bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B103: Transparent tumor tomography (T3): Spatial 3D mapping of immune responses in a whole tumor after immunotherapy
Authors: Lee Steve Seung-Young , Bindokas Vytas , Kron Stephen J. 
Published: May 2016

Abstract
This research seeks to develop an imaging technique for 3D mapping of immune contexts within a tumor. Capability to determine location, density, and functional orientation of the different immune cell populations within a whole tumor would be a powerful tool to examine crosstalk between a tumor microenvironment and immune system but also to advance development of effective cancer immunotherapy strategies. Although immunofluorescence staining has long been used in cancer immunology, the conventional immunofluorescence method is restricted to the localization of targeted antigens in limited two-dimensional (2D) tumor sections or small tumor volumes. Thus, 2D immunofluorescence cannot provide integrated spatial information about the immune cell distributions or other features of tumor tissue, leaving room to misinterpret the extent or significance of responses to therapy or downstream effects. To overcome these challenges, we developed a three-dimensional (3D) immunofluorescence tomography approach to map whole tumors at single cell resolution. Thus, we optimized optical clearing of tumor macroslices, increased penetration of antibodies to permit immunofluorescence staining, applied multicolor 3D microscopy imaging, enabled tomographic reconstruction of the images, and implemented automated image analysis. This approach allows us to spatially and quantitatively determine the distribution of tumor-infiltrating T cells (CD4+, CD8+, and regulatory (CD4+CD25+Foxp3+) T cells) in whole mouse mammary (TUBO) tumors. To demonstrate utility in evaluating immune responses, we performed intratumoral injection of the STING agonist DMXAA and evaluated anti-tumor immune responses in the whole tumor, including detecting damage to the microvasculature using the CD31 endothelial marker and increase in tumor-infiltrating CD8+ T cells. Our results establish a new method, Transparent Tumor Tomography (T3), that provides integrated spatial information regarding immune contexts in whole tumors as a new tool for cancer immunotherapy research.
Citation Format: Steve Seung-Young Lee, Vytas Bindokas, Stephen J. Kron. Transparent tumor tomography (T3): Spatial 3D mapping of immune responses in a whole tumor after immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B103.
Abstract B106: Noninvasive imaging of immune responses
Authors: Rashidian Mohammad 
Published: May 2016

Abstract
Tumors are often surrounded and invaded by bone marrow-derived cells. Imaging the infiltration of such immune cells into tumors may therefore be an attractive means of detecting tumors or of tracking the response to anticancer therapy. We developed alpaca-derived antibody fragments specific for mouse class II MHC and CD11b products, expressed on the surface of a variety of myeloid cells. We validated these reagents by flow cytometry and two-photon microscopy to obtain images at cellular resolution. To enable noninvasive imaging of the targeted cell populations, we developed a method to site-specifically label VHHs [the variable domain (VH) of a camelid heavy-chain only antibody] with 18F or 64Cu. Radiolabeled VHHs rapidly cleared the circulation (t1/2 ~15min) and clearly visualized lymphoid organs. We used VHHs to explore the possibility of imaging inflammation in both xenogeneic and syngeneic tumor models, which resulted in detection of tumors with remarkable specificity. We also imaged the infiltration of myeloid cells upon injection of complete Freund's adjuvant. Both anti-class II MHC and anti-CD11b VHHs detected inflammation with excellent specificity. Given the ease of manufacture and labeling of VHHs, we believe that this method could transform the manner in which antitumor responses and/or infectious events may be tracked. The ability to monitor the immune response in the course of therapy will enable early determination of the efficacy of treatment and will inform decisions as to whether treatment should be stopped or continued. Noninvasive monitoring could therefore change how therapies are applied and assessed, to the benefit of many patients.
Citation Format: Mohammad Rashidian. Noninvasive imaging of immune responses. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B106.
Abstract B113: In vivo characterization of anti-PD-1 antibody REGN2810 in human PD-1 knock-in mice
Authors: Burova Elena , Allbritton Omaira , Poueymirou William , Lai Venus , Waite Janelle , Skokos Dimitris , Papadopoulos Nicholas , Murphy Drew , Lowy Israel , Ioffe Ella , Thurston Gavin 
Published: May 2016

Abstract
The Programmed Death-1 (PD-1) receptor is an immunologic inhibitory checkpoint, expressed by activated T cells. PD-1 signals upon binding to its ligands PD-L1 and PD-L2 expressed on antigen presenting cells and some types of cancer cells, and delivers inhibitory signals to T cells, resulting in suppression of T-cell effector function. In cancer patients, PD-1 is expressed on tumor-infiltrating lymphocytes and inhibits antitumor immune responses through ligand binding. Clinically, it has been shown that antibodies (Abs) that block the interaction between PD-1 and PD-L1 can release the cytotoxic function of tumor-specific T cells, yielding durable objective responses in multiple cancer types. This study describes preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 monoclonal Ab that binds to the extracellular domain of human PD-1 with high affinity and specificity and inhibits interaction of PD-1 with its ligands. Taking advantage of the ability of human PD-1 to interact with murine PD-L1, we generated a mouse with human PD-1 gene knock-in allowing direct testing of our anti-human PD-1 Ab. Human PD-1 knock-in mice express a hybrid protein containing the extracellular portion of human PD-1, and transmembrane and intracellular domains of mouse PD-1. We demonstrated functional PD-1/PD-L1 signaling and immune responses in this model, and confirmed REGN2810 binding to hybrid PD-1 receptor on mouse T cells in vivo following REGN2810 injections. Prophylactic and therapeutic treatments of subcutaneous syngeneic tumors with REGN2810 in human PD-1 knock-in mice resulted in a dose-dependent suppression of tumor growth. Currently REGN2810 anti-PD-1 Ab is in phase 1 clinical trials for oncology indications.
Citation Format: Elena Burova, Omaira Allbritton, William Poueymirou, Venus Lai, Janelle Waite, Dimitris Skokos, Nicholas Papadopoulos, Drew Murphy, Israel Lowy, Ella Ioffe, Gavin Thurston. In vivo characterization of anti-PD-1 antibody REGN2810 in human PD-1 knock-in mice. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B113.
Abstract B162: Comprehensive analyses of tumor immunity with implications to cancer immunotherapies
Authors: Li Bo , Liu Jun , Liu X. Shirley 
Published: May 2016

Abstract
Checkpoint blockade drugs have recently achieved remarkable success in treating late stage melanoma, non-small cell lung carcinomas and renal cell carcinomas. This breakthrough stimulated more than two hundred clinical trials involving anti-CTLA4 or anti-PD-1/PD-L1 drugs over 20 human cancers worldwide in the past few years. Although many patients have shown promising results in Phase I/II trials, a substantial fraction failed to respond. Efforts have been made to elucidate the functions of selected immune cells and provide prognostic predictors. However, the clinical impact of other immune cells in many cancers remains poorly understood. We integrated high-throughput molecular profiles combined with clinical data to systematically model six immune components in the tumor microenvironment in over 10,000 samples across 23 cancer types. We showed that lymphocyte infiltration generally associates with better outcome, while tumor associated myelocytes are negative prognostic predictors. We identified diverse associations between tumor-infiltrating immune cells and patient clinical features, including patient survival, disease recurrence, clinical stage, age, gender and viral infection status. We found immune cell infiltration to be correlated with somatic mutation load and microsatellite instability (MSI) status, suggesting the mechanism of immunosurveillance. We observed correlation between cancer/testis antigen MAGEA3 expression with CD8 T-cell infiltration in melanoma but not in non-small cell lung carcinomas (NSCLC), and implicated CTAGE1 and CALR3 as alternative candidates for cancer vaccines in NSCLC. Furthermore, we found PD-1 and CTLA4 expression to be associated with CD8 T-cell level in most cancers with exceptions in glioblastoma and ovarian cancer, suggesting cancer-specific usage of checkpoint blockade drugs. Our study indicates that systematic analysis of tumor immunity has the potential to inform effective cancer vaccines and checkpoint blockade therapies.
Citation Format: Bo Li, Jun Liu, X. Shirley Liu. Comprehensive analyses of tumor immunity with implications to cancer immunotherapies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B162.
Abstract B171: A novel tumor-microenvironment-based prognostic score in patients with primary operable colorectal cancer
Authors: Park James H. , McMillan Donald C. , Edwards Joanne , Horgan Paul G. , Roxburgh Campbell S.D. 
Published: May 2016

Abstract
The tumor-associated inflammatory cell infiltrate and stroma hold independent prognostic value in patients with colorectal cancer. However, whether such measures hold complimentary prognostic value and how this may be applied alongside routine pathological staging remains unknown. The present study proposes a novel tumor microenvironment score, termed the Glasgow Microenvironment Score (GMS), comprising assessment of the inflammatory cell infiltrate (using Klintrup-Mäkinen grade (KM)) and tumor stroma percentage (TSP), with prognostic value independent of TNM stage. The GMS stratified patients into three prognostic groups: GMS=0 (strong KM), GMS=1 (weak KM/low TSP) and GMS=2 (weak KM/high TSP) with five-year cancer-specific survival of 89%, 75% and 51%, respectively (P&lt;0.001). Furthermore, when combined with node status, venous invasion or mismatch repair status, GMS further stratified survival (92% to 37%, 93% to 27% and 100% to 37%, respectively). Indeed, the GMS is routinely available and may be readily validated in patients with primary operable colorectal cancer.
Citation Format: James H. Park, Donald C. McMillan, Joanne Edwards, Paul G. Horgan, Campbell S.D. Roxburgh. A novel tumor-microenvironment-based prognostic score in patients with primary operable colorectal cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B171.
Abstract IA47: Nonviral gene transfer to redirect T cell specificity
Authors: Cooper Laurence 
Published: May 2016

Abstract
The administration of ex vivo engineered T cells is championed by academia and industry alike and has resulted in dramatic clinical responses. I will discuss how T cells can be engineered ex vivo using a transposon/transposase system for in vivo applications. We will discuss how this non-viral approach to gene therapy can be combined immunotherapy to redirect specificity and improve the effector functions of T cells manufactured for clinical trials. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs) and T-cell receptors (TCRs) to redirect specificity for protein and carbohydrates antigens. I will reveal how the non-viral Sleeping Beauty (SB) system can be adapted and used to stably express CARs and TCRs to improve the therapeutic potential of clinical grade T cells. These clinical data serve as a foundation for additional genetic engineering to co-express transgenes to improve persistence as well as provide the opportunity for genome editing to eliminate undesired endogenous genes to improve T-cell potency. As genetically modified T cells achieve FDA approval and enter into the mainstream of clinical practice a central question remains how to broaden the number of recipients that can receive such immunotherapy. This anticipated need can met by the use of non-viral gene transfer which provides an avenue for academia and industry to develop distribution systems to widen the human application of next-generation T-cell therapies.
Citation Format: Laurence Cooper. Nonviral gene transfer to redirect T cell specificity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA47.
Challenges and Prospects for Reducing Coupled Climate Model SST Biases in the Eastern Tropical Atlantic and Pacific Oceans: The U.S. CLIVAR Eastern Tropical Oceans Synthesis Working Group
Authors: Zuidema Paquita , Chang Ping , Medeiros Brian , Kirtman Ben P. , Mechoso Roberto , Schneider Edwin K. , Toniazzo Thomas , Richter Ingo , Small R. Justin , Bellomo Katinka , Brandt Peter , de Szoeke Simon , Farrar J. Thomas , Jung Eunsil , Kato Seiji , Li Mingkui , Patricola Christina , Wang Zaiyu , Wood Robert , Xu Zhao 
Published: May 2016

Abstract
Well-known problems trouble coupled general circulation models of the eastern Atlantic and Pacific Ocean basins. Model climates are significantly more symmetric about the equator than is observed. Model sea surface temperatures are biased warm south and southeast of the equator, and the atmosphere is too rainy within a band south of the equator. Near-coastal eastern equatorial SSTs are too warm, producing a zonal SST gradient in the Atlantic opposite in sign to that observed. The U.S. Climate Variability and Predictability Program (CLIVAR) Eastern Tropical Ocean Synthesis Working Group (WG) has pursued an updated assessment of coupled model SST biases, focusing on the surface energy balance components, on regional error sources from clouds, deep convection, winds, and ocean eddies; on the sensitivity to model resolution; and on remote impacts. Motivated by the assessment, the WG makes the following recommendations: 1) encourage identification of the specific parameterizations contributing to the biases in individual models, as these can be model dependent; 2) restrict multimodel intercomparisons to specific processes; 3) encourage development of high-resolution coupled models with a concurrent emphasis on parameterization development of finer-scale ocean and atmosphere features, including low clouds; 4) encourage further availability of all surface flux components from buoys, for longer continuous time periods, in persistently cloudy regions; and 5) focus on the eastern basin coastal oceanic upwelling regions, where further opportunities for observational–modeling synergism exist.
Influence of the Tian Shan on Arid Extratropical Asia
Authors: Baldwin Jane , Vecchi Gabriel 
Published: May 2016

Abstract
Arid extratropical Asia (AEA) is bisected at the wetter Tian Shan (a northern offshoot of the Tibetan Plateau) into east and west deserts, each with unique climatological characteristics. The east deserts (~35°–55°N, ~75°–115°E) have a summer precipitation maximum, and the west deserts (~35°–55°N, ~45°–75°E) have a winter–spring precipitation maximum. A new high-resolution (50 km atmosphere–land) global coupled climate model is run with the Tian Shan removed to determine whether these mountains are responsible for the climatological east–west differentiation of AEA. Multicentennial simulations for the Control and NoTianshan runs highlight statistically significant effects of the Tian Shan. Overall, the Tian Shan are found to enhance the precipitation seasonality gradient across AEA, mostly through altering the east deserts. The Tian Shan dramatically change the precipitation seasonality of the Taklimakan Desert directly to its east (the driest part of AEA) by blocking west winter precipitation, enhancing subsidence over this region, and increasing east summer precipitation. The Tian Shan increase east summer precipitation through two mechanisms: 1) orographic precipitation, which is greatest on the eastern edge of the Tian Shan in summer, and 2) remote enhancement of the East Asian summer monsoon through alteration of the larger-scale seasonal mean atmospheric circulation. The decrease in east winter precipitation also generates remote warming of the Altai and Kunlun Shan, mountains northeast and southeast of the Tian Shan, respectively, due to reduction of snow cover and corresponding albedo decrease.
Power, Policy, and Citizen Participation in Santo André, Brazil
Authors: Albert Victor 
Published: May 2016

City master plans assumed a central role in urban planning in Brazil with the promulgation of a new constitution in 1988 and the passage of enacting legislation in 2001. Citizen participation became an important part of this new urban planning framework. In contrast to some of Brazil’s other democratic experiments, participation in urban planning has been received critically or with only cautious optimism. A comparison of two participatory forums in Santo André, São Paulo, shows that established patterns of administrative power can decisively influence the participation of the public in city planning. Differences in the executive structures of the two institutions enabled one of them but not the other to foster open-ended deliberation on policies with members of disadvantaged groups. The study suggests that participation might be enhanced by reserving executive positions for civil society participants, including the public at all stages of policy development, choosing participants largely from disadvantaged groups, and keeping the forum small. Planos diretores para cidades desempenharam papel fundamental no planejamento urbano brasileiro com a promulgação da Constituição de 1988 e o sancionamento da legislação em 2001. Demais, a participação de cidadãos tornou-se importante elemento dessa nova moldura de planejamento urbanístico. Ainda assim, em contraste com outros experimentos democráticos no Brasil, a participação no planejamento urbano tem sido recebida de maneira crítica ou no máximo com otimismo cauteloso. Contudo, uma comparação entre dois forums participativos em Santo André, São Paulo, demonstra que padrões estabelecidos de poder administrativo tiveram influência decisiva na participação pública no planejamento urbano. Diferenças na estrutura executiva das duas instituições permitiram que uma delas, mas não a outra, promovesse deliberações transparentes sobre iniciativas enquanto permitia a participação de grupos menos privilegiados. O estudo sugere que a participação pode ser ampliada com a nomeação de participantes da sociedade civil a cargos executivos, incluindo-se o público em todos os estágios da política de desenvolvimento e escolhendo-se indivíduos majoritariamente entre segmentos mais desfavorecidos da população. O forum deve, ainda, manter-se pequeno.
Are There Other Options?
Authors: Becevic Mirna , Green Timothy , Walker Laine Young , Hicks Lanis , Mutrux Ellen R. 
Published: May 2016

This study compared University of Missouri child and adolescent telepsychiatry services patients’ specific zip codes to child and adolescent psychiatrists’ practice locations to learn if telehealth was an appropriate option for this group of patients. In demographically and geographically diverse state such as Missouri, patients in rural areas may have limited or no access to timely, affordable and quality care. Many large urban health-care institutions have turned to telehealth as a means of providing equal access to care for all population, no matter where they choose to live. The management analyst system Cognos/Analyzer was used as a data source. Patient- and provider-specific zip codes were processed using GeoKettle software, and ArcGIS explorer was used for map visualization. While patients utilizing child and adolescent telepsychiatry services come from various parts of the state, providers are mostly clustered in urban locations along the Interstate 70. This greatly limits access to specialty care for rural and other vulnerable populations. Telehealth provides adequate and timely access to child and adolescent psychiatry services for the youth that may otherwise not be able to get needed care. Barriers such as mental health crisis and access to care for rural population have been more or less successfully addressed by telehealth for several decades now. However, the shortage of specialty physicians adds an additional layer of complexity to this issue. Health-care organizations with informatics tools such as telemedicine need to focus their efforts on maximizing usage to allow more access for the underserved population.
Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study
Authors: Gold Ralf , Arnold Douglas L , Bar-Or Amit , Hutchinson Michael , Kappos Ludwig , Havrdova Eva , MacManus David G , Yousry Tarek A , Pozzilli Carlo , Selmaj Krysztof , Sweetser Marianne T , Zhang Ray , Yang Minhua , Potts James , Novas Mark , Miller David H , Kurukulasuriya Nuwan C , Fox Robert J , Phillips Theodore J 
Published: May 2016

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.