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11. Dietary tryptophan catabolite released by intratumoral Lactobacillus reuteri facilitates αPD-L1 therapy

Author

Mackenzie Bender, Alex McPherson, Catherine Phelps, Mohit Rana, Surya Pandey, Jake Shapira, Angela Gocher, Steven Mullett, Stacy Wendell, Diwakar Davar, Reinhard Hinterleitner, Dario Vignali, Alok Joglekar, Hassane Zarour, and Marlies Meisel

Abstract

The gut microbiome has been identified as a critical factor influencing cancer patient responses to immune checkpoint inhibitor (ICI) therapy; however, the underlying mechanisms of how gut microbes modulate ICI therapy efficacy remain enigmatic. Here, we show that gut-commensal Lactobacillus reuteri (L. reuteri) translocates to melanoma tumors where it mediates antitumor interferon-γ-producing CD8 T cell (Tc1 cell) immunity and facilitates ICI therapy via its released aryl hydrocarbon receptor (AhR) ligand, indole-3-aldehyde (I3A). This dietary tryptophan (Trp) catabolite is necessary and sufficient for antitumor immunity, and AhR signaling within CD8 T cells is required for L. reuteri to suppress melanoma growth. Further, a Trp-enriched diet potentiated L. reuteri- and ICI-induced antitumor immunity. Finally, we uncovered a role of I3A in promoting ICI therapy responses and survival in advanced melanoma patients. Collectively, our findings elucidate a novel crosstalk within the tumor microenvironment between the microbial metabolite I3A and CD8 T cells that facilitates ICI therapy efficacy, paving the way for dietary- and probiotic-based cancer therapeutics.

Published
2022

12. Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy

Author

Lilit Karapetyan, Arivarasan Karunamurthy, Anthony Cillo, Anjali Rohatgi, Ryan Campbell Massa, William E. Gooding, Yana G. Najjar, Diwakar Davar, Jason J. Luke, Tullia C. Bruno, Dario Vignali, and John M. Kirkwood

Subjects
Cancer Research, Oncology
Abstract

9514 Background: A phase II study of nivo and rela was designed to evaluate the antitumor activity and mechanism of this combination and components for first-line treatment of pts with advanced melanoma. Pts received lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy. We assessed the effect of each lead-in treatment on immune-related pathological response (irPR) at 4-wk biopsy to develop early biomarkers of antitumor response. Methods: Core biopsy of an index lesion was performed at baseline and after 4 wk on-treatment. Immune characteristics of pathological response were assessed on H&E sections, including presence of tumor-infiltrating lymphocytes (TIL), neovascularization, proliferative fibrosis, plasma cells, and lymphoid aggregates. irPR score was calculated as described by Stein JE et al Ann Oncol 2019, from 0 (no irPR features) to 3 (major pathologic response on biopsy [MPRbx], ≤10% residual viable tumor). We assessed the association between irPR and radiological response (RECIST v1.1) at 4-wk evaluations. Results: The current cohort includes 22 pts, median age = 67, male = 13. Pts were randomized to nivo = 7, rela = 7, and nivo-rela = 8 lead-in groups. Two pts had no irPR evaluation due to early progression and unscorable tumor. Among 20 evaluable pts, proliferative fibrosis, neovascularization, plasma cells, brisk TIL, and lymphoid aggregates were identified in 50%, 35%, 26.3%, 25%, and 5% of cases, respectively. Lead-in nivo (n = 2/6), rela (n = 0/6), and nivo-rela (n = 3/8) resulted in irPR = 3 in 25% of pts. Radiological response was identified as partial response (PR) = 1/22 (4.5%), stable disease (SD) = 12/22 (54.5%), and progressive disease (PD) = 9/22 (41%). Among pts with PD, 44% received rela-, 33% nivo-, and 22% nivo-rela- lead-in. Pts with irPR score = 3 had radiological PR = 1, SD = 3, and PD = 1 at 4wks. No association was found between MPRbx and radiological response at 4 wks. Conclusions: Four-wk MPRbx may serve as an early biomarker of treatment response in advanced melanoma. Lead-in treatment resulted in MPRbx of 25% and was greatest with nivo-rela lead-in. Correlations between 4 wk MPRbx and later radiological responses, survival and other endpoints will be made at completion of trial accrual. Clinical trial information: NCT03743766. [Table: see text]

Published
2022

13. Intra-islet CD8+ T cells are restrained by an exhaustion program that can be reversed by LAG3 deletion

Author

Stephanie J Grebinoski, Qianxia Zhang, Anthony R Cillo, Jishnu Das, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

CD8+ T cell exhaustion or dysfunction is a differentiation state in which T cells become unresponsive to stimulation and lose effector function1. Impaired chronic viral and tumor clearance has been attributed to CD8+ T cell exhaustion and can be partially reversed upon blockade of inhibitory receptors (IR) such as programmed cell death protein 1 (PD1). Despite detailed analysis of CD8+T cell in tumors and chronic viral infection, the role of the exhaustion program and the transcriptional networks that control CD8+T cell function and fate in autoimmunity are still unknown. Here we show that intra-islet CD8+T cells phenotypically and transcriptionally possess features of exhausted T cells, yet maintain key differences, such as an expanded repertoire of effector mechanisms, that contribute to their persistent pathogenicity in autoimmune diabetes. This dual identity, which we refer to as a ‘divergent’ exhaustion program, can be perturbed substantively by CD8+ T cell-restricted deletion of the IR Lymphocyte Activating Gene 3 (LAG3), causing enhanced effector-like function and pathogenicity. Understanding this divergent exhaustion program and its key mediators will guide future immunotherapeutic interventions by characterizing ways to promote exhaustion in autoimmunity and reversing exhaustion programs in chronic viral infections and tumors.

Published
2021

14. Treg-restricted deletion of TRAIL (Tnfsf10) reduces autoimmune diabetes

Author

Rebekah Dadey, Stephanie J Grebinoski, Qianxia Zhang, Angela Gocher, Erin Brunazzi, Lawrence Peter Andrews, Amanda Burton, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) are a suppressive cell population that limit the anti-tumor response. One mechanism Tregs utilize is production of suppressive cytokines. We previously asked if deletion of the two main suppressive cytokines made by Tregs would have any overall effect on the suppressive ability of the Tregs. We found that Treg-restricted deletion of the cytokines IL-10 and IL-35 led to a compensatory upregulation of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; Tnfsf10). In these studies, upregulation of TRAIL was dependent on deletion of IL-10 and IL-35; however, we also wondered if TRAIL could also be upregulated in inflammatory environments and if deletion would affect Treg function in these environments. We made a Tnfsf10L/L mouse, backcrossed onto both B6 and NOD backgrounds, and crossed each with respective Foxp3Cre lines. Surprisingly, we found little effect on tumor growth in B6 mice but found a substantive decrease in autoimmune diabetes incidence in the NOD mouse model. In the latter, we found that Treg-restricted deletion of TRAIL may extrinsically effect CD8+ and CD4+ T cell phenotype by increasing expression of suppressive molecules such as CD73 and LAP-TGFβ in these cells. Future studies are necessary to understand if this phenotypic change is responsible for the decrease in diabetes incidence.

Published
2020

15. PD1 and LAG3 converge to limit polyfunctionality and systemic immunity

Author

Lawrence Peter Andrews, Sasikanth Manne, E. John Wherry, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Targeting PD1 has yielded clinical success across many tumor types, yet a significant proportion of patients remain unresponsive to treatment. Co-expression of PD1 and LAG3 inhibitory receptors (IRs) on CD8+ tumor-infiltrating T cells (TIL) is associated with an exhausted phenotype and dual blockade synergistically limits tumor growth, greater than targeting PD1 alone. The cellular and mechanistic basis for PD1/LAG3 synergy is unknown. We have generated conditional knockin mice that facilitates the CD8+ T cell-restricted deletion of Pdcd1 and/or Lag3 when crossed to E8ICre.GFP. These mice have also been crossed with a pMEL TCR transgenic mouse, congenically marked to allow intrinsic analysis of PD1 and/or LAG3-deficient CD8+ T cells, and controls, in a ‘quad’ co-adoptive transfer system. Pdcd1L/L and/or Lag3L/L-yfp E8ICre.GFP mice show reduced B16-F10 tumor growth with improved survival, compared to Lag3L/L-yfp E8ICre.GFP mice and controls. CD8+ TIL frequency is increased with loss of both IRs, as a result of enhanced proliferation. Although expression of TIM3, TIGIT and 2B4 IRs is maintained, CD8+ TIL isolated from Pdcd1L/LE8ICre.GFP and Pdcd1L/ Lag3L/L-yfp E8ICre.GFP mice show increased polyfunctionality, by IFNg, TNFa and GzmB release. This was confirmed to be largely driven by effector and chemoattractive secretions by analysis with a 28-plex single-cell cytokine response panel (Isoplexis). Overall, these data suggest that PD1 and LAG3 synergize to have a dominant effect on CD8+ TIL and limit antitumor immune effects, as intrinsic removal of both IRs results in reduced tumor growth that substantially impacts anti-tumor immunity. These results are encouraging for the development of co-targeting LAG3 and PD1 in the clinic.

Published
2020

16. Distinct B cell signatures and tertiary lymphoid structures are driven by two etiol-ogies in head and neck cancer

Author

Ayana T Ruffin, Anthony R Cillo, Tracey Tabib, Angen Liu, Sayali Onkar, Sheryl Kunning, Caleb Lampfield, Irina Abecassis, Zengbiao Qi, Ryan Soose, Umamaheswar Duvvuri, Seungwon Kim, Robert Lafyatis, Robert L Ferris, Dario Vignali, and Tullia C Bruno

Subjects
Immunology, Immunology and Allergy
Abstract

B cells can regulate immune responses by presenting antigen, producing antigen-specific antibodies and immunomodulatory cytokines. Their role in the anti-tumor immune response is poorly understood. However, in many cancers including head and neck squamous cell carcinoma (HNSCC), intratumoral B cells correlate with better survival. HNSCC has two distinct etiologies (HPV−) and (HPV+) where patients who are HPV+ have increased B cell infiltration and respond better to therapy. We hypothesized that (1) intratumoral B cell phenotype is different between HPV+ and HPV− HNSCC (2) location within the tumor microenvironment (TME) is distinct and (3) antibodies produced by intratumoral B cell in HPV+ HNSCC are specific for viral antigens. Using single-cell RNA sequencing and spectral flow cytometry, we observed that B cell signatures in HPV− HNSCC patients were predominantly memory B cells and plasma cells, while the signatures in HPV+ HNSCC were naïve and germinal center (GC) B cells. Further, we quantified B cells in tertiary lymphoid structures (TLS) using multispectral immunofluorescence, and the presence of GC-rich TLS were increased in HPV+ patients. In fact, GC-rich TLS within the tumor of HPV+ patients correlated with increased overall survival. Overall, high enrichment for GC B cells were positively associated with longer progression-free survival. Antibodies produced by intratumoral B cells from HPV+ patients were positive for HPV viral antigens. Ultimately, characterization of B cell phenotype and function in HNSCC is important for devising new therapeutic options for cancer patients. Specifically, therapeutics to enhance B cell responses in the TME should be prioritized as a compliment to T-cell mediated therapies.

Published
2020

17. LAG3 mediates its inhibitory function by associating with the TCR:CD3 complex and inducing co-receptor:p56lck dissociation

Author

Creg Workman, Cliff Guy, Diana Mitrea, Po-Chien Chou, Jamshid Temirov, Kate Vignali, Xueyan Liu, Hui Zhang, Richard Kriwacki, Marcel Bruchez, Simon Watkins, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Lymphocyte activation gene 3 (LAG3) is an inhibitory receptor that is highly expressed on exhausted T cells in the tumor microenvironment. Despite over ten LAG3-targeting immunotherapeutics in clinical trials, we still do not know how LAG3 mediates its inhibitory activity. We show that LAG3 can function in the absence of MHC class II ligation and that in the absence of LAG3 there is a 2–3 fold increase in T cell receptor signaling resulting in increased proliferation. We show that both murine and human LAG3 molecules track to the immunological synapse (IS) by close association with the T cell receptor (TCR):CD3 complex. A phylogenetically conserved, acidic tandem glutamic acid–proline repeat in the LAG3 cytoplasmic tail can lower local pH at the IS and chelate Zn2+, limiting T cell activating signals by causing the dissociation of CD4:p56lck, which interact via a di-cystine:Zn2+ complex. This in turn causes a loss of co-receptor:TCR signaling. This novel inhibitory pH-mediated, Zn2+-displacement mechanism highlights LAG3 as a “signal disruptor” that can function in an MHC class II independent manner, providing critical insight into the mechanism of action of LAG3-targeting immunotherapies.

Published
2020

18. LAG3 limits the diabetogenicity of intra-islet CD8 T cells

Author

Stephanie J Grebinoski, Qianxia Zhang, Anthony R Cillo, Andrea Szymczak-Workman, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Tight control of effector T cells is necessary to limit autoimmune diabetes (AD). One mechanism by which this is achieved is through inhibitory receptor (IR) expression. Lymphocyte Activating Gene 3 (LAG3) is one critical IR that limits disease progression and incidence of AD. Using a mouse model in which LAG3 deletion is restricted to CD8+ T cells, Lag3L/L-YFPE8iCRE-GFP.NOD, and wild type (WT) controls, E8iCRE-GFP.NOD, we find that CD8+ T cell-restricted deletion of LAG3 is sufficient to accelerate diabetes incidence and insulitis. Interestingly, we see Lag3L/L-YFPE8iCRE-GFP.NOD mice have an increased intra-islet CD8:Treg ratio, and increased tetramer (Nrpv7, IGRP mimotope) staining. These observations drive our hypothesis that LAG3 limits those autoreactive CD8+ T cell. 5′ single cell RNAseq in conjunction with TCRseq reveals that LAG3-deficient (Lag3−/−) intra-islet CD8+ T cells are transcriptionally unique compared to WT controls, exhibiting a more activated phenotype along with lower geneset enrichment for markers of exhaustion. This was validated by flow cytometry in which WT CD8+ T cells possess an expanded PD1Hi, Tox+ population, while Lag3−/− CD8+ T cells have an expanded PD1mid population, express more CD44, KLRG1, BrdU, Ki67, and less aCasp3. This indicates that WT CD8+ T cells are able to appropriately upregulate PD1 and Tox in response to chronic self-antigen stimulation, while Lag3−/− CD8+ T cells maintain a more activated population. Strikingly, LAG3 deletion on CD8+ T cells appears to be sufficient to overcome a normal “exhaustion-like” program in intra-islet CD8+ T cells, resulting in accelerated diabetes incidence. These data highlight an important role for LAG3 and CD8+ T cell exhaustion programs in AD.

Published
2020

19. Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement

Author

Konstantina Iliadi, Wahbi K. El-Bouri, David M. Simpson, Diederik Bulters, A.A. Birch, Dario Vignali, and Robert J Marchbanks

Subjects
Adult, Male, Tympanic Membrane, Adolescent, Intracranial Pressure, genetic structures, Physiology, 0206 medical engineering, Biomedical Engineering, Biophysics, 02 engineering and technology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Physiology (medical), Heart rate, Respiration, Humans, Coherence (signal processing), Arterial Pressure, Aged, Intracranial pressure, integumentary system, Pulse (signal processing), Chemistry, musculoskeletal, neural, and ocular physiology, Middle Aged, 020601 biomedical engineering, humanities, nervous system diseases, Blood pressure, Harmonic, Female, Respiration rate, 030217 neurology & neurosurgery
Abstract

Objective: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. Approach: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1–5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. Main results: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. Significance: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies—respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD.

Published
2018

20. Quasi-linear modelling of the coupled cochlea using the WKB method

Author

Stephen J. Elliott, Ben Lineton, Angelis Karlos, and Dario Vignali

Subjects
Physics, Cochlear amplifier, Admittance, Quantitative Biology::Tissues and Organs, Mathematical analysis, Finite difference, WKB approximation, Nonlinear system, Distribution (mathematics), Computer Science::Sound, otorhinolaryngologic diseases, Wavenumber, sense organs, Cochlea
Abstract

The WKB method provides a convenient way of predicting the coupled response of the linear cochlea, given the distribution of the complex wavenumber along it. With one-dimensional (1D) fluid coupling, the local wavenumber can be calculated from the micromechanical admittance, which can be either passive or active. In practice, the degree of activity at some point along the cochlea will depend on the level of response at this point, due to the nonlinearity of the cochlear amplifier. Quasi-linear models have previously been used, by Kanis and de Boer for example, to estimate the response of a nonlinear cochlear model to single tones or combinations of tones, by iteratively solving for the coupled response and re-evaluating the effective gain of the cochlear amplifier along the length of the cochlea, using the Finite Difference (FD) method. In this paper we consider calculating the coupled response in such a quasi-linear model to single tones using the WKB method, instead of FD, thus gaining an analytical insightful solution. An even simpler quasi-linear model is also explored, in which only a single gain is assumed for the cochlear amplifier along the whole length of the cochlea. It is found that for single tones the coupled response predicted by this simplified quasi-linear model is very similar to that predicted by the quasi-linear model with a distribution of cochlear amplifier gains along the cochlea. The reasons for this similarity are explored and its implications discussed.

Published
2018

21. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. 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Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016

22. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016

23. Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure

Author

Robert J Marchbanks, A.A. Birch, Dario Vignali, Cherith M. Campbell-Bell, and Diederik Bulters

Subjects
Adult, Male, Tympanic Membrane, Supine position, Intracranial Pressure, Physiology, Posture, Biomedical Engineering, Biophysics, Sitting, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Physiology (medical), Humans, Medicine, Displacement (orthopedic surgery), 030223 otorhinolaryngology, Aged, Intracranial pressure, Aged, 80 and over, business.industry, Healthy population, Non invasive, Middle Aged, Perilymph, Healthy Volunteers, Reference intervals, Female, business, Nuclear medicine, 030217 neurology & neurosurgery
Abstract

OBJECTIVE Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. APPROACH Measurements were made in 154 healthy adults. Results were quantified by V m, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. MAIN RESULTS The range in which 95% of scores fall is -283 to 722 nl (M = 132 nl) left sitting, -232 to 623 nl (M = 97 nl) right sitting, -543 to 717 nl (M = 37 nl) left supine and -584 to 504 nl (M = -15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. SIGNIFICANCE We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for V m. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use.

Published
2018

24. Comparison of the nonlinear responses of a transmission-line and a filter cascade model of the human cochlea

Author

Stephen J. Elliott, Shuokai Pan, and Dario Vignali

Subjects
Masking (art), Basilar membrane, Nonlinear system, Engineering, Signal processing, Cascade, Control theory, business.industry, Electronic engineering, Automatic gain control, Dynamic range compression, Filter (signal processing), business
Abstract

Models of the mammalian cochlea have been proposed in a number of ways and they have varying degree of realism and complexity. The transmission-line (TL) models are faithful to the physiology, particularly in terms of cochlear nonlinearity, but are computationally demanding. The pole-zero filter cascade (PZFC) model, however, is much more efficient to implement, but the nonlinearity is included implicitly, using an automatic gain control network. In this study, the connection between the linear responses of these two models is first discussed, followed by a comparison of their nonlinear responses in terms of self-suppression and two-tone suppression on the level of the basilar membrane. Both models are capable of simulating dynamic range compression as measured on the cochlear partition, but the TL model is more reasonable in representing two-tone suppression, with the PZFC having lower suppression thresholds and over-predicting the suppression due to high-side suppressors. Further tuning of its parameters and structure, especially the automatic gain control (AGC) network may be possible to make it more compatible with these experimental observations. After adapting the PZFC model to have a more realistic nonlinear behavior, its use for investigating auditory signal processing such as masking effects, and hence as a front-end processor for acoustic signals can be enhanced, while retaining its computational efficiency.

Published
2015

25. Modeling dynamic properties of spontaneous otoacoustic emissions: Low-frequency biasing and entrainment

Author

Ben Lineton, Stephen J. Elliott, and Dario Vignali

Subjects
Physics, Acoustics and Ultrasonics, Quantitative Biology::Tissues and Organs, Local oscillator, Acoustics, Biasing, Low frequency, Standing wave, Nonlinear system, medicine.anatomical_structure, Arts and Humanities (miscellaneous), medicine, Auditory system, Entrainment (chronobiology), Cochlea
Abstract

Spontaneous otoacoustic emissions (SOAE) are sounds generated inside the living cochlea and are regarded as by-products of the active mechanism present in the peripheral auditory system. There is still debate whether these emissions are the product of local oscillators located at various positions along the cochlea (local oscillator model) or if they result from standing waves due to a global collective phenomenon that involves different aspects of the cochlea (global standing wave model). This paper uses a global standing wave cochlear model to predict various features of SOAEs. This involves a state-space formulation with a spatially distributed set of nonlinear active micromechanical elements coupled via cochlear fluid coupling. Simulation results have been compared with available experimental data and demonstrate two interesting nonlinear features of the cochlea: first, nonlinear properties of SOAEs modulated by external low-frequency bias tones are easily predicted and can be used to investigate the ...

Published
2016

26. Antigen-presenting tumor B cells impact the phenotype of CD4 tumor infiltrating T cells in lung cancer patients

Author

Tullia Carmela Bruno, Peggy Ebner, Brandon Moore, Olivia Squalls, Katherine Waugh, Evgeniy B Eruslanov, Sunil Singhal, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent E Palmer, Jeffrey Kern, Dario Vignali, and Jill E Slansky

Subjects
Immunology, Immunology and Allergy
Abstract

The focus of immunotherapy has been on CD8 and CD4 tumor infiltrating lymphocytes (TILs), however, tumor infiltrating B cells (TIL-Bs) are understudied with no focus on their role as antigen presenting cells. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs. Using un-manipulated, primary human B cells from fresh tumor, we generated a specific in vitro antigen presentation assay and observed three types of CD4 TIL responses when TIL-Bs presented autologous tumor antigens. There were activated responder CD4 TILs that proliferated when combined with TIL-Bs alone, which indicates stimulation with endogenous tumor antigens. There were antigen-associated responders that required autologous tumor lysate to elicit a CD4 TIL response, and there were patient CD4 TILs that did not respond to antigen presentation. Exhausted B cells have been described in chronic infection i.e. HIV, and thus, to parallel our studies to a model of chronic infection, we analyzed activated and exhausted TIL-Bs with our antigen presentation assay. If TIL-Bs were activated (HLADR+CD69+CD27+CD21+), the resultant CD4 TILs were T helper (anti-tumor) CD4 T cells and if the TIL-Bs were exhausted (HLADR+CD69+CD27−CD21−), the resultant CD4 TILs were T regulatory cells (pro-tumor). These data suggest that TIL-Bs influence CD4 TILs in NSCLC patient tumors. In conclusion, determining if TIL-Bs are activated or exhausted in NSCLC patients will determine the extent of their anti-tumor function in human cancer. Ultimately, results from this study will dictate how to target TIL-Bs in future immunotherapies.

Published
2017

29. Neuropilin-1 enforces Treg stability and function in the tumor microenvironment. (TUM2P.889)

Author

Abigail Overacre, Greg Delgoffe, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) play an integral role in the adaptive immune system by suppressing detrimental self-reactive responses. However, Tregs have deleterious effects in cancer through suppression of the anti-tumor immune response. Therefore, it is advantageous to understand the role of Tregs in the tumor microenvironment in order to create targeted cancer therapies. Our lab has uncovered a novel function for neuropilin-1 (Nrp1) on Tregs in tumors. In the absence of Nrp1 ligation by its ligand, Sema4a, Tregs lose stability and suppressive capabilities, leading to enhanced anti-tumor immunity and reduced tumor growth or tumor clearance. We hypothesize that the loss of Nrp1 expression on Tregs reduces intratumoral stability through altered intracellular pathways and diminished Foxp3 expression, transforming Tregs from an anti-inflammatory to a pro-inflammatory T cell population. Nrp1-deficient Tregs have a hypermethylated Foxp3 CNS2/TSDR locus in the tumor microenvironment, comparable to Teff, and display TH1-like characteristics, with upregulation of Tbet, CXCR3, and IFNγ, and the reduction of suppressive molecules, IL-10 and CD73. Furthermore, in competitive environments Nrp1-deficient Tregs undermine and limit the function of wild-type Tregs. Further mechanistic analysis and fate mapping studies will elucidate the cell-intrinsic and cell-extrinsic impact of Nrp1 loss on Treg function and tumor clearance.

Published
2014

30. The inhibitory cytokine IL-35 in Treg-mediated control of allergic diseases (HYP7P.285)

Author

Deepali Sawant, David Corry, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) represent a critical suppressive T cell population that maintains immune homeostasis and tolerance. Increasing evidence suggests reduced Treg numbers or compromised Treg function in atopic and asthmatic individuals. Treg derived suppressive cytokines, IL-10 and TGFβ, alleviate Th2 inflammation through allergen-specific immunotherapy. Studies on experimental asthma highlight an undisputed role for Tregs in allergic diseases; however, they fail to pinpoint a single/predominant mechanism employed by Tregs to control asthmatic inflammation. Our lab has identified a novel Treg-derived suppressive cytokine IL-35 (a heterodimer of Ebi3 and Il12a/p35) that is essential for their maximal suppressive activity. IL-35 also induces the conversion of naïve T cells into an IL-35-dependent suppressive population termed iTr35 cells. We hypothesize that IL-35-secreting Tregs and iTr35 cells are potent suppressors of Th2 allergic responses. We demonstrate that allergic inflammation induces the IL-35-mediated regulatory milieu (IL-35-expressing Tregs and iTr35 cells) in two distinct models of asthma (OVA/Alum and fungal protease). Further, IL-35 neutralization exacerbates asthmatic inflammation. Current studies using IL-35 reporter and gene-deficient mouse strains are directed at evaluating the expression, function and mechanisms of IL-35-mediated Treg control of allergic inflammation and have the potential to lead to novel IL-35-based therapeutic regimens.

Published
2014

31. Regulatory T cells use LAG-3 as the 'brake' in autoimmune diabetes but the 'accelerator' in tumor environment (IRC4P.487)

Author

Qianxia Zhang, Amy Beres, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Lymphocyte Activation Gene-3 (LAG-3, CD223) is an inhibitory receptor that is expressed upon TCR activation, is highly up-regulated on exhausted conventional T cells, and regulates T cell expansion, homeostasis and function via both cell intrinsic and extrinsic mechanisms. LAG-3 is also required for maximal regulatory T cell (Treg) function. Our lab has previously shown that LAG-3 modulates tolerance mechanisms, but the specific function of LAG-3 expressed by Tregs remains unknown. To elucidate the role of LAG-3 in Treg-mediated immune suppression, we generated mice in which active, membrane-expressed LAG-3 is specifically deleted in Foxp3+ Tregs. We used both the non-obese diabetes (NOD) and B6 mouse backgrounds to study the role of LAG-3-deficient Tregs in autoimmune diabetes and B16 melanoma, respectively. Surprisingly, the deletion of LAG-3 in Tregs both protected NOD mice from autoimmune diabetes and resulted in decreased B16 melanoma growth. In an autoimmune environment, the number of Tregs infiltrating the islets was limited by LAG-3, which facilitated the breakdown of self-tolerance. However, in the tumor microenvironment, LAG-3 activity was required for Treg-mediated immune suppression. These data suggest opposing roles for LAG-3 on Tregs in an inflammatory versus an immunosuppressive microenvironment. Therefore, specifically targeting LAG-3 on Tregs may provide a strategy for limiting tumor growth without subsequent development of autoimmunity.

Published
2014

32. IL35 neutralization enhances tumor specific immunity in mouse models of cancer (P2024)

Author

Meghan Turnis, David Gravano, Greg Delgoffe, Heidi Steinkamp, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Treg) are critical to maintenance of self-tolerance and prevention of autoimmunity; however, they also function to limit anti-cancer responses.Therefore, clarifying the mechanisms of Treg-mediated suppression in the context of cancer will aid in the rational design of new therapies.Our lab has identified a novel suppressive role for the IL35 heterodimer in Treg. IL35 is a member of the IL12 family composed of IL12a and Ebi3 subunits and is preferentially expressed by Treg. Treg and other suppressive factors in the tumor microenvironment inhibit antigen-specific cytotoxic lymphocyte responses; depletion or inhibition of Treg has been shown to decrease tumor burden and enhance patient outcome in both animal models and the clinic. We hypothesize that IL35 contributes critically to the tumor microenvironment and that its elimination will enhance tumor specific immunity. Using neutralizing antibodies specific for IL35-Ebi3, we have shown that systemic neutralization of IL35 significantly slows tumor growth compared with IgG control and enhances survival in the B16 melanoma model. Molecular analysis of tumor-infiltrating lymphocytes (TILs) has shown increased numbers, more activated CD8+ cells (CD44+CD62L-), and a greater proportion of proliferative cells by BrdU/Ki-67 staining in IL35-neutralized animals. We are currently extending studies to include metastatic and genetic models to better understand the mechanism of IL35 activity in the tumor microenvironment.

Published
2013

33. Potentiation of regulatory T cell stability and function via a neuropilin-1:semaphorin-4a axis (P1057)

Author

Greg Delgoffe, Seng Woo, Meghan Turnis, David Gravano, Cliff Guy, Matthew Bettini, David Finkelstein, Peter Vogel, Jody Bonnevier, Creg Workman, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells represent a critical immunoregulatory component of the immune system. The signals that maintain Treg stability and potentiate their function remain obscure. Here we show that the immune cell surface ligand semaphorin-4a on conventional murine and human T cells and dendritic cells interacts with the Treg-restricted receptor neuropilin-1 to potentiate Treg function and enhance survival. Mice with a Treg-restricted deletion of Nrp1 exhibit extremely limited tumor-induced tolerance, and thus substantial resistance to certain tumors, yet do not develop any autoimmune or inflammatory manifestations. Sema4a or Nrp1 blockade also had therapeutic efficacy against pre-existing tumors. In addition, Nrp1-deficient Treg cells fail to suppress inflammatory colitis. Upon Sema4a ligation, Nrp1 was recruited to the immunological synapse and repressed Akt activity via PTEN, which facilitated Foxo nuclear translocation. This induced a transcriptional program that promoted Treg stability, survival and function while repressing the induction of lineage-specific transcription factors. Thus, Nrp1 ligation enforces Treg stability and function in highly inflammatory sites but is dispensable for the maintenance of immune homeostasis, highlighting Nrp1 as a potential immunotherapeutic target in cancer.

Published
2013

34. Exosomes represent a novel mechanism of regulatory T cell suppression (P1079)

Author

Heidi Steinkamp, Greg Delgoffe, Sharon Frase, Ashley Castellaw, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells suppress via a variety of mechanisms, both contact-dependent and -independent mechanisms. These is some controversy as to which mechanisms play more dominant roles during various disease states as well as maintenance of immune homeostasis. Our laboratory has found that regulatory T cells secrete exosome-like vesicles that are 20 to 50 nm in diameter. Membrane vesicles have been shown to mediate communication amongst immune cells, but they also mediate communication between immune cells and cancer cells and between and immune cells and pathogens. Membrane vesicles mediate physiologic changes in recipient cells by initiating cellular signaling events following receptor binding, or via uptake and integration of vesicular cargo, which can include receptors, enzymes, cytokines, chemokines and genetic material. We have found that functional regulatory T cell membrane vesicles mediate suppression of conventional CD4+ T cells, whereas resting regulatory T cell and conventional T cell vesicles do not. Furthermore, we have found that 293F cells package overexpressed immunosuppressive cytokines into exosomes following transfection. Taken together these data suggest that exosome-like vesicles represent a bridge between contact dependent and independent regulatory T cell suppression.

Published
2013

35. Analyzing the contributions of TCR affinity to the pathogenesis of experimental autoimmune encephalomyelitis (P4129)

Author

J. Lori Blanchfield, Maria Bettini, Dario Vignali, and Brian Evavold

Subjects
Immunology, Immunology and Allergy
Abstract

Myelin oligodendrocyte glycoprotein (MOG) specific CD4+ T cell infiltrates from the central nervous system (CNS) have exhibited a range of affinities (low to high) for MOG peptide:MHC class II during peak EAE symptoms. Tetramer binding analyses and two-dimensional affinity assays have indicated that high affinity, MOG specific T cells comprise a rare yet significant population within the polyclonal repertoire; however, their functional contributions to the pathogenesis of chronic autoimmunity is not clear. Preliminary experiments suggested that a high precursor frequency (15 x 106) of polyclonal tetramer positive MOG specific T cells promotes early onset and greater disease severity when compared to tetramer negative T cells. Analysis of a high affinity MOG specific, CD4+ T cell (TCR Vα4β1) revealed a two dimensional affinity of 6.4x10-4 μm4 that was similar to the mean affinity (1.6x10-4 μm4) of pathogenic CD4+ T cells at peak LCMV Armstrong infection. Retrogenic models were used to assess the pathogenicity of TCR affinity in order to circumvent the limited number of endogenous high affinity T cells. The TCR Vα4β1 retrogenic mice developed spontaneous EAE even in the presence of FoxP3 positive (6%) T cells. T cells progressed though thymic selection without altering CD4 or TCR expression while maintaining their high two-dimensional affinity. Overall, MOG specific, high affinity CD4+ T cells are pathogenic and may predispose mice to a rapid progressive course of EAE.

Published
2013

36. Gfi1 couples maturation of DP thymocytes and generation of nTreg cells (P4418)

Author

Lewis Zhichang Shi, Nishan Kalupahana, Meghan Turnis, Geoffrey Neale, Dario Vignali, and Hongbo Chi

Subjects
Immunology, Immunology and Allergy
Abstract

Double-positive (DP) thymocytes respond to intrathymic TCR signaling by undergoing positive selection and lineage differentiation. Concomitant with these well-characterized events is the acquisition of mature T-cell gene-expression programs, notably the upregulation of effector molecules that are essential for their proper survival and trafficking, a process that is much less understood. nTreg cells also develop from immature thymocytes, but how their development is linked to the thymocyte maturation remains unclear. Here we report that Gfi1 has a central role in coupling DP cell maturation and thymic generation of nTreg cells. Using a conditional Gfi1 deletion system, we observed that specific ablation of Gfi1 in DP cells led to premature expression of mature effector genes and transcription factors, thereby facilitating developmental maturation. Associated with this “expedited” maturation of DP cells was expansion of nTreg cells. Mechanistically, we identified that elevated IL-2 signaling in the absence of Gfi1 drove the expansion of nTreg cells via a non-cell-autonomous mechanism. Finally, we provide evidence that deficiency of Gfi1 dampened anti-tumor immunity. Our results establish a Gfi1-dependent mechanism that actively maintains DP cell fate for proper developmental maturation and generation of nTreg cells.

Published
2013

37. Functional plasticity of regulatory T cells (168.7)

Author

Meenu R. Pillai, Lauren Collison, David Finkelstein, Jerold Rehg, Kelli Boyd, Andrea Workman, Thomas Griffith, Thomas Ferguson, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) play a pivotal role in maintaining immune homeostasis, preventing autoimmunity, controlling exaggerated immune responses against infections and suppressing anti-tumor immunity. Tregs utilize multiple mechanisms to mediate their function. However, the number of mechanisms critical to exert maximal suppressive activity is unclear. It is conceivable that suppressive mechanisms could be tightly regulated by cross-regulatory networks. It has been shown that interleukin 10 (IL10) and IL35 have critical role in Treg function. Therefore, we assessed the functional capacity of Tregs lacking the ability to secrete IL10 and IL35. Surprisingly, our study revealed that Tregs lacking both IL10 and IL35 (Ebi3-/-Il10-/- or Il12a-/-Il10-/-) were fully functional and were able to suppress Tconv cells both in vitro and in vivo . Absence of IL10 and IL35 was compensated by an increase in cathepsin E (CTSE), influencing the release of soluble TRAIL and thereby resulting in suppression of target cells in a TRAIL-dependent manner. Inhibiting TRAIL activity disrupted the function of Ebi3-/-Il10-/- Tregs. The loss of suppressive function was maximal in Tregs lacking IL10, IL35 and TRAIL (Ebi3-/-Il10-/-Tnfsf10-/-Tregs). These data suggests the existence of cross-regulatory networks which controls the utilization of suppressive factors, thereby maintaining Treg functional plasticity.

Published
2011

38. Interleukin-35 subunit dimerization and stability is unique among IL-12 cytokine family members (134.9)

Author

Lindsay Jones, Lauren Collison, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

IL-35 is a newly discovered cytokine that contributes to the suppressive capacity of regulatory T cells. IL-35 is a heterodimer consisting of an α chain (p35) and a β chain (Ebi3). It is a member of the IL-12 cytokine family, which is characterized by the sharing of three α (p19, p28, p35) and two β (p40 and Ebi3) subunits, and also includes IL-12 (p35/p40), IL-23 (p19/p40) and IL-27 (p28/Ebi3). In this study, relative pairing and secretion efficiencies and the dimerization interfaces of IL-12 family members were characterized, with emphasis on IL-35. Specific p35 residues that are known to contribute to formation of the IL-12 interface were assessed for their contribution to the IL-35 interface in mutagenesis studies. Similarly, several candidate Ebi3 residues were screened for their contribution to both IL-27 and IL-35 interfaces. Several residues were identified as critical to the IL-12 or IL-27 interfaces. Conversely, no single mutation was identified that completely disrupts p35/Ebi3 pairing, indicating that p35 and Ebi3 may pair differently to form IL-35. Preliminary data also indicate that IL-35 is poorly secreted by transfected cells, compared to IL-12 and IL-27, suggesting IL-35 formation is unfavorable or the secreted protein in unstable. Thus IL-35 appears to be different from other IL-12 family members in terms of both dimerization interface and stability. This work is supported by grants from the NIH and ALSAC.

Published
2010

39. Interleukin-35-mediated induction of a novel regulatory T cell population (49.7)

Author

Lauren Collison, Abigail Henderson, Vandana Chaturvedi, Mary Turk, and Dario Vignali

Subjects
Immunology, Immunology and Allergy
Abstract

Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self tolerance and immune homeostasis. Due to their potent immunosuppressive properties, the ex vivo generation of regulatory T cells is an important goal of immunotherapy. We show that treatment of conventional T cells (Tconv) with the inhibitory cytokine IL-35 induces IL-35 expression and confers suppressive capacity, in the absence of Foxp3, IL-10 and TGFβ expression, upon Tconv cells. IL-35-dependent induced Tregs, termed iTR35, are strongly suppressive in vitro and in in vivo models including IBD, EAE, and a B16 tumor model. Treg-mediated suppression induces the generation of iTR35 in an IL-35- and IL-10-dependent manner in vitro and within the tumor microenvironment. Human IL-35 can mediate the generation of human iTR35 that express IL-35 and are suppressive. iTR35 may constitute a key mediator of infectious tolerance and ex vivo generated iTR35 may possess therapeutic utility in various human diseases.

Published
2010

40. Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement.

Author

Wahbi K El-Bouri, Dario Vignali, Konstantina Iliadi, Diederik Bulters, Robert J Marchbanks, Anthony A Birch, and David M Simpson

Subjects
*INTRACRANIAL pressure, *ARTERIAL pressure, *TYMPANIC membrane, *INTENSIVE care units, *HEART rate monitoring
Abstract

Objective: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. Approach: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1–5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. Main results: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. Significance: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies—respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD. [ABSTRACT FROM AUTHOR]

Published
2018
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41. Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure.

Author

Cherith M Campbell-Bell, Anthony A Birch, Dario Vignali, Diederik Bulters, and Robert J Marchbanks

Subjects
TYMPANIC membrane, INTRACRANIAL pressure, CEREBROSPINAL fluid, PERILYMPH, NONINVASIVE diagnostic tests
Abstract

Objective: Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. Approach: Measurements were made in 154 healthy adults. Results were quantified by Vm, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. Main results: The range in which 95% of scores fall is  −283 to 722 nl (M  =  132 nl) left sitting, −232 to 623 nl (M  =  97 nl) right sitting, −543 to 717 nl (M  =  37 nl) left supine and  −584 to 504 nl (M  =  −15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. Significance: We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for Vm. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use. [ABSTRACT FROM AUTHOR]

Published
2018
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