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1.  Proceedings of the Canadian society of allergy and clinical immunology annual scientific meeting 2015 
Côté, Marie-Ève | Boulay, Marie-Ève | Plante, Sophie | Chakir, Jamila | Boulet, Louis-Philippe | Ahmed, Hanan | Ospina, Maria-Beatriz | Sideri, Kyriaki | Vliagoftis, Harissios | Johnson, Sara F. | Woodgate, Roberta L. | Cros, Guilhem | Teira, Pierre | Cellot, Sonia | Bittencourt, Henrique | Decaluwe, Helene | Vachon, Marie France | Duval, Michel | Haddad, Elie | Kim, Vy H. D. | Pham-Huy, Anne | Grunebaum, Eyal | Oliveria, John-Paul | Phan, Stephanie | Tenn, Mark W. | Tworek, Damian | Smith, Steven G. | Baatjes, Adrian J. | Obminski, Caitlin D. | Munoz, Caroline E. | Scime, Tara X. | Sehmi, Roma | Gauvreau, Gail M. | Salter, Brittany M. | Smith, Steven G. | Obminski, Caitlin D. | Munoz, Caroline E. | Schlatman, Abbey | Scime, Tara X. | Watson, Rick | Sherkat, Roya | Khoshnevisan, Razieh | Sheikhbahaei, Saba | Betschel, Stephen | Warrington, Richard | Schellenberg, Robert | Fein, Michael N. | Pelletier, Jean-Philippe | Kan, Manstein | Labrosse, Roxane | Mak, Raymond | Loh, James | Kanani, Amin | Nowak, Dominik A. | Keith, Paul K. | Pannozzo, Daniel | Lima, Hermenio C. | Pham, Diana | Pham, Hoang | Alvarez, Gonzalo G. | Bencze, Istvan T. | Sharma, Krishna B. | Smith, Mark | Aaron, Shawn | Block, Jennifer | Keays, Tara | Leech, Judith | Schneidermen, David | Cameron, Jodi | Forgie, Jennifer | Ring, Alicia | O’Quinn, John W. | Santucci, Stephanie | Yang, William H. | Gaudet, Ena | Aaron, Shawn | Voisin, Mathew R. | Borici-Mazi, Rozita | Vostretsova, Kateryna | Stark, Donald F. | Yeboah, Elizabeth | Martin-Rhee, Michelle | Gula, Cheryl | Cheng, Clare | Paltser, Geoff | Dery, Alizée | Clarke, Ann | Nadeau, Kari | Harada, Laurie | Weatherall, Kimberley | Greenwood, Celia | Daley, Denise | Asai, Yuka | Ben-Shoshan, Moshe | Ling, Ling | Ospina, Maria B. | Protudjer, Jennifer L. P. | Vetander, Mirja | van Hage, Marianne | Olén, Ola | Wickman, Magnus | Bergström, Anna | Teoh, Timothy | Mill, Christopher | Wong, Tiffany | Baerg, Ingrid | Alexander, Angela | Hildebrand, Kyla J. | Dean, John | Kuzeljevic, Boris | Chan, Edmond S. | Argeny, Jonathan | Gona-Hoepler, Mia | Fucik, Petra | Nachbaur, Edith | Gruber, Saskia | Crameri, Reto | Glaser, Andreas | Szépfalusi, Zsolt | Rhyner, Claudio | Eiwegger, Thomas | Plunkett, Greg | Mire, Brad | Yazicioglu, Mehtap | Can, Ceren | Ciplak, Gokce | Cook, Victoria E. | Portales-Casamar, Elodie | Nashi, Emil P. | Gabrielli, Sofianne | Primeau, Marie-Noel | Lejtenyi, Christine | Netchiporouk, Elena | Dery, Alizee | Shand, Greg | Hoe, Erica | Liem, Joel | Ko, Jason K. | Huang, David J. T. | Mazza, Jorge A. | McHenry, Mary | Otley, Anthony | Watson, Wade | Kraft, John N. | Paina, Mihaela | Darwish Hassan, Ahmed A. | Heroux, Delia | Crawford, Lynn | Gauvreau, Gail | Denburg, Judah | Pedder, Linda | Chad, Zave | Sussman, Gordon | Hébert, Jacques | Frankish, Charles | Olynych, Timothy | Cheema, Amarjit | Del Carpio, Jaime | Harrison, Rachel | Torabi, Bahar | Medoff, Elaine | Mill, Jennifer | Quirt, Jaclyn A. | Wen, Xia | Kim, Jonathan | Herrero, Angel Jimenez | Kim, Harold L. | Grzyb, Magdalena J. | Primeau, Marie-Noël | Azad, Meghan B. | Lu, Zihang | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Boucher-Lafleur, Anne-Marie | Gagné-Ouellet, Valérie | Jacques, Éric | Laprise, Catherine | Chen, Michael | McGovern, Toby | Adner, Mikael | Martin, James G. | Cosic, Nela | Ntanda, Henry | Giesbrecht, Gerald | Kozyrskyj, Anita | Letourneau, Nicole | Dawod, Bassel | Marshall, Jean | De Schryver, Sarah | Halbrich, Michelle | La Vieille, Sebastian | Eisman, Harley | Alizadehfar, Reza | Joseph, Lawrence | Morris, Judy | Feldman, Laura Y. | Thacher, Jesse D. | Kull, Inger | Melén, Erik | Pershagen, Göran | Protudjer, Jennifer L. P. | Hosseini, Ali | Hackett, Tillie L. | Hirota, Jeremy | McNagny, Kelly | Wilson, Susan | Carlsten, Chris | Huq, Saiful | Chooniedass, Rishma | Gerwing, Brenda | Huang, Henry | Lefebvre, Diana | Becker, Allan | Khamis, Mona M. | Awad, Hanan | Allen, Kevin | Adamko, Darryl J. | El-Aneed, Anas | Kim, Young Woong | Gliddon, Daniel R. | Shannon, Casey P. | Singh, Amrit | Hickey, Pascal L. C. | Ellis, Anne K. | Neighbour, Helen | Larche, Mark | Tebbutt, Scott J. | Ladouceur, Erika | Stewart, Miriam | Evans, Josh | Masuda, Jeff | To, Teresa | King, Malcolm | Larouche, Miriam | Liang, Liming | Legere, Stephanie A. | Haidl, Ian D. | Legaré, Jean-Francois | Marshall, Jean S. | Sears, Malcolm | Moraes, Theo J. | Ratjen, Felix | Gustafsson, Per | Lou, Wendy | North, Michelle L. | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Brook, Jeff | Rahman, Tanvir | Lejtenyi, Duncan | Fiter, Ryan | Piccirillo, Ciriaco | Mazer, Bruce | Simons, Elinor | Hildebrand, Kyla | Turvey, Stuart | DeMarco, Mari | Le Cao, Kim-Anh | Gauvreau, Gail M. | Mark FitzGerald, J. | O’Byrne, Paul M. | Stiemsma, Leah T. | Arrieta, Marie-Claire | Cheng, Jasmine | Dimitriu, Pedro A. | Thorson, Lisa | Yurist, Sophie | Lefebvre, Diana L. | Mandhane, Piush | McNagny, Kelly M. | Kollmann, Tobias | Mohn, William W. | Brett Finlay, B. | Tran, Maxwell M. | Lefebvre, Diana L. | Ramasundarahettige, Chinthanie F. | Dai, Wei Hao | Mandhane, Piush J. | Tworek, Damian | O’Byrne, Seamus N. | O’Byrne, Paul M. | Denburg, Judah A. | Walsh, Laura | Soliman, Mena | Steacy, Lisa M. | Adams, Daniel E. | Warner, Linda | Mauro, Mary Ann | Mamonluk, Robby | Yang, ChenXi | Conway, Ed M.
Table of contents
A1 Role of fibrocytes in allergic rhinitis
Marie-Ève Côté, Marie-Ève Boulay, Sophie Plante, Jamila Chakir, Louis-Philippe Boulet
A2 Patterns of aeroallergens sensitization in Northern Alberta
Hanan Ahmed, Maria-Beatriz Ospina, Kyriaki Sideri, Harissios Vliagoftis
A3 Addressing acceptable risk for adolescents with Food-Induced Anaphylaxis (FIA)
Sara F. Johnson, Roberta L. Woodgate
A4 Outcomes of matched related and unrelated bone marrow transplantation after reduced-toxicity conditioning for children suffering from Chronic Granulomatous Disease
Guilhem Cros, Pierre Teira, Sonia Cellot, Henrique Bittencourt, Helene Decaluwe, Marie France Vachon, Michel Duval, Elie Haddad
A5 Outcomes of patients with severe combined immunodeficiency (SCID) prior to and after initiation of newborn screening for SCID in Ontario
Vy H.D. Kim, Anne Pham-Huy, Eyal Grunebaum
A6 Detection of regulatory B cells in the airways of subjects with asthma
John-Paul Oliveria, Stephanie Phan, Mark W. Tenn, Damian Tworek, Steven G. Smith, Adrian J. Baatjes, Caitlin D. Obminski, Caroline E. Munoz, Tara X. Scime, Roma Sehmi, Gail M Gauvreau
A7 Characterization of IgE-expressing B cells in the airways and peripheral blood of allergic asthmatic subjects
John-Paul Oliveria, Stephanie Phan, Mark W. Tenn, Brittany M Salter, Steven G Smith, Caitlin D Obminski, Caroline E Munoz, Abbey Schlatman, Tara X Scime, Rick Watson, Roma Sehmi, Gail M Gauvreau
A8 Pregnancy: could it be a risk factor for primary immunodeficient patients
Roya Sherkat, Razieh Khoshnevisan, Saba Sheikhbahaei
A9 Clinical experience with Octagam: a Canadian retrospective chart review
Stephen Betschel, Richard Warrington, Robert Schellenberg
A10 Kounis syndrome secondary to contrast media with inferior ST elevations and bilateral ischemic stroke
Michael N Fein, Jean-Philippe Pelletier
A11 Honey bee venom immunotherapy ineffective in bumble bee-induced anaphylaxis: case report and review of literature
Manstein Kan, Robert Schellenberg
A12 Delayed immune reconstitution occurring after multiple immune complications of hematological stem cell transplantation for a leaky SCID
Roxane Labrosse, Guilhem Cros, Pierre Teira, Henrique Bittencourt, Helene Decaluwe, Michel Duval, Elie Haddad
A13 Comparison of Three Case Reports of Acquired Angioedema: presentation, management and outcome
Raymond Mak, James Loh, Amin Kanani
A14 Sitagliptin-associated angioedema not related to concurrent use of ARB or ACE inhibitor
Dominik A. Nowak, Paul K. Keith
A15 Sneddon-Wilkinson subcorneal pustular dermatosis associated with an IgA monoclonal gammopathy
Daniel Pannozzo, Dominik A. Nowak, Hermenio C. Lima
A16 Omalizumab can be effective in patients with allergic bronchopulmonary aspergillosis
Diana Pham, Hoang Pham, Gonzalo G. Alvarez, Istvan T. Bencze, Krishna B. Sharma, Mark Smith, Shawn Aaron, Jennifer Block, Tara Keays, Judith Leech, David Schneidermen, Jodi Cameron, Jennifer Forgie, Alicia Ring, John W. O’Quinn, Stephanie Santucci, William H. Yang
A17 Efficacious use of omalizumab in the treatment of cystic fibrosis
Diana Pham, Hoang Pham, Ena Gaudet, Shawn Aaron, Stephanie Santucci, William H. Yang
A18 HAE with normal C1-INH with inconsistent response to C1 esterase inhibitor infusion but reliably responsive to icatibant
Hoang Pham, Stephanie Santucci, William H. Yang
A19 Anaphylaxis reaction to lactase enzyme
Mathew R. Voisin, Rozita Borici-Mazi
A20 Risk of solid tumor malignancies in patients with primary immune deficiency
Kateryna Vostretsova, Donald F. Stark
A21 Is it time to adopt the chromogenic assay for measuring C1 esterase inhibitor function in patients with HAE Type 2?
Elizabeth Yeboah, Paul K. Keith
A22 Emergency department visits for anaphylaxis and allergic reactions
Michelle Martin-Rhee, Cheryl Gula, Clare Cheng, Geoff Paltser
A23 START: Susceptibility To food Allergies in a Registry of Twins
Alizée Dery, Ann Clarke, Kari Nadeau, Laurie Harada, Kimberley Weatherall, Celia Greenwood, Denise Daley, Yuka Asai, Moshe Ben-Shoshan
A24 Qualifying the diagnostic approach employed by allergists when managing patients with self-diagnosed non-celiac gluten sensitivity (NCGS)
Lee Horgan, Teresa Pun
A25 Retrospective analysis on the agreement between skin prick test and serum food specific IgE antibody in adults with suspected food allergy
Ling Ling, Maria B. Ospina, Kyriaki Sideri, Harissios Vliagoftis
A26 Staple food hypersensitivity from infancy to adolescence: a report from the BAMSE cohort
Jennifer L.P. Protudjer, Mirja Vetander, Marianne van Hage, Ola Olén, Magnus Wickman, Anna Bergström
A27 Evaluating the impact of supervised epinephrine autoinjector administration during food challenges on perceived parent confidence
Timothy Teoh, Christopher Mill, Tiffany Wong, Ingrid Baerg, Angela Alexander, Kyla J. Hildebrand, John Dean, Boris Kuzeljevic, Edmond S. Chan
A28 Local immunoglobulin production to Aspergillus fumigatus cystic fibrosis
Jonathan Argeny, Mia Gona-Hoepler, Petra Fucik, Edith Nachbaur, Saskia Gruber, Reto Crameri, Andreas Glaser, Zsolt Szépfalusi, Claudio Rhyner, Thomas Eiwegger
A29 Extract consumption with skin prick test (SPT) devices
Greg. Plunkett, Brad Mire
A30 Evaluation of our cases with nonsteroidal anti-inflammatory drug reactions
Mehtap Yazicioglu, Ceren Can, Gokce Ciplak
A31 Reasons for referral and final diagnoses in a tertiary care pediatric allergy clinic
Victoria E. Cook, Kyla J. Hildebrand, Elodie Portales-Casamar, Christopher Mill, Edmond S. Chan
A32 Internist referral practices for inpatients with self-reported penicillin allergies at a tertiary care teaching hospital
Michael N Fein, Emil P Nashi
A33 Assessing the risk of reactions in children with a negative oral challenge after a subsequent use of amoxicillin
Sofianne Gabrielli, Christopher Mill, Marie-Noel Primeau, Christine Lejtenyi, Elena Netchiporouk, Alizee Dery, Greg Shand, Moshe Ben-Shoshan
A34 Validity of self-reported penicillin allergies
Erica Hoe, Joel Liem
A35 Effectiveness of allergy-test directed elimination diets in eosinophilic esophagitis
Jason K. Ko, David J.T. Huang, Jorge A. Mazza
A36 Allergy testing and dietary management in pediatric eosinophilic esophagitis (EoE): A retrospective review of a tertiary Canadian centre’s experience
Mary McHenry, Anthony Otley,Wade Watson
A37 Visualizing the impact of atopic and allergic skin disease
Dominik A. Nowak, John N. Kraft
A38 Cystic fibrosis with and without nasal polyposis in pediatric patients: a cross-sectional comparative study
Mihaela Paina, Ahmed A. Darwish Hassan, Delia Heroux, Lynn Crawford, Gail Gauvreau, Judah Denburg, Linda Pedder, Paul K. Keith
A39 Evaluation of macrolide antibiotic hypersensitivity: the role of oral challenges in children
Bahar Torabi, Marie-Noel Primeau, Christine Lejtenyi, Elaine Medoff, Jennifer Mill, Moshe Ben-Shoshan
A40 Venom allergy testing: is a graded approach necessary?
Jaclyn A. Quirt, Xia Wen, Jonathan Kim, Angel Jimenez Herrero, Harold L. Kim
A41 The role of oral challenges in evaluating cephalosporin hypersensitivity reactions in children
Magdalena J. Grzyb, Marie-Noël Primeau, Christine Lejtenyi, Elaine Medoff, Jennifer Mill, Moshe Ben-Shoshan
A42 Breastfeeding and infant wheeze, atopy and atopic dermatitis: findings from the Canadian Healthy Infant Longitudinal Development Study
Meghan B. Azad, Zihang Lu, Allan B. Becker, Padmaja Subbarao, Piushkumar J. Mandhane, Stuart E. Turvey, Malcolm R. Sears, the CHILD Study Investigators
A43 IL33 DNA methylation in bronchial epithelial cells is associated to asthma
Anne-Marie Boucher-Lafleur, Valérie Gagné-Ouellet, Éric Jacques, Sophie Plante, Jamila Chakir, Catherine Laprise
A44 NRF2 mediates the antioxidant response to organic dust-induced oxidative stress in bronchial epithelial cells
Michael Chen, Toby McGovern, Mikael Adner, James G. Martin
A45 The effects of perinatal distress, immune biomarkers and mother-infant interaction quality on childhood atopic dermatitis (rash) at 18 months
Nela Cosic, Henry Ntanda, Gerald Giesbrecht, Anita Kozyrskyj, Nicole Letourneau
A46 Examining the immunological mechanisms associated with cow’s milk allergy
Bassel Dawod, Jean Marshall
A47 Tryptase levels in children presenting with anaphylaxis to the Montréal Children’s Hospital
Sarah De Schryver, Michelle Halbrich, Ann Clarke, Sebastian La Vieille, Harley Eisman, Reza Alizadehfar, Lawrence Joseph, Judy Morris, Moshe Ben-Shoshan
A48 Secondhand tobacco smoke exposure in infancy and the development of food hypersensitivity from childhood to adolescence
Laura Y. Feldman, Jesse D. Thacher, Inger Kull, Erik Melén, Göran Pershagen, Magnus Wickman, Jennifer L. P. Protudjer, Anna Bergström
A49 Combined exposure to diesel exhaust and allergen enhances allergic inflammation in the bronchial submucosa of atopic subjects
Ali Hosseini, Tillie L. Hackett, Jeremy Hirota, Kelly McNagny, Susan Wilson, Chris Carlsten
A50 Comparison of skin-prick test measurements by an automated system against the manual method
Saiful Huq, Rishma Chooniedass, Brenda Gerwing, Henry Huang, Diana Lefebvre, Allan Becker
A51 The accurate identification and quantification of urinary biomarkers of asthma and COPD through the use of novel DIL- LC-MS/MS methods
Mona M. Khamis, Hanan Awad, Kevin Allen, Darryl J. Adamko, Anas El-Aneed
A52 Systemic immune pathways associated with the mechanism of Cat-Synthetic Peptide Immuno-Regulatory Epitopes, a novel immunotherapy, in whole blood of cat-allergic people
Young Woong Kim, Daniel R. Gliddon, Casey P. Shannon, Amrit Singh, Pascal L. C. Hickey, Anne K. Ellis, Helen Neighbour, Mark Larche, Scott J. Tebbutt
A53 Reducing the health disparities: online support for children with asthma and allergies from low-income families
Erika Ladouceur, Miriam Stewart, Josh Evans, Jeff Masuda, Nicole Letourneau, Teresa To, Malcolm King
A54 Epigenetic association of PSORS1C1 and asthma in the Saguenay-Lac-Saint-Jean asthma study
Miriam Larouche, Liming Liang, Catherine Laprise
A55 IL-33 induces cytokine and chemokine production in human mast cells
Stephanie A. Legere, Ian D. Haidl, Jean-Francois Legaré, Jean S. Marshall
A56 Reference ranges for lung clearance index from infancy to adolescence for Canadian population
Zihang Lu, Malcolm Sears, Theo J. Moraes, Felix Ratjen, Per Gustafsson, Wendy Lou, Padmaja Subbarao
A57 Kingston Allergy Birth Cohort: cohort profile and mother/child characteristics to age 2
Michelle L. North, Elizabeth Lee, Vanessa Omana, Jenny Thiele, Jeff Brook, Anne K. Ellis
A58 Cow’s milk protein specific IgE, IgA and IgG4 as a predictor of outcome in oral immunotherapy
Tanvir Rahman, Duncan Lejtenyi, Sarah De Schryver, Ryan Fiter, Ciriaco Piccirillo, Moshe Ben-Shoshan, Bruce Mazer
A59 Age of peanut introduction and development of reactions and sensitization to peanut
Elinor Simons, Allan B. Becker, Rishma Chooniedass, Kyla Hildebrand, Edmond S. Chan, Stuart Turvey, Padmaja Subbarao, Malcolm Sears
A60 Multi-omic blood biomarker signatures of the late phase asthmatic response
Amrit Singh, Casey P. Shannon, Young Woong Kim, Mari DeMarco, Kim-Anh Le Cao, Gail M. Gauvreau, J. Mark FitzGerald, Louis-Philippe Boulet, Paul M. O’Byrne, Scott J. Tebbutt
A61 Early life gut microbial alterations in children diagnosed with asthma by three years of age
Leah T. Stiemsma, Marie-Claire Arrieta, Jasmine Cheng, Pedro A. Dimitriu, Lisa Thorson, Sophie Yurist, Boris Kuzeljevic, Diana L. Lefebvre, Padmaja Subbarao, Piush Mandhane, Allan Becker, Malcolm R. Sears, Kelly M. McNagny, Tobias Kollmann, the CHILD Study Investigators, William W. Mohn, B. Brett Finlay, Stuart E. Turvey
A62 The relationship between food sensitization and atopic dermatitis at age 1 year in a Canadian birth cohort
Maxwell M. Tran, Diana L. Lefebvre, Chinthanie F. Ramasundarahettige, Allan B. Becker, Wei Hao Dai, Padmaja Subbarao, Piush J. Mandhane, Stuart E. Turvey, Malcolm R. Sears
A63 Allergen inhalation enhances Toll-like receptor-induced thymic stromal lymphopoietin receptor expression by hematopoietic progenitor cells in mild asthmatics
Damian Tworek, Delia Heroux, Seamus N. O’Byrne, Paul M. O’Byrne, Judah A. Denburg
A64 The Allergic Rhinitis Clinical Investigator Collaborative – replicated eosinophilia on repeated cumulative allergen challenges in nasal lavage samples
Laura Walsh, Mena Soliman, Jenny Thiele, Lisa M. Steacy, Daniel E. Adams, Anne K. Ellis
A65 The CHILD Study: optimizing subject retention in pediatric longitudinal cohort research
Linda Warner, Mary Ann Mauro, Robby Mamonluk, Stuart E. Turvey
A66 Differential expression of C3a and C5a in allergic asthma
ChenXi Yang, Amrit Singh, Casey P. Shannon, Young Woong Kim, Ed M. Conway, Scott J. Tebbutt
doi:10.1186/s13223-016-0118-0
PMCID: PMC5009563
2.  Assay optimisation and technology transfer for multi-site immuno-monitoring in vaccine trials 
PLoS ONE  2017;12(10):e0184391.
Cellular immunological assays are important tools for the monitoring of responses to T-cell-inducing vaccine candidates. As these bioassays are often technically complex and require considerable experience, careful technology transfer between laboratories is critical if high quality, reproducible data that allows comparison between sites, is to be generated. The aim of this study, funded by the European Union Framework Program 7-funded TRANSVAC project, was to optimise Standard Operating Procedures and the technology transfer process to maximise the reproducibility of three bioassays for interferon-gamma responses: enzyme-linked immunosorbent assay (ELISA), ex-vivo enzyme-linked immunospot and intracellular cytokine staining. We found that the initial variability in results generated across three different laboratories reduced following a combination of Standard Operating Procedure harmonisation and the undertaking of side-by-side training sessions in which assay operators performed each assay in the presence of an assay ‘lead’ operator. Mean inter-site coefficients of variance reduced following this training session when compared with the pre-training values, most notably for the ELISA assay. There was a trend for increased inter-site variability at lower response magnitudes for the ELISA and intracellular cytokine staining assays. In conclusion, we recommend that on-site operator training is an essential component of the assay technology transfer process and combined with harmonised Standard Operating Procedures will improve the quality, reproducibility and comparability of data produced across different laboratories. These data may be helpful in ongoing discussions of the potential risk/benefit of centralised immunological assay strategies for large clinical trials versus decentralised units.
doi:10.1371/journal.pone.0184391
PMCID: PMC5636064  PMID: 29020010
3.  Structural Features and Inhibitors of Bromodomains 
Bromodomains are conserved structural modules responsible for recognizing acetylated-lysine residues on histone tails and other transcription-associated proteins, such as transcription factors and co-factors. Owing to their important functions in the regulation of ordered gene transcription in chromatin, bromodomains of the BET family proteins have recently been shown as druggable targets for a wide array of human diseases, including cancer and inflammation. Here we review the structural and functional features of the bromodomains and their small-molecule inhibitors. Additional new insights provided herein highlight the landscape of the ligand binding sites in the bromodomains that will hopefully facilitate further development of new inhibitors with optimal affinity and selectivity.
doi:10.1016/j.ddtec.2016.09.001
PMCID: PMC5325140  PMID: 27769355
4.  Whole Blood Profiling of Bacillus Calmette–Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation 
Vaccination of infants with bacillus Calmette–Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated in vitro with non-related microbial stimuli. Our aim was to examine an extensive panel of secreted immune biomarkers to characterize the profile of trained innate immunity in infants. Stimulation of whole blood for 48 h was performed 4 months after BCG vaccination, or in control unvaccinated infants. Stimulants were lipopolysaccharide; Pam3Cys (P3C); heat-killed Candida albicans, Staphylococcus aureus, Escherichia coli, and a lysate of Mycobacterium tuberculosis. Culture supernatants were tested for secreted cytokines and chemokines by 42-plex bead array and monocytes and natural killer (NK) cells assessed for expression of activation markers by flow cytometry. BCG-vaccinated infants displayed increases in 11 cytokines and chemokines in response to different non-specific innate immunity stimuli: epidermal growth factor (EGF); eotaxin; IL-6; IL-7; IL-8; IL-10; IL-12p40; monocyte chemotactic protein-3; macrophage inflammatory protein-1α; soluble CD40 ligand and platelet-derived growth factor (PDGF)-AB/BB. Although each stimulant induced a distinct response profile, three analytes, EGF, IL-6, and PDGF-AB/BB, were commonly higher after stimulation with Pam3Cys, C. albicans, and S. aureus. Conversely, certain cytokines such as interferon gamma-inducible protein-10, IL-2, IL-13, IL-17, GM-CSF, and GRO were suppressed in BCG-vaccinated infants, while no increases in TNFα or IL-1β production were detected. We did not observe a concomitant, BCG-associated change in monocyte surface activation markers in response to non-specific stimuli, but we detected a significant increase in CD69 expression on NK cells in response to Pam3Cys. Pam3Cys-induced NK cell activation correlated with the magnitude of IL-12p40 and IL-10 responses to the same stimulant. This study reveals a novel cytokine/chemokine biomarker signature of BCG-induced trained innate immunity in infants and the involvement of NK cells in these responses.
doi:10.3389/fimmu.2017.00644
PMCID: PMC5459878
bacillus Calmette–Guérin; vaccination; heterologous effects; trained immunity; infants; cytokines; chemokines; natural killer
5.  Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7 
ACS Medicinal Chemistry Letters  2016;7(6):601-605.
The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16INK4a through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16INK4a in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.
doi:10.1021/acsmedchemlett.6b00042
PMCID: PMC4904266  PMID: 27326334
Chromodomain; polycomb repressive complex; antagonist; gene transcription
6.  Canadian Society of Allergy and Clinical Immunology annual scientific meeting 2016 
Alsayegh, Mohammad A. | Alshamali, Hanan | Khadada, Mousa | Ciccolini, Amanda | Ellis, Anne K. | Quint, Diana | Powley, William | Lee, Laurie | Fiteih, Yahya | Baksh, Shairaz | Vliagoftis, Harissios | Gerega, Sebastien K. | Millson, Brad | Charland, Katia | Barakat, Stephane | Sun, Xichun | Jimenez, Ricardo | Waserman, Susan | FitzGerald, Mark J. | Hébert, Jacques | Cognet-Sicé, Josiane | Renahan, Kevin E. | Huq, Saiful | Chooniedass, Rishma | Sawyer, Scott | Pasterkamp, Hans | Becker, Allan | Smith, Steven G. | Zhang, Shiyuan | Jayasundara, Kavisha | Tacon, Claire | Simidchiev, Alex | Nadeau, Gilbert | Gunsoy, Necdet | Mullerova, Hana | Albers, Frank | Kim, Young Woong | Shannon, Casey P. | Singh, Amrit | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J. | Klopp, Annika | Vehling, Lorena | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Azad, Meghan B. | Loewen, Keely | Monchka, Barret | Mahmud, Salaheddin M. | Jong, Geert ‘t | Longo, Cristina | Bartlett, Gillian | Ducharme, Francine M. | Schuster, Tibor | MacGibbon, Brenda | Barnett, Tracie | North, Michelle L. | Brook, Jeff | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Steacy, Lisa M. | Evans, Greg | Diamond, Miriam | Sussman, Gordon L. | Amistani, Yann | Abiteboul, Kathy | Tenn, Mark W. | Yang, ChenXi | Carlsten, Christopher | Conway, Edward M. | Mack, Douglas | Othman, Yasmin | Barber, Colin M. | Kalicinsky, Chrystyna | Burke, Andrea E. | Messieh, Mary | Nair, Parameswaran | Che, Chun T. | Douglas, Lindsay | Liem, Joel | Duan, Lucy | Miller, Charlotte | Dupuis, Pascale | Connors, Lori A. | Fein, Michael N. | Shuster, Joseph | Hadi, Hani | Polk, Brooke | Raje, Nikita | Labrosse, Roxane | Bégin, Philippe | Paradis, Louis | Roches, Anne Des | Lacombe-Barrios, Jonathan | Mishra, Sanju | Lacuesta, Gina | Chiasson, Meredith | Haroon, Babar | Robertson, Kara | Issekutz, Thomas | Leddin, Desmond | Couban, Stephen | Connors, Lori | Roos, Adrienne | Kanani, Amin | Chan, Edmond S. | Schellenberg, Robert | Rosenfield, Lana | Cvetkovic, Anna | Woodward, Kevin | Quirt, Jaclyn | Watson, Wade T. A. | Castilho, Edson | Sullivan, Jennifer A. | Temple, Beverley | Martin, Donna | Cook, Victoria E. | Mills, Christopher | Portales-Casamar, Elodie | Fu, Lisa W. | Ho, Alexander | Zaltzman, Jeffrey | Chen, Lucy | Vadas, Peter | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Graham, François | Barnes, Charles | Portnoy, Jay | Stagg, Vincent | Simons, Elinor | Lefebvre, Diana | Dai, David | Mandhane, Piushkumar | Sears, Malcolm | Tam, Herman | Simons, F. Estelle R. | Alotaibi, Dhaifallah | Dawod, Bassel | Tunis, Matthew C. | Marshall, Jean | Desjardins, Marylin | Béland, Marianne | Lejtenyi, Duncan | Drolet, Jean-Phillipe | Lemire, Martine | Tsoukas, Christos | Noya, Francisco J.D. | Alizadehfar, Reza | McCusker, Christine T. | Mazer, Bruce D. | Maestre-Batlle, Danay | Gunawan, Evelyn | Rider, Christopher F. | Bølling, Anette K. | Pena, Olga M. | Suez, Daniel | Melamed, Isaac | Hussain, Iftikhar | Stein, Mark | Gupta, Sudhir | Paris, Kenneth | Fritsch, Sandor | Bourgeois, Christelle | Leibl, Heinz | McCoy, Barbara | Noel, Martin | Yel, Leman | Scott, Ori | Reid, Brenda | Atkinson, Adelle | Kim, Vy Hong-Diep | Roifman, Chaim M. | Grunebaum, Eyal | AlSelahi, Eiman | Aleman, Fernando | Oberle, Amber | Trus, Mike | Sussman, Gordon | Kanani, Amin S. | Chambenoi, Olivier | Chiva-Razavi, Sima | Grodecki, Savannah | Joshi, Nikhil | Menikefs, Peter | Holt, David | Pun, Teresa | Tworek, Damian | Hanna, Raphael | Heroux, Delia | Rosenberg, Elli | Stiemsma, Leah | Turvey, Stuart | Denburg, Judah | Mill, Christopher | Teoh, Timothy | Zimmer, Preeti | Avinashi, Vishal | Paina, Mihaela | Darwish Hassan, Ahmed A. | Oliveria, John Paul | Olesovsky, Chris | Gauvreau, Gail | Pedder, Linda | Keith, Paul K. | Plunkett, Greg | Bolner, Michelle | Pourshahnazari, Persia | Stark, Donald | Vostretsova, Kateryna | Moses, Andrew | Wakeman, Andrew | Singer, Alexander | Gerstner, Thomas | Abrams, Elissa | Johnson, Sara F. | Woodgate, Roberta L.
doi:10.1186/s13223-017-0192-y
PMCID: PMC5390240
7.  What Have We Learnt about BCG Vaccination in the Last 20 Years? 
Frontiers in Immunology  2017;8:1134.
A number of new tuberculosis (TB) vaccines have been or are entering clinical trials, which include genetically modified mycobacteria, mycobacterial antigens delivered by viral vectors, or mycobacterial antigens in adjuvant. Some of these vaccines aim to replace the existing BCG vaccine but others will be given as a boosting vaccine following BCG vaccination given soon after birth. It is clear that the existing BCG vaccines provide incomplete and variable protection against pulmonary TB. This review will discuss what we have learnt over the last 20 years about how the BCG vaccine induces specific and non-specific immunity, what factors influence the immune responses induced by BCG, and progress toward identifying correlates of immunity against TB from BCG vaccination studies. There is still a lot to learn about the BCG vaccine and the insights gained can help the development of more protective vaccines.
doi:10.3389/fimmu.2017.01134
PMCID: PMC5601272
BCG; vaccination; tuberculosis; efficacy; biomarkers; correlates of protection; immune responses; infants
8.  AllerGen’s 8th research conference 
Arrieta, Marie-Claire | Arevalos, Andrea | Stiemsma, Leah | Chico, Marta E. | Sandoval, Carlos | Jin, Minglian | Walter, Jens | Cooper, Phil | Finlay, Brett | Bernatchez, Emilie | Gold, Matthew J. | Langlois, Anick | Blais-Lecours, Pascale | Duchaine, Caroline | Marsolais, David | McNagny, Kelly M. | Blanchet, Marie-Renée | Brubacher, Jordan | Chhetri, Bimal | Sabaliauskas, Kelly | Bassil, Kate | Kwong, Jeff | Coates, Frances | Takaro, Tim K. | Chow, Angela | Miller, Gregory E. | Chen, Edith | Mandhane, Piushkumar J. | Turvey, Stuart E. | Elliott, Susan J. | Becker, Allan B. | Subbarao, Padmaja | Sears, Malcolm R. | Kozyrskyj, Anita L. | Dubeau, Aimée | Lu, Zihang | Balkovec, Susan | Kowalik, Krzysztof | Gustafsson, Per | Ratjen, Felix | Edgar, Rachel D. | Bush, Nicole R. | MacIssac, Julie L. | McEwen, Lisa M. | Boyce, Thomas W. | Kobor, Michael S. | Emmerson, Melanie | Dubeau, Aimée | Lu, Zihang | Shen, Bingqing | Kowalik, Krzysztof | Ratjen, Felix | Moraes, Theo J. | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Islam, Sumaiya A. | Brückmann, Christof | Nieratschker, Vanessa | Jamieson, Kyla C. | Proud, David | Kanagaratham, Cynthia | Camateros, Pierre | Kopriva, Frantisek | Henri, Jennifer | Hajduch, Marian | Radzioch, Danuta | Kang, Liane J. | Koleva, Petya T. | Field, Catherine J. | Konya, Tedd | Scott, James A. | Konya, Theodore | Azad, Meghan B. | Brook, Jeff | Guttman, David | Kumari, Manjeet | Bridgman, Sarah L. | Tun, Mon H. | Mandal, Rupasri | Wishart, David S. | Lee, Amy H. Y. | Xia, Jeff | Gill, Erin | Hancock, Bob | Maestre, Danay | Sutherland, Darren | Hirota, Jeremy | Pena, Olga | Carlsten, Christopher | McEwen, Lisa M. | Jones, Meaghan J. | MacIsaac, Julia L. | Dow, William H. | Rosero-Bixby, Luis | Rehkopf, David H. | Morimoto, Takeshi | Smith, Steven G. | Oliveria, John-Paul | Beaudin, Suzanne | Schlatman, Abbey | Howie, Karen | Obminski, Caitlin | Nusca, Graeme | Sehmi, Roma | Gauvreau, Gail M. | O’Byrne, Paul M. | North, Michelle | Peng, Cheng | Sanchez-Guerra, Marco | Byun, Hyang-Min | Ellis, Anne K. | Baccarelli, Andrea A. | Okeme, Joseph O. | Dhal, Suman | Saini, Aman | Diamond, Miriam L. | Olesovsky, Christopher J. | Salter, Brittany M. | Wang, Michael | Lacy, Paige | O’Sullivan, Michael J. | Park, Chan Y. | Fredberg, Jeffrey J. | Lauzon, Anne-Marie | Martin, James G. | Ryu, Min Hyung | Mookherjee, Neeloffer | Carlsten, Christopher | Simons, Elinor | Lefebvre, Diana | Dai, David | Singh, Amrit | Shannon, Casey P. | Kim, Young Woong | Yang, Chen Xi | Mark FitzGerald, J. | Boulet, Louis-Philippe | Tebbutt, Scott J. | Singhera, Gurpreet K. | JasemineYang, S. | Dorscheid, Delbert R. | Sinnock, Hasantha | Goruk, Susan | Tavakoli, Hamid | Lynd, Larry D. | Sadatsafavi, Mohsen | Tenn, Mark W. | Thiele, Jenny | Adams, Daniel E. | Steacy, Lisa M. | Ellis, Anne K. | Torabi, Bahar | De Schryver, Sarah | Lejtenyi, Duncan | Baerg, Ingrid | Chan, Edmond S. | Mazer, Bruce D. | Tran, Maxwell M. | Dai, Wei Hao | Lou, Wendy | Chari, Radha S. | Conway, Edward M. | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J
doi:10.1186/s13223-016-0164-7
PMCID: PMC5260783
9.  Small Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain 
Chemistry & biology  2015;22(2):161-168.
SUMMARY
Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, de-represses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.
doi:10.1016/j.chembiol.2014.11.021
PMCID: PMC4336573  PMID: 25660273
10.  The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda 
PLoS ONE  2016;11(1):e0146098.
Background
In the absence of a gold standard for the diagnosis of latent tuberculosis (TB) infection (LTBI), the current tests available for the diagnosis of LTBI are limited by their inability to differentiate between LTBI and active TB disease. We investigated IP-10 as a potential biomarker for LTBI among household contacts exposed to sputum positive active TB cases.
Methods
Active TB cases and contacts were recruited into a cohort with six months’ follow-up. Contacts were tested for LTBI using QuantiFERON®-TB Gold In-Tube (QFN) assay and the tuberculin skin test (TST). Baseline supernatants from the QFN assay of 237 contacts and 102 active TB cases were analysed for Mycobacterium tuberculosis (MTB) specific and mitogen specific IP-10 responses.
Results
Contacts with LTBI (QFN+TST+) had the highest MTB specific IP-10 responses at baseline, compared to uninfected contacts (QFN-TST-) p<0.0001; and active cases, p = 0.01. Using a cut-off of 8,239 pg/ml, MTB specific IP-10 was able to diagnose LTBI with a sensitivity of 87.1% (95% CI, 76.2–94.3) and specificity of 90.9% (95% CI, 81.3–96.6). MTB specific to mitogen specific IP-10 ratio was higher in HIV negative active TB cases, compared to HIV negative latently infected contacts, p = 0.0004. Concentrations of MTB specific IP-10 were higher in contacts with TST conversion (negative at baseline, positive at 6-months) than in those that were persistently TST negative, p = 0.001.
Conclusion
IP-10 performed well in differentiating contacts with either latent or active TB from those who were uninfected but was not able to differentiate LTBI from active disease except when MTB specific to mitogen specific ratios were used in HIV negative adults. In addition, IP-10 had the potential to diagnose ‘recent TB infection’ in persons classified as having LTBI using the TST. Such individuals with strong IP-10 responses would likely benefit from chemoprophylaxis.
doi:10.1371/journal.pone.0146098
PMCID: PMC4714877  PMID: 26771653
11.  Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study 
BMC Infectious Diseases  2015;15:438.
Background
With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis.
Methods
Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months’ follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months.
Results
Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95 % confidence interval (CI), p-value) -1488.6 pg/ml ((−2682.5, −294.8), p = 0.01), and IL- 2 (−213.1 pg/ml (−419.2, −7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95 % CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6.
Conclusions
IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.
Trial registration
ISRCTN registry, ISRCTN15705625. Registered on 30th September 2015.
doi:10.1186/s12879-015-1201-8
PMCID: PMC4619204  PMID: 26493989
Latent tuberculosis infection; Household contacts; Randomised design; Cytokines; Antibodies; Isoniazid preventive therapy
12.  Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines 
PLoS ONE  2015;10(9):e0138042.
Intracellular cytokine staining combined with flow cytometry is one of a number of assays designed to assess T-cell immune responses. It has the specific advantage of enabling the simultaneous assessment of multiple phenotypic, differentiation and functional parameters pertaining to responding T-cells, most notably, the expression of multiple effector cytokines. These attributes make the technique particularly suitable for the assessment of T-cell immune responses induced by novel tuberculosis vaccines in clinical trials. However, depending upon the particular nature of a given vaccine and trial setting, there are approaches that may be taken at different stages of the assay that are more suitable than other alternatives. In this paper, the Tuberculosis Vaccine Initiative (TBVI) TB Biomarker Working group reports on efforts to assess the conditions that will determine when particular assay approaches should be employed. We have found that choices relating to the use of fresh whole blood or peripheral blood mononuclear cells (PBMC) and frozen PBMC; use of serum-containing or serum-free medium; length of stimulation period and use of co-stimulatory antibodies can all affect the sensitivity of intracellular cytokine assays. In the case of sample material, frozen PBMC, despite some loss of sensitivity, may be more advantageous for batch analysis. We also recommend that for multi-site studies, common antibody panels, gating strategies and analysis approaches should be employed for better comparability.
doi:10.1371/journal.pone.0138042
PMCID: PMC4569436  PMID: 26367374
13.  The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils 
PPAR Research  2012;2012:235231.
PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis) and random cell movement (chemokinesis). To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist), GW9578 (PPARα agonist), GW501516 (PPARδ agonist), or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P = 0.0038), and SDF-1α-induced migration of immature eosinophils (P = 0.0538). Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P = 0.0042). The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function.
doi:10.1155/2012/235231
PMCID: PMC3395269  PMID: 22966220
14.  Length-Based Assessment of Coral Reef Fish Populations in the Main and Northwestern Hawaiian Islands 
PLoS ONE  2015;10(8):e0133960.
The coral reef fish community of Hawaii is composed of hundreds of species, supports a multimillion dollar fishing and tourism industry, and is of great cultural importance to the local population. However, a major stock assessment of Hawaiian coral reef fish populations has not yet been conducted. Here we used the robust indicator variable “average length in the exploited phase of the population (L¯)”, estimated from size composition data from commercial fisheries trip reports and fishery-independent diver surveys, to evaluate exploitation rates for 19 Hawaiian reef fishes. By and large, the average lengths obtained from diver surveys agreed well with those from commercial data. We used the estimated exploitation rates coupled with life history parameters synthesized from the literature to parameterize a numerical population model and generate stock sustainability metrics such as spawning potential ratios (SPR). We found good agreement between predicted average lengths in an unfished population (from our population model) and those observed from diver surveys in the largely unexploited Northwestern Hawaiian Islands. Of 19 exploited reef fish species assessed in the main Hawaiian Islands, 9 had SPRs close to or below the 30% overfishing threshold. In general, longer-lived species such as surgeonfishes, the redlip parrotfish (Scarus rubroviolaceus), and the gray snapper (Aprion virescens) had the lowest SPRs, while short-lived species such as goatfishes and jacks, as well as two invasive species (Lutjanus kasmira and Cephalopholis argus), had SPRs above the 30% threshold.
doi:10.1371/journal.pone.0133960
PMCID: PMC4534412  PMID: 26267473
15.  The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette–Guérin immunization 
Bacille Calmette–Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml−1 [3300–11 050] in cord blood) and six weeks (0.00 ng ml−1 [0–288]). Frequencies of PPD-specific IFN-γ-expressing CD4+T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4+T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4+T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI −0.041% (−0.082, −0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study.
doi:10.1098/rstb.2014.0137
PMCID: PMC4527383  PMID: 25964450
maternal infection; mycobacteria; bacille Calmette–Guérin; purified protein derivative; tuberculosis; immunization
16.  Privileged Diazepine Compounds and their Emergence as Bromodomain Inhibitors 
Chemistry & biology  2014;21(5):573-583.
Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control bromodomain-related gene expression in human diseases.
doi:10.1016/j.chembiol.2014.03.004
PMCID: PMC4035449  PMID: 24746559
17.  ChEpiMod: a knowledgebase for chemical modulators of epigenome reader domains 
Bioinformatics  2014;30(10):1481-1483.
Context: Epigenome reader domains are rapidly emerging as a new class of drug targets for a wide array of human diseases. To facilitate study of structure–activity relationship and small-molecule ligand design for these domains, we have created ChEpiMod. ChEpiMod is a free knowledgebase of chemical modulators with documented modulatory activity for epigenome reader domains.
Methods: ChEpiMod organizes information about chemical modulators and their associated binding-affinity data, as well as available structures of epigenome readers from the Protein Data Bank. The data are gathered from the literature and patents. Entries are supplemented by annotation. The current version of ChEpiMod covers six epigenome reader domain families (Bromodomain, PHD finger, Chromodomain, MBT, PWWP and Tudor). The database can be used to browse existing chemical modulators and bioactivity data, as well as, all available structures of readers and their molecular interactions. The database is updated weekly.
Availability: ChEpiMod is freely available at http://chepimod.org
Contact: ming-ming.zhou@mssm.edu
Supplementary information: Supplementary data is available at Bioinformatics online.
doi:10.1093/bioinformatics/btu052
PMCID: PMC4016710  PMID: 24470572
18.  Factors affecting immunogenicity of BCG in infants, a study in Malawi, The Gambia and the UK 
BMC Infectious Diseases  2014;14:184.
Background
BCG immunogenicity in infants differs between populations and these differences have been attributed to various factors. In this study, the influence of geographical location, season of birth, timing of vaccination, micronutrient status (zinc) and inflammatory status (C-reactive protein, CRP) were assessed.
Methods
Immunogenicity was assessed by cytokine signature in culture supernatants from diluted whole blood samples stimulated with M. tuberculosis PPD, using a multiplex bead assay. Results were correlated with the plasma zinc and CRP concentrations at the time of sampling, and with interview and household data. BCG vaccinated infants were recruited in Malawi, The Gambia and the UK.
Results
In Malawi, infants vaccinated within the first week after birth showed lower production of most cytokines measured than those vaccinated later. The number of cytokines showing significant differences between Malawian and Gambian infants decreased after adjusting for season of birth. In Malawi, a proportion of infants had zinc deficiency and elevated plasma CRP (>10 mg/L), but neither zinc deficiency nor high CRP was associated with production of any of the cytokines measured.
Conclusions
The cytokine/chemokine signatures observed in response to M. tuberculosis PPD in infants at 3 months post BCG vaccination were affected by geographical location, season of birth, and timing of vaccination but not associated with the concentration of plasma zinc or inflammatory status. These factors should be considered in future trials of new TB vaccines.
doi:10.1186/1471-2334-14-184
PMCID: PMC4101864  PMID: 24708690
BCG vaccination; CRP; Cytokine; Infant immune response; M. tuberculosis PPD; Zinc
19.  Screening vaccine formulations for biological activity using fresh human whole blood 
Human Vaccines & Immunotherapeutics  2014;10(4):1129-1135.
Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired.
During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans.
For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety.
The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression.
doi:10.4161/hv.27657
PMCID: PMC4896559  PMID: 24401565
WBA; adjuvant modulation; vaccine; functionality; tuberculosis
20.  Methods for assessment of short-term coral reef fish movements within an acoustic array 
Movement Ecology  2013;1(1):7.
Background
Arrays of passive receivers are a widely used tool for tracking the movements of acoustically-tagged fish in marine ecosystems; however, the spatial and temporal heterogeneity of coral reef environments pose challenges for the interpretation of tag detection data. To improve this situation for reef fishes, we introduced a novel response variable method that treats signal detections as proportions (i.e., percent transmissions detected or “detection rates”) and compared this against prior approaches to examine the influence of array and transmitter performance, signal distance and environmental factors on detection rates. We applied this method to tagged snappers and groupers in the Florida reef ecosystem and controlled range-tests on static targets in Bayboro Harbor, Florida, to provide methodological guidance for the planning and evaluation of passive array studies for coral reef fishes.
Results
Logistic regression analysis indicated detection rates were primarily a non-linear function of tag distance from receiver. A ‘model-weighted’ function was developed to incorporate the non-linear relationship between detection rate and distance to provide robust positioning estimates and allow for easy extension to tags with different ping rates.
Conclusions
Optimal acoustic array design requires balancing the interplay between receiver spacing, detection rates, and positioning error. Spacing receivers at twice the distance of the modeled 50% detection rate may be appropriate when quantification of overall space use is a priority, and would provide a minimum of 75% detection rate. However, for research where missing detections within the array is unacceptable or time-at-arrival based fine-scale positioning is needed, tighter receiver spacing may be required to maintain signal detection probability near 100%.
doi:10.1186/2051-3933-1-7
PMCID: PMC4337750  PMID: 25709821
Acoustic telemetry; Marine reserves; Acoustic array; Coral reef; Fish movements; Dry Tortugas; Reef fish
21.  Long-Lived Memory B-Cell Responses following BCG Vaccination 
PLoS ONE  2012;7(12):e51381.
The role of T-cells in immunity against Mycobacterium tuberculosis (M. tuberculosis) infection has been extensively studied, however, that of B-cells still remains comparatively unexplored. In this study, we determined the presence and frequencies of mycobacteria-specific memory B-cells (MBCs) in peripheral blood from clinically healthy, Bacillus Calmette Guerin (BCG) vaccinated (n = 79) and unvaccinated (n = 14) donors. Purified protein derivative (PPD)-specific MBCs were present in most donors (both vaccinated and unvaccinated) but their frequencies were significantly higher in vaccinated than in unvaccinated donors. MBCs specific for other mycobacterial antigens [antigen-85A (Ag85A), antigen-85B (Ag85B), 6 kDalton early secretory antigenic target (ESAT-6) and the 10 kDalton-culture filtrate protein (CFP-10)] were less prevalent than those recognising PPD. Furthermore, PPD-specific MBCs were detected in BCG vaccinated donors without ESAT-6 and CFP-10 specific responses. Together, these results indicate that BCG vaccination induces long-lived MBC responses. Similar patterns of response were seen when we examined mycobacteria-specific antibody and T-cell responses in these donors. Our data show for the first time that BCG vaccination elicits long-lived mycobacteria-specific MBC responses in healthy individuals, suggesting a more substantial role of B-cells in the response to BCG and other mycobacterial infections than previously thought.
doi:10.1371/journal.pone.0051381
PMCID: PMC3519837  PMID: 23240017
22.  BCG Vaccination Induces Different Cytokine Profiles Following Infant BCG Vaccination in the UK and Malawi 
The Journal of Infectious Diseases  2011;204(7):1075-1085.
Background. BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants.
Methods. Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses.
Results. We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants.
Conclusions. Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.
doi:10.1093/infdis/jir515
PMCID: PMC3164434  PMID: 21881123
23.  Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining 
BMC Immunology  2010;11:35.
Background
The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG) administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination.
Results
Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p < 0.0025) 1 month after BCG vaccination when compared to paired samples (n = 12) taken prior to vaccination (IFNγ, TNFα, IL-1α, IL-2, IL-6, IL-10, IL-17, GM-CSF, MIP1α, IP-10). All of these remained detectable by multiplex bead array in samples taken 12 months after BCG vaccination of a partially overlapping adolescent group (n = 12). Intracellular cytokine staining after 24 hour Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNγ expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNγ alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFα producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells.
Conclusions
The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were not present in vaccinated adolescents who, based on earlier epidemiological studies, should have developed protection against pulmonary tuberculosis. This may be due to the later sampling time point available for testing or on the kinetics of the assays used.
doi:10.1186/1471-2172-11-35
PMCID: PMC2910033  PMID: 20609237
24.  Complex cytokine profiles induced by BCG vaccination in UK infants 
Vaccine  2010;28(6):1635-1641.
IFNγ plays an important part in immunity to tuberculosis (TB), but although it is necessary, it is not on its own sufficient for protection against TB. To identify other cytokines that play a role in the protection against TB induced by BCG vaccination, immune responses were compared between vaccinated and unvaccinated infants from the UK where BCG is known to provide protection. Twenty-one cytokines and chemokines were tested in supernatants from diluted whole blood cultures that had been stimulated for 6 days with Mycobacterium tuberculosis PPD. For 15 out of 21 of the cytokines tested responses were much higher in BCG vaccinated infants than in unvaccinated infants. These included: pro-inflammatory cytokines; IFNγ (median 1705 pg/ml vs. 1.6 pg/ml in vaccinated and unvaccinated infants, respectively), TNFα (median 226 pg/ml vs. 18 pg/ml), as well as IL-2, IL-1α and IL-6; TH2 cytokines: IL-4, IL-5 and IL-13 (median 104 pg/ml vs. 1.6 pg/ml); the regulatory cytokine IL-10 (median response 96 pg/ml vs. 8 pg/ml); the TH17 cytokine IL-17, chemokines (IP-10, MIP-1α and IL-8) and growth factors (GM-CSF and G-CSF). The greatest increase in cytokine production in BCG vaccinees compared to unvaccinated infants was seen with IFNγ. While responses for many cytokines were correlated with the IFNγ response, others including IL-17 and IL-10 were not. The pattern of cytokine induction following BCG vaccination is complex and measurement of one of two cytokines does not reveal the whole picture of vaccine-induced protection.
doi:10.1016/j.vaccine.2009.11.004
PMCID: PMC2824844  PMID: 19941997
BCG vaccination; Infant immune response; Cytokines
25.  Identification of Major Factors Influencing ELISpot-Based Monitoring of Cellular Responses to Antigens from Mycobacterium tuberculosis 
PLoS ONE  2009;4(11):e7972.
A number of different interferon-γ ELISpot protocols are in use in laboratories studying antigen-specific immune responses. It is therefore unclear how results from different assays compare, and what factors most significantly influence assay outcome. One such difference is that some laboratories use a short in vitro stimulation period of cells before they are transferred to the ELISpot plate; this is commonly done in the case of frozen cells, in order to enhance assay sensitivity. Other differences that may be significant include antibody coating of plates, the use of media with or without serum, the serum source and the number of cells added to the wells. The aim of this paper was to identify which components of the different ELISpot protocols influenced assay sensitivity and inter-laboratory variation. Four laboratories provided protocols for quantifying numbers of interferon-γ spot forming cells in human peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis derived antigens. The differences in the protocols were compared directly. We found that several sources of variation in assay protocols can be eliminated, for example by avoiding serum supplementation and using AIM-V serum free medium. In addition, the number of cells added to ELISpot wells should also be standardised. Importantly, delays in peripheral blood mononuclear cell processing before stimulation had a marked effect on the number of detectable spot forming cells; processing delay thus should be minimised as well as standardised. Finally, a pre-stimulation culture period improved the sensitivity of the assay, however this effect may be both antigen and donor dependent. In conclusion, small differences in ELISpot protocols in routine use can affect the results obtained and care should be given to conditions selected for use in a given study. A pre-stimulation step may improve the sensitivity of the assay, particularly when cells have been previously frozen.
doi:10.1371/journal.pone.0007972
PMCID: PMC2776358  PMID: 19956718

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