianas no Centro Histórico de São Paulo, através da observação empírica do presente como espessura que remete ao passado e futuro. Ao contrário de alguns discursos, não há uma redução de sua vida pública, o que há é uma mudança nesta, que adquire maior complexidade: novos usos e dinâmicas ocupam seus lugares públicos. Hoje a área central tem como herança um rico sistema de espaços livres que protagoniza grandes momentos da vida pública paulistana; estes, independentemente do perfil e da apropriação dos usuários, são fortemente utilizados.
Políticas para gerenciamento da mídia exterior na paisagem urbana: um paralelo entre os casos de São Paulo e Florianópolis
Authors: Casarin Vanessa , Santiago Alina Gonçalves 
Published: October 2015

A mídia exterior está presente de forma ostensiva nas grandes cidades contemporâneas e tem sido utilizada de forma desordenada na paisagem, causando prejuízos para as cidades e seus usuários e contribuindo para a “poluição visual” urbana. Este artigo tem por objetivo traçar um paralelo entre duas experiências distintas no enfrentamento dessa situação, a da cidade de Florianópolis, que implantou um projeto intitulado Renovar, em 1993, no perímetro central de caráter histórico, e a recente iniciativa implementada na cidade de São Paulo, através da Lei Cidade Limpa, que abrangeu a totalidade do município. A discussão se dá com base em dados coletados através de entrevistas realizadas com os profissionais envolvidos na implantação dos referidos projetos. Os resultados das experiências abordadas através da reflexão sobre a prática foram confrontados e apontaram para uma dificuldade no gerenciamento da mídia exterior visível do espaço público, apesar de ela ser apenas um dos aspectos que compõem o cenário visual urbano, e que, no entanto, tem forte impacto na imagem da cidade. Nesse sentido, também ficou evidente a necessidade de o município controlar e gerenciar a mídia exterior em conjunto com os demais aspectos que contribuem com a qualidade visual urbana.