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1.  Modulation of the IL-6 Receptor α Underlies GLI2-mediated regulation of Immunoglobulin Secretion in Waldenström macroglobulinemia cells 
Immunoglobulin (Ig) secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its over-production is a defining characteristic of several B cell malignancies including Waldenström macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. Here, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6 receptor alpha subunit (IL-6Rα/gp80) as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Rα promoter and regulates its activity as well as the expression of this receptor. In addition, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Rα, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog (HH) signaling, a known regulator of GLI2, as manipulation of HH had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.
doi:10.4049/jimmunol.1402974
PMCID: PMC4561187  PMID: 26238488
2.  7th drug hypersensitivity meeting: part one 
Carr, Daniel F. | Chung, Wen-Hung | Jenkiins, Rosalind E. | Chaponda, Mas | Nwikue, Gospel | Cornejo Castro, Elena M. | Antoine, Daniel J. | Pirmohamed, Munir | Wuillemin, Natascha | Dina, Dolores | Eriksson, Klara K. | Yerly, Daniel | Pavlos, Rebecca | Mckinnin, Elizabeth | Ostrov, David | Peters, Bjoern | Buus, Soren | Koelle, David | Chopra, Abha | Rive, Craig | Redwood, Alec | Restrepo, Susana | Bracey, Austin | Yuan, Jing | Gaudieri, Silvana | Carrington, Mary | Haas, David | Mallal, Simon | Phillips, Elizabeth | De Boer, Douwe | Menheere, Paul | Nieuwhof, Chris | Bons, Judith | Jonsson, Friederike | De Chaisemartin, Luc | Granger, Vanessa | Gillis, Caitlin | Gouel, Aurelie | Neukirch, Catherine | Dib, Fadia | Nicaise, Pascale Roland | Longrois, Dan | Tubach, Florence | Martin, Sylvie | Bruhns, Pierre | Chen, Kai-Lung | Liao, Shu-Ling | Sheen, Yi-Shuan | Cho, Yung-Tsu | Yang, Che-Wen | Liau, Jau-Yu | Chu, Chia-Yu | Aguiar, Rita | Lopes, Anabela | Fernandes, Natália | Viegas, Leonor | Pereira-Barbosa, M. A. | Bünter, Antonia | Gupta, Nisha | Petkovic, Tatjana Pecaric | Wirth, Nicole | Pichler, Werner J. | Hausmann, Oliver | Yazicioglu, Mehtap | Ozdemir, Pinar G. | Ciplak, Gokce | Kaya, Ozkan | Cooke, Peter John | Mota, Inês | Gaspar, Ângela | Benito-Garcia, Filipe | Chambel, Marta | Morais-Almeida, Mário | Marques, Luis | Alcoceba, Eva | Lara, Silvia | Carneiro-Leão, Leonor | Botelho, Carmen | Dias-Castro, Eunice | Cernadas, Josefina R. | Nicholls, Katherine | Lay, William | Smith, Olivia | Collins, Christine | Unglik, Gary | Spriggs, Kymble | Auyeung, Priscilla | McComish, Jeremy | Douglass, Jo A. | Peter, Jonny G. | Potter, Paul | Carolino, Fabrícia | De Castro, Eunice Dias | Moreira, Ana Sofia | Abreu, Carmo | Gomes, Eva | Cardoso, Bárbara Kong | Tomaz, Elza | Correia, Sara | Inácio, Filipe | Arnold, Annabelle | Bear, Natasha | Rueter, Kristina | Gong, Grace | O’Sullivan, Michael | Muthusamy, Saravanan | Noble, Valerie | Lucas, Michaela | Buterleviciute, Neringa | Rudzeviciene, Odilija | Abreu, Carmo | May, Sara | Pongdee, Thanai | Park, Miguel | Griguola, Linas | Vinikovas, Arturas | Kašinskaite, Simona | Kvedariene, Violeta | Aktas, Ayse | Rahman, Suheyla | Elbi, Huseyin | Ozyurt, Beyhan Cengiz | Cavkaytar, Ozlem | Karaatmaca, Betul | Cetinkaya, Pinar Gur | Esenboga, Saliha | Sahiner, Umit M. | Sekerel, Bulent E. | Soyer, Ozge | Zubrinich, Celia | Tong, Bianca | Patel, Mittal | Giles, Michelle | O’Hehir, Robyn | Puy, Robert | Amaral, Luís | Demir, Semra | Gelincik, Asli | Olgac, Muge | Caskun, Raif | Unal, Derya | Colakoglu, Bahauddin | Buyukozturk, Suna | Matute, Olga Vega | Bernad, Amalia | Gastaminza, Gabriel | Madamba, Roselle | Lacasa, Carlos | Goikoetxea, M. J. | D’Amelio, Carmen | Rifón, Jose | Martínez, Nicolas | Ferrer, Marta | Ribeiro, Carmelita | Faria, Emília | Frutuoso, Cristina | Barros, Anabela | Lebre, Rosário | Pego, Alice | Bom, Ana Todo | Ensina, Luis Felipe | Aranda, Carolina | Nunes, Ines Camelo | Martins, Ana Maria | Solé, Dirceu | Bavbek, Sevim | Kendirlinan, Resat | Çerçi, Pamir | Tutluer, Seda | Soyyigit, Sadan | Sözener, Zeynep Çelebi | Aydin, Ömür | Gümüsburun, Reyhan | Almeida, Marta | Sai, Kimie | Imatoh, Takuya | Nakamura, Ryosuke | Fukazawa, Chisato | Hinomura, Yasushi | Saito, Yoshiro | Sousa-Pinto, Bernardo | Correia, Cláudia | Gomes, Lídia | Gil-Mata, Sara | Araújo, Luís | Delgado, Luís | Sai, Kimie | Okamoto-Uchida, Yoshimi | Kajinami, Koji | Matsunaga, Kayoko | Aihara, Michiko | Wang, Chuang-Wei | Su, Shih-Chi | Hung, Shuen-Iu | Ho, Hsin-Chun | Yang, Chih-Hsun | Paulmann, Maren | Dunant, Ariane | Mockenhaupt, Maja | Sekula, Peggy | Schumacher, Martin | Kardaun, Sylvia | Naldi, Luigi | Bellón, Teresa | Creamer, Daniel | Haddad, Cynthia | Sassolas, Bruno | Lebrun-Vignes, Bénédicte | Valeyrie-Allanore, Laurence | Roujeau, Jean-Claude | Paulmann, Maren | Kremmler, Carmen | Mockenhaupt, Maja | Dodiuk-Gad, Roni P. | Olteanu, Cristina | Feinstein, Anthony | Hashimoto, Rena | Alhusayen, Raed | Whyte-Croasdaile, Sonia | Finkelstein, Yaron | Burnett, Marjorie | Sade, Shachar | Cartotto, Robert | Jeschke, Marc | Shear, Neil H. | Takamura, Naoko | Yamane, Yumiko | Matsukura, Setsuko | Nakamura, Kazuko | Watanabe, Yuko | Yamaguchi, Yukie | Kambara, Takeshi | Ikezawa, Zenro | Aihara, Michiko | Hashimoto, Rena | Chew, Hall | Burnett, Marjorie | Jeschke, Marc | Knezevic, Brittany | Ionmhain, Una Nic | Barraclough, Allison | Anstey, Matthew | Usui, Toru | Meng, Xiaoli | Farrell, John | Whitaker, Paul | Watson, John | French, Neil | Park, Kevin | Naisbitt, Dean | Neves, Ana Castro | Cadinha, Susana | Moreira, Ana | Da Silva, J. P. Moreira | Drvar, Daniela Ledic | Gulin, Sandra Jerkovic | Hadzavdic, Suzana Ljubojevic | Ceovic, Romana | De Francisco, Ana Montoro | De Vicente Jiménez, Talía | Luque, Amelia García | David, Natalia Rosado | Galván, José Mª Mateos | Darlenski, Razvigor | Gulin, Dario | Sikic, Jozica | Habek, Jasna Cerkez | Galic, Edvard | Specht, Philip | Staab, Doris | Mayer, Beate | Roehmel, Jobst | Solovan, Caius | Chiriac, Anca | Djurinec, Paola | Kostovic, Kresimir | Bradamante, Mirna | Almeida, Jose Pedro | Caiado, Joana | Pedro, Elisa | Da Silva, Pedro Canas | Barbosa, Manuel Pereira | Bogas, Gador | Blanca-López, Natalia | Pérez-Alzate, Diana | Doña, Inmaculada | Agúndez, José Augusto | García-Martín, Elena | Cornejo-García, José Antonio | Mayorga, Cristobalina | Torres, María José | Canto, Maria Gabriela | Blanca, Miguel | Aksakal, Sengül | Sin, Aytül Zerrin | Koç, Zeynep Peker | Günsen, Fatma Düsünür | Ardeniz, Ömür | Gökmen, Emine Nihal Mete | Gülbahar, Okan | Kokuludag, Ali | Pérez-Sánchez, Natalia | Salas, María | Salas, Maria | Gomez, Francisca | Barrionuevo, Esther | Andreu, Inmaculada | Miranda, Miguel Ángel | Didžiokaite, Gabija | Gaidej, Olesia | Kašinskaite, Simona | Garcimartin, Maria Isabel | Somoza, Maria Luisa | Bojas, Gador | Cornejo-Garcia, Jose Antonio | Perez, Francisco Javier Ruano | Miranda, Miguel Angel | Jerschow, Elina | Pelletier, Teresa | Ren, Zhen | Hudes, Golda | Sanak, Marek | Morales, Esperanza | Schuster, Victor | Spivack, Simon D | Rosenstreich, David | Erzen, Renato | Silar, Mira | Bajrovic, Nissera | Rijavec, Matija | Zidarn, Mihaela | Korosec, Peter | Castro, Eunice | Al-Ahmad, Mona | Rodriguez, Tito | Azevedo, João Pedro | Tavares, Beatriz | Regateiro, Frederico | Todo-Bom, Ana | Miranda, Pablo Andrés | De La Cruz Hoyos, Bautista | Abuzeid, Waleed | Akbar, Nadeem | Gibber, Marc | Fried, Marvin | Han, Weiguo | Keskin, Taha | Tamayev, Robert | Spivack, Simon D. | Rosenstreich, David | Jerschow, Elina | Boni, Elisa | Russello, Marina | Mauro, Marina | Neto, Marta Ferreira | Brosseron, Lise | Malheiro, Daniela | Barreira, Patrícia | Sprigg, Dustin | Trevenen, Michelle | Seet, Jason | Trubiano, Jason | Smith, William | Jeelall, Yogesh | Vale, Sandra | Loh, Richard | Mclean-Tooke, Andrew | Müller, Sabine | Amstutz, Ursula | Jörg, Lukas | Yawalkar, Nikhil | Krähenbühl, Stephan | Leblanc, Ana | Ribeiro, Laura | Vega, Arantza | Rivas, Raquel Gutierrez | Alonso, Ana | Beitia, Juan Maria | Mateo, Belén | Cárdenas, Remedios | Garcia-Dominguez, Juan Jesus | Pavlos, Rebecca | Strautins, Kaija | James, Ian | Mallal, Simon | Redwood, Alec | Aguiar, Rita | Lopes, Anabela | Neves, Ana | Do Céu Machado, Maria | Dalgiç, Ceyda Tunakan | Gökmen, Emine Nihal Mete | Bulut, Gökten | Ardeniz, Fatma Ömür | Gülbahar, Okan | Sin, Aytül Zerrin | Hsu, Shao-Hsuan | Yang, Che-Wen | Ye, Young-Min | Hur, Gyu-Young | Park, Hae-Sim | Kim, Seung-Hyun | Ali, Syed | Hollingsworth, Peter N. | Mclean-Tooke, Andrew P. C. | Chadly, Zohra | Fredj, Nadia Ben | Aouam, Karim | Romdhane, Haifa Ben | Boughattas, Naceur A. | Chaabane, Amel | Salazar, Marina Lluncor | Pola, Beatriz | Fiandor, Ana | Ramírez, Elena | Ortega, Javier Domínguez | Quirce, Santiago | Cabañas, Rosario | Baynova, Krasimira | Labella, Marina | Prados, Manuel | Ramonaite, Agne | Bajoriuniene, Ieva | Sitkauskiene, Brigita | Sakalauskas, Raimundas | Kwon, Jae-Woo | Park, Shinyoung | Silva, Diana | Leão, Leonor Carneiro | Castro, Eunice | Garcimartin, Maria | De La Torre, Maria Vazquez | Pérez, Francisco Javier Ruano | Haroun, Elisa | Diez, Gabriela Canto | Ónodi-Nagy, Katinka | Kinyó, Ágnes | Kemény, Lajos | Bata-Csörgo, Zsuzsanna | Pita, Joana Sofia | Fernandes, Rosa Anita | Moura, Ana | Sousa, Nuno | Loureiro, Carlos | Pfützner, Wolfgang | Marrouche, Nadine | Grattan, Clive | Chen, Yu-En | Chen, Chun-Bing | Hsiao, Yu-Ping | Garcimartin, Maria Isabel | Ruano, Francisco Javier
Table of contents
Oral Abstracts
O1 Functionally distinct HMGB1 isoforms correlate with physiological processes in drug-induced SJS/TEN
Daniel F. Carr, Wen-Hung Chung, Rosalind E. Jenkiins, Mas Chaponda, Gospel Nwikue, Elena M. Cornejo Castro, Daniel J. Antoine, Munir Pirmohamed
O2 Hypersensitivity reactions to beta-lactams, does the t cell recognition pattern influence the clinical picture?
Natascha Wuillemin, Dolores Dina, Klara K. Eriksson, Daniel Yerly
O3 Specific binding characteristics of HLA alleles associated with nevirapine hypersensitivity
Rebecca Pavlos, Elizabeth Mckinnin, David Ostrov, Bjoern Peters, Soren Buus, David Koelle, Abha Chopra, Craig Rive, Alec Redwood, Susana Restrepo, Austin Bracey, Jing Yuan, Silvana Gaudieri, Mary Carrington, David Haas, Simon Mallal, Elizabeth Phillips
O4 Do we need to measure total ige for the interpretation of analytical results of ImmunoCAP dnd 3gAllergy specific IgE?
Douwe De Boer, Paul Menheere, Chris Nieuwhof, Judith Bons
O5 Neutrophil activation in systemic anaphylaxis: results from the multicentric NASA study
Friederike Jonsson, Luc De Chaisemartin, Vanessa Granger, Caitlin Gillis, Aurelie Gouel, Catherine Neukirch, Fadia Dib, Pascale Roland Nicaise, Dan Longrois, Florence Tubach, Sylvie Martin, Pierre Bruhns, NASA Study Group
O6 Purpuric drug eruptions due to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for non-small-cell lung cancer (NSCLC): a clinic-pathological study of 32 cases
Kai-Lung Chen, Shu-Ling Liao, Yi-Shuan Sheen, Yung-Tsu Cho, Che-Wen Yang, Jau-Yu Liau, Chia-Yu Chu
Poster presentations: Poster Walk 1—Anaphylaxis (P01–P09)
P1 Anaphylactic reactions during anaesthesia and the perioperative period
Rita Aguiar, Anabela Lopes, Natália Fernandes, Leonor Viegas, M. A. Pereira-Barbosa
P2 Anaphylaxis to chlorhexidine: is there a cross-reactivity to alexidine?
Antonia Bünter, Nisha Gupta, Tatjana Pecaric Petkovic, Nicole Wirth, Werner J. Pichler, Oliver Hausmann
P3 Cefotaxime-induced severe anaphylaxis in a neonate
Mehtap Yazicioglu, Pinar G. Ozdemir, Gokce Ciplak, Ozkan Kaya
P4 Clinical features and diagnosis of anaphylaxis resulting from exposure to chlorhexidine
Peter John Cooke
P5 Drug-induced anaphylaxis: five-year single-center survey
Inês Mota, Ângela Gaspar, Filipe Benito-Garcia, Marta Chambel, Mário Morais-Almeida
P6 Intraoperative severe anaphylactic reaction due to patent blue v dye
Luis Marques, Eva Alcoceba, Silvia Lara
P7 Kounis syndrome in the setting of anaphylaxis to diclofenac
Leonor Carneiro-Leão, Carmen Botelho, Eunice Dias-Castro, Josefina Cernadas
P8 Perioperative anaphylaxis audit: Royal Melbourne Hospital
Katherine Nicholls, William Lay, Olivia Smith, Christine Collins, Gary Unglik, Kymble Spriggs, Priscilla Auyeung, Jeremy McComish, Jo A. Douglass
P9 Recurrent peri-operative anaphylaxis: a perfect storm
Jonny G. Peter, Paul Potter
Poster Walk 2: DH regions and patient groups (P10–P19)
P10 A rare presentation of amoxicillin allergy in a young child
Fabrícia Carolino, Eunice Dias De Castro, Josefina R. Cernadas
P11 Adverse drug reactions in children: antibiotics or virus?
Ana Sofia Moreira, Carmo Abreu, Eva Gomes
P12 Allergic reactions in invasive medical procedures
Bárbara Kong Cardoso, Elza Tomaz, Sara Correia, Filipe Inácio
P13 Antibiotic allergy in children: room for improvement
Annabelle Arnold, Natasha Bear, Kristina Rueter, Grace Gong, Michael O’Sullivan, Saravanan Muthusamy, Valerie Noble, Michaela Lucas
P14 Drug hypersensitivity reactions in children and results of diagnostic evaluation
Neringa Buterleviciute, Odilija Rudzeviciene
P15 Nonimmediate cutaneous drug reactions in children: are skin tests required?
Ana Sofia Moreira, Carmo Abreu, Eva Gomes
P16 Pediatric patients with a history of penicillin allergy and a positive penicillin skin test may not be at an increased risk for multiple drug allergies
Sara May, Thanai Pongdee, Miguel Park
P17 Proved hypersensitivity to drugs according data of Vilnius University Hospital Santariskiu Klinikos
Linas Griguola, Arturas Vinikovas, Simona Kašinskaite, Violeta Kvedariene
P18 Self-reported prevalence of drug hypersensitivity reactions among students in Celal Bayar University, Turkey
Ayse Aktas, Suheyla Rahman, Huseyin Elbi, Beyhan Cengiz Ozyurt
P19 Severe drug hypersensitivity reactions in pediatric age
Ozlem Cavkaytar, Betul Karaatmaca, Pinar Gur Cetinkaya, Saliha Esenboga, Umit M. Sahiner, Bulent E. Sekerel, Ozge Soyer
Poster Walk 3: Desensitisation (P20–P28)
P20 A protocol for desensitisation to valaciclovir
Celia Zubrinich, Bianca Tong, Mittal Patel, Michelle Giles, Robyn O’Hehir, Robert Puy
P21 A rare case of desensitization to modafinil
Josefina Cernadas, Luís Amaral, Fabrícia Carolino
P22 A sixteen-day desensitization protocol in delayed type hypersensitivity reactions to oral drugs
Semra Demir, Asli Gelincik, Muge Olgac, Raif Caskun, Derya Unal, Bahauddin Colakoglu, Suna Buyukozturk
P23 Desensitization to intravenous etoposide using a 12 and a 13-step protocol. Two cases report
Olga Vega Matute, Amalia Bernad, Gabriel Gastaminza, Roselle Madamba, Carlos Lacasa, M. J. Goikoetxea, Carmen D’Amelio, Jose Rifón, Nicolas Martínez, Marta Ferrer
P24 Drug desensitisation in oncology: the experience of an immunoallergology department for 5 years
Carmelita Ribeiro, Emília Faria, Cristina Frutuoso, Anabela Barros, Rosário Lebre, Alice Pego, Ana Todo Bom
P25 Filgrastim anaphylaxis: a successful desensitization protocol
Luis Amaral, Josefina Cernadas
P26 Galsulfase hypersensitivity and desensitization of a mucopolysaccharidosis VI patient
Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Ana Maria Martins, Dirceu Solé
P27 Rapid drug desensitization with biologicals: one-center experience with four biologicals
Sevim Bavbek, Resat Kendirlinan, Pamir Çerçi, Seda Tutluer, Sadan Soyyigit, Zeynep Çelebi Sözener, Ömür Aydin, Reyhan Gümüsburun
P28 Successful desensitization to a high dose of methotrexate in a delayed type hypersensitivity reaction
Josefina Cernadas, Leonor Carneiro-Leão, Fabrícia Carolino, Marta Almeida
Poster Walk 4: SJS (P29–P38)
P29 Assessment of impact of infection on drug-induced severe cutaneous adverse reactions and rhabdomyolysis using the Japanese adverse drug event report database
Kimie Sai, Takuya Imatoh, Ryosuke Nakamura, Chisato Fukazawa, Yasushi Hinomura, Yoshiro Saito
P30 Characterization of erythema multiforme and severe cutaneous adverse reactions hospitalizations
Bernardo Sousa-Pinto, Cláudia Correia, Lídia Gomes, Sara Gil-Mata, Luís Araújo, Luís Delgado
P31 Effects of infection on incidence/severity of SJS/TEN and myopathy in Japanese cases analyzed by voluntary case reports
Ryosuke Nakamura, Kimie Sai, Takuya Imatoh, Yoshimi Okamoto-Uchida, Koji Kajinami, Kayoko Matsunaga, Michiko Aihara, Yoshiro Saito
P32 Efficacy of tumor necrosis factor—a antagonists in Stevens–Johnson syndrome and toxic epidermal necrolysis: a randomized controlled trial and immunosuppressive effects evaluation
Chuang-Wei Wang, Shih-Chi Su, Shuen-Iu Hung, Hsin-Chun Ho, Chih-Hsun Yang, Wen-Hung Chung
P33 Evolution of drug causality in Stevens–Johnson syndrome and toxic epidermal necrolysis in Europe: analysis of 10 years RegiSCAR-Study
Maren Paulmann, Ariane Dunant, Maja Mockenhaupt, Peggy Sekula, Martin Schumacher, Sylvia Kardaun, Luigi Naldi, Teresa Bellón, Daniel Creamer, Cynthia Haddad, Bruno Sassolas, Bénédicte Lebrun-Vignes, Laurence Valeyrie-Allanore, Jean-Claude Roujeau
P34 Long-term sequelae in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis: a 5-year analysis
Maren Paulmann, Carmen Kremmler, Peggy Sekula, Laurence Valeyrie-Allanore, Luigi Naldi, Sylvia Kardaun, Maja Mockenhaupt
P35 Major emotional complications and decreased health related quality of life among survivors of Stevens–Johnson syndrome and toxic epidermal necrolysis
Roni P. Dodiuk-Gad, Cristina Olteanu, Anthony Feinstein, Rena Hashimoto, Raed Alhusayen, Sonia Whyte-Croasdaile, Yaron Finkelstein, Marjorie Burnett, Shachar Sade, Robert Cartotto, Marc Jeschke, Neil H. Shear
P36 Retrospective analysis of Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients: treatment and outcome
Naoko Takamura, Yumiko Yamane, Setsuko Matsukura, Kazuko Nakamura, Yuko Watanabe, Yukie Yamaguchi, Takeshi Kambara, Zenro Ikezawa, Michiko Aihara
P37 Severe physical complications among survivors of Stevens–Johnson syndrome and toxic epidermal necrolysis
Roni P. Dodiuk-Gad, Cristina Olteanu, Rena Hashimoto, Hall Chew, Raed Alhusayen, Sonia Whyte-Croasdaile, Yaron Finkelstein, Marjorie Burnett, Shachar Sade, Robert Cartotto, Marc Jeschke, Neil H. Shear
P38 Stevens–Johnson syndrome/toxic epidermal necrolysis combined with haemophagocytic lymphohistiocytosis: a case report
Brittany Knezevic, Una Nic Ionmhain, Allison Barraclough, Michaela Lucas, Matthew Anstey
Poster Walk 5: Other organs/unexpected immune reactions (P39–P47)
P39 A case report of patient with anti-tuberculosis drug-related severe liver failure
Toru Usui, Xiaoli Meng, John Farrell, Paul Whitaker, John Watson, Neil French, Kevin Park, Dean Naisbitt
P40 Acute interstitial nephritis induced by ibuprofen
Ana Castro Neves, Susana Cadinha, Ana Moreira, J. P. Moreira Da Silva
P41 Cetuximab induced acneiform rash—two case reports
Daniela Ledic Drvar, Sandra Jerkovic Gulin, Suzana Ljubojevic Hadzavdic, Romana Ceovic
P42 Enteropathy associated with losartan
Ana Montoro De Francisco, Talía De Vicente Jiménez, Amelia García Luque, Natalia Rosado David, José Mª Mateos Galván
P43 Granuloma annulare after therapy with canakinumab
Razvigor Darlenski
P44 Hypersensitivity eosinophilic myocarditis or acute coronary syndrome? Case report
Dario Gulin, Jozica Sikic, Jasna Cerkez Habek, Sandra Jerkovic Gulin, Edvard Galic
P45 Piperacillin-induced immune haemolytic anaemia: a severe and frequent complication of antibiotic treatment in patients with cystic fibrosis
Philip Specht, Doris Staab, Beate Mayer, Jobst Roehmel
P46 Progesterone triggered pemphigus foliaceus: case report
Sandra Jerkovic Gulin, Caius Solovan, Anca Chiriac
P47 Ramipril: triggered generalized pustular psoriasis
Paola Djurinec, Kresimir Kostovic, Mirna Bradamante, Sandra Jerkovic Gulin, Romana Ceovic
Poster Walk 6: NSAIDs (P48–P56)
P48 Aspirin desensitization in cardiovascular disease—Portuguese experience
Jose Pedro Almeida, Joana Caiado, Elisa Pedro, Pedro Canas Da Silva, Manuel Pereira Barbosa
P49 Asthma and/or rhinitis to NSAIDs with good tolerance to ASA
Gador Bogas, Natalia Blanca-López, Diana Pérez-Alzate, Inmaculada Doña, José Augusto Agúndez, Elena García-Martín, José Antonio Cornejo-García, Cristobalina Mayorga, María José Torres, Gabriela Canto, Miguel Blanca
P50 Clinical characteristics of 196 patients with non-steroidal anti-inflammatory drug (NSAIDs) hypersensitivity
Sengül Aksakal, Aytül Zerrin Sin, Zeynep Peker Koç, Fatma Düsünür Günsen, Ömür Ardeniz, Emine Nihal Mete Gökmen, Okan Gülbahar, Ali Kokuludag
P51 Development of immediate hypersensitivity to several NSAIDs maintaining good tolerance to ASA
Natalia Pérez-Sánchez, Natalia Blanca-López, Diana Pérez-Alzate, Gador Bogas, Inmaculada Doña, María Salas, María José Torres, Miguel Blanca, Gabriela Canto
P52 Diagnosis of hypersensitivity reactions to paracetamol in a large series of cases
Inmaculada Doña, Maria Salas, Francisca Gomez, Natalia Blanca-Lopez, Diana Perez-Alzate, Gador Bogas, Esther Barrionuevo, Maria Jose Torres, Inmaculada Andreu, Miguel Ángel Miranda, Gabriela Canto, Miguel Blanca
P53 Hypersensitivity to paracetamol according to the new classification of hypersensitivity to NSAIDs
Gabija Didžiokaite, Olesia Gaidej, Simona Kašinskaite, Violeta Kvedariene
P54 Ibuprofen and other aryl propionic derivates can induce immediate selective hypersensitivity responses
Diana Perez-Alzate, Natalia Blanca-López, Maria Isabel Garcimartin, Inmaculada Doña, Maria Luisa Somoza, Cristobalina Mayorga, Maria Jose Torres, Gador Bojas, Jose Antonio Cornejo-Garcia, Maria Gabriela Canto, Miguel Blanca
P55 Subjects developing immediate responses to several NSAIDs can be selective with good tolerance to ASA
Natalia Blanca-Lopez, Diana Pérez-Alzate, Francisco Javier Ruano Perez, Inmaculada Doña, Maria Luisa Somoza, Inmaculada Andreu, Miguel Angel Miranda, Cristobalina Mayorga, Maria Jose Torres, Jose Antonio Cornejo-Garcia, Miguel Blanca, Maria Gabriela Canto
P56 Utility of low-dose oral aspirin challenges for diagnosis of aspirin exacerbated respiratory disease
Elina Jerschow, Teresa Pelletier, Zhen Ren, Golda Hudes, Marek Sanak, Esperanza Morales, Victor Schuster, Simon D. Spivack, David Rosenstreich
Poster Walk 7: NSAID 2 (P57–P65)
P57 Alternate regulation of cyclooxygenase-2 (COX-2) MRNA expression may predispose patients to aspirin-induced exacerbations
Renato Erzen, Mira Silar, Nissera Bajrovic, Matija Rijavec, Mihaela Zidarn, Peter Korosec
P58 Anaphylaxis to diclofenac: what about the underlying mechanism?
Leonor Carneiro-Leão, Fabrícia Carolino, Luís Amaral, Carmen Botelho, Eunice Dias-Castro, Josefina Cernadas
P59 COX-2 inhibitors: are they always a safe alternative in hypersensitivity to nonsteroidal anti-inflammatory drugs?
Luis Amaral, Fabricia Carolino, Eunice Castro, Josefina Cernadas
P60 Management of patients with history of NSAIDs reactions prior to coronary angioplasty
Mona Al-Ahmad, Tito Rodriguez
P61 Oral drug challenge with non-steroidal anti-inflammatory drug under spirometric control: clinical series of 110 patients
João Pedro Azevedo, Emília Faria, Beatriz Tavares, Frederico Regateiro, Ana Todo-Bom
P62 Prevalence and incidence of analgesic hypersensitivity reactions in Colombia
Pablo Andrés Miranda, Bautista De La Cruz Hoyos
P63 Recent endoscopic sinus surgery lessens reactions during aspirin challenge in patients with aspirin exacerbated respiratory disease
Teresa Pelletier, Waleed Abuzeid, Nadeem Akbar, Marc Gibber, Marvin Fried, Weiguo Han, Taha Keskin, Robert Tamayev, Golda Hudes, Simon D. Spivack, David Rosenstreich, Elina Jerschow
P64 Safe use of imidazole salycilate in a case of multiple NSAIDs induced urticaria-angioedema
Elisa Boni, Marina Russello, Marina Mauro
P65 Selective hypersensitivity reactions to ibuprofen—seven years experience
Marta Ferreira Neto
Poster Walk 8: Epidemiological methods (P66–P72)
P66 Allopurinol hypersensitivity: a 7-year review
Lise Brosseron, Daniela Malheiro, Susana Cadinha, Patrícia Barreira, J. P. Moreira Da Silva
P67 Antibiotic allergy labelling is associated with increased hospital readmission rates in Australia
Brittany Knezevic, Dustin Sprigg, Michelle Trevenen, Jason Seet, Jason Trubiano, William Smith, Yogesh Jeelall, Sandra Vale, Richard Loh, Andrew Mclean-Tooke, Michaela Lucas
P68 Experts’ opinions on severe cutaneous adverse drug reactions-report of a survey from the 9th international congress on cutaneous adverse drug reactions 2015
Roni P. Dodiuk-Gad, Cristina Olteanu, Wen-Hung Chung, Neil H. Shear
P69 HLA-A*31-positive AGEP with carbamazepine use and other severe cutaneous adverse drug reactions (SCARs) detected by electronic medical records screening
Sabine Müller, Ursula Amstutz, Lukas Jörg, Nikhil Yawalkar, Stephan Krähenbühl
P70 Patients with suspected drug allergy: a specific psychological profile?
Eunice Dias-Castro, Ana Leblanc, Laura Ribeiro, Josefina R. Cernadas
P71 Use of an electronic device and a computerized mathematic algorithm to detect the allergic drug reactions through the analysis of heart rate variability
Arantza Vega, Raquel Gutierrez Rivas, Ana Alonso, Juan Maria Beitia, Belén Mateo, Remedios Cárdenas, Juan Jesus Garcia-Dominguez
P72 Variation in ERAP influences risk for HLA-B*57:01 positive abacavir hypersensitivity
Rebecca Pavlos, Kaija Strautins, Ian James, Simon Mallal, Alec Redwood, Elizabeth Phillips
Poster Walk 9: DRESS/AGEP (P73–P81)
P73 A clinical case of DRESS syndrome in a child after administration of amoxicillin-clavulanic acid
Rita Aguiar, Anabela Lopes, Ana Neves, Maria Do Céu Machado, M. A. Pereira-Barbosa
P74 Acute generalized exanthematous pustulosis (AGEP) induced by mesalazine, reliable and oftenly used drug to treat inflammatory bowel disease
Ceyda Tunakan Dalgiç, Emine Nihal Mete Gökmen, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Ali Kokuludag, Aytül Zerrin Sin
P75 Changes of blood plasmacytoid dendritic cells, myeloid dendritic cells, and basophils during the acute stage of drug reaction with eosinophilia and systemic symptoms (DRESS) and other drug eruptions
Shao-Hsuan Hsu, Yung-Tsu Cho, Che-Wen Yang, Kai-Lung Chen, Chia-Yu Chu
P76 Characterization of isoniazid/rifampicin-specific t-cell responses in patients with DRESS syndrome
Young-Min Ye, Gyu-Young Hur, Hae-Sim Park, Seung-Hyun Kim
P77 DRESS syndrome secondary to sulfasalazine with delayed TEN: a case presentation
Syed Ali, Michaela Lucas, Peter N. Hollingsworth, Andrew P. C. Mclean-Tooke
P78 Drug rash with eosinophilia and systemic symptoms (DRESS) features according to the culprit drug
Zohra Chadly, Nadia Ben Fredj, Karim Aouam, Haifa Ben Romdhane, Naceur A. Boughattas, Amel Chaabane
P79 Drug reaction with eosinophilia and systemic symptoms induced by allopurinol: not always easy to diagnose
Marina Lluncor Salazar, Beatriz Pola, Ana Fiandor, Teresa Bellón, Elena Ramírez, Javier Domínguez Ortega, Santiago Quirce, Rosario Cabañas
P80 Drug reaction with eosinophilia and systemic symptoms syndrome induced by two drugs simultaneously: a case report
Krasimira Baynova, Marina Labella, Manuel Prados
P81 The drug reaction with eosinophilia and systemic symptoms (DRESS) induced by the second-line antituberculosis drugs and Epstein–Barr virus infection
Agne Ramonaite, Ieva Bajoriuniene, Brigita Sitkauskiene, Raimundas Sakalauskas
Poster Walk 10: Miscellaneous drug hypersensitivity (P82–P91)
P82 A case of cycloserine-induced lichenoid drug eruption confirmed with a lymphocatye transformation test
Jae-Woo Kwon, Shinyoung Park
P83 Allergic reaction to topical eye drops: 5 years’ retrospective study in a drug allergy unit
Diana Silva, Leonor Carneiro Leão, Fabricia Carolino, Eunice Castro, Josefina Cernadas
P84 Allergy to heparins
Diana Perez-Alzate, Natalia Blanca-López, Maria Luisa Somoza Alvarez, Maria Garcimartin, Maria Vazquez De La Torre, Francisco Javier Ruano Pérez, Elisa Haroun, Gabriela Canto Diez
P85 Allopurinol-induced adverse drug reactions
Katinka Ónodi-Nagy, Ágnes Kinyó, Lajos Kemény, Zsuzsanna Bata-Csörgo
P86 Analysis of a population with immediate hypersensitivity to corticosteroids: an 11 year review
Joana Sofia Pita, Emília Faria, Rosa Anita Fernandes, Ana Moura, Nuno Sousa, Carmelita Ribeiro, Carlos Loureiro, Ana Todo Bom
P87 Anaphylaxis against mivacurium in a 12-months old boy at first-time exposure
Wolfgang Pfützner
P88 Antihistamine-exacerbated chronic spontaneous urticaria: a paradox?
Nadine Marrouche, Clive Grattan
P89 Anti-osteoporotic agents-induced cutaneous adverse drug reactions in Asians
Yu-En Chen, Chun-Bing Chen, Wen-Hung Chung, Yu-Ping Hsiao, Chia-Yu Chu
P90 Diagnosis of allergic reactions to eye drops
Maria Vazquez De La Torre, Natalia Blanca-Lopez, Diana Perez-Alzate, Maria Isabel Garcimartin, Francisco Javier Ruano, Maria Luisa Somoza, Elisa Haroun, Gabriela Canto
P91 Diagnostic approach in suspected hypersensitivity reactions to corticosteroids
Fabrícia Carolino, Eunice Dias De Castro, Josefina R. Cernadas
doi:10.1186/s13601-016-0121-z
PMCID: PMC5009634
3.  Modeling Heterogeneity in Direct Infectious Disease Transmission in a Compartmental Model 
Mathematical models have been used to understand the transmission dynamics of infectious diseases and to assess the impact of intervention strategies. Traditional mathematical models usually assume a homogeneous mixing in the population, which is rarely the case in reality. Here, we construct a new transmission function by using as the probability density function a negative binomial distribution, and we develop a compartmental model using it to model the heterogeneity of contact rates in the population. We explore the transmission dynamics of the developed model using numerical simulations with different parameter settings, which characterize different levels of heterogeneity. The results show that when the reproductive number, R0, is larger than one, a low level of heterogeneity results in dynamics similar to those predicted by the homogeneous mixing model. As the level of heterogeneity increases, the dynamics become more different. As a test case, we calibrated the model with the case incidence data for severe acute respiratory syndrome (SARS) in Beijing in 2003, and the estimated parameters demonstrated the effectiveness of the control measures taken during that period.
doi:10.3390/ijerph13030253
PMCID: PMC4808916  PMID: 26927140
infectious diseases; mathematical models; homogeneous mixing; heterogeneity; negative binomial distribution
4.  Genome Wide Methylome Alterations in Lung Cancer 
PLoS ONE  2015;10(12):e0143826.
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)–non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.
doi:10.1371/journal.pone.0143826
PMCID: PMC4684329  PMID: 26683690
5.  Smoking-Related Gene Expression in Laser Capture Microdissected Human Lung 
Purpose
Inter-individual differences in quantitative expression could underlie a propensity for lung cancer. To determine precise individual gene expression signatures on a lung compartment-specific basis, we investigated the expression of carcinogen metabolism genes encoding cytochromes P450 (CYP) 1B1, 2A13, glutathione S-transferase (GST) P1, and a tumor suppressor gene p16 in laser capture microdissected samples of human alveolar compartment (AC) and bronchial epithelial compartment (BEC) lung tissue from 62 smokers and non-smokers.
Experimental Design
Tobacco exposure was determined by plasma nicotine, cotinine, and smoking history. Precise mRNA expression was determined using our RNA-specific qRT-PCR strategy, and correlated with detailed demographic and clinical characteristics.
Results
Several correlations of mRNA expression included: (a) CYP1B1 in AC (positively with plasma nicotine level, P = 0.008; plasma cotinine level, P = 0.001); (b) GSTP1 in AC (positively with plasma cotinine level, P = 0.003); (c) GSTP1 in BEC (negatively with smoke dose, P = 0.043; occupational risk, P = 0.019). CYP2A13 was rarely expressed in AC, and not expressed in BEC. p16 expression was not correlated with any measured factor. For each gene, subjects showed expression that was individually concordant between these compartments. No clear association of mRNA expression with lung cancer risk was observed in this pilot analysis.
Conclusions
The association between lung mRNA expression and tobacco exposure implies that gene-tobacco interaction is a measurable quantitative trait, albeit with wide inter-individual variation. Gene expression tends to be concordant for alveolar and bronchial compartments for these genes in an individual, controlling for proximate tobacco exposure.
doi:10.1158/1078-0432.CCR-09-1694
PMCID: PMC4238890  PMID: 19996203
Lung carcinoma; gene expression; laser capture microdissection; lung epithelial cells; tobacco smoking
6.  A quantitative method to identify microRNAs targeting a messenger RNA using a 3′UTR RNA affinity technique 
Analytical biochemistry  2013;443(1):1-12.
The identification of specific microRNAs (miRNAs) that target a given messenger RNA (mRNA) is essential for studies in gene regulation, but the available bioinformatic software programs are often unreliable. We have developed a unique experimental miRNA affinity assay whereby a 3′UTR RNA is end-labeled with biotin, immobilized, and then used as a bait sequence for affinity pull-down of miRNAs. After washes and release, cloning and sequencing identify the miRNAs. Binding affinity is quantitated by quantitatvie polymerase chain reaction (qPCR), comparing released and original input concentrations. As an initial demonstration, the TCF8/ZEB1 mRNA affinity pull-down yielded miR-200 family member miRs in the majority of clones, and binding affinity was approximately 100%; virtually all copies of miR-200c bound the immobilized mRNA transcript. For validation in cells, miR-200c strongly inhibited expression of a TCF8 luciferase reporter, native TCF8 mRNA, and protein levels, which contrasted with other recovered miRNAs with lower binding affinities. For Smad4 mRNA, miR-150 (and others) displayed a binding affinity of 39% (or less) yet did not inhibit a Smad4 reporter, native Smad4 mRNA, or protein levels. These results were not predicted by available software. This work demonstrates this miRNA binding affinity assay to be a novel yet facile experimental means of identification of miRNAs targeting a given mRNA.
doi:10.1016/j.ab.2013.08.002
PMCID: PMC4112567  PMID: 23938772
miRNA; mRNA; miRNA:mRNA binding; Gene targeting; Gene modulation
7.  Genetic and epigenetic regulation of AHR gene expression in MCF-7 breast cancer cells: role of the proximal promoter GC-rich region 
Biochemical pharmacology  2012;84(5):722-735.
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, contributes to carcinogenesis through its role in the regulation of cytochrome P450 1 (CYP1)-catalyzed metabolism of carcinogens. Here, we investigated genetic and epigenetic mechanisms that affect AhR expression. Analyses of the human AHR proximal promoter in MCF-7 human breast cancer cells using luciferase assays and electrophoretic mobility shift assays revealed multiple specificity protein (Sp) 1 binding sequences that are transcriptional activators in vitro. The regulation of AhR expression was evaluated in long-term estrogen exposed (LTEE) MCF-7 cells, which showed increased AhR expression, enhanced CYP1 inducibility, and increased capacity to form DNA adducts when exposed to the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. The increased AhR expression in LTEE cells was found not to result from increased mRNA stability, differential RNA processing, or decreased DNA methylation. Analysis of the AHR proximal promoter region using chromatin immunoprecipitation confirmed that enhanced expression of AhR in LTEE cells involves changes in histone modifications, notably decreased trimethylation of histone 3, lysine 27. Upon further examination of the GC-rich Sp1-binding region, we confirmed that it contains a polymorphic (GGGGC)n repeat. In a population of newborns from New York State, the allele frequency of (GGGGC)n was n = 4>5≫6, 2. Circular dichroism spectroscopy revealed the ability of sequences of this GC-rich region to form guanine-quadruplex structures in vitro. These studies revealed multiple levels at which AhR expression may be controlled, and offer additional insights into mechanisms regulating AhR expression that can ultimately impact carcinogenesis.
doi:10.1016/j.bcp.2012.06.013
PMCID: PMC3965201  PMID: 22728919
aryl hydrocarbon receptor; long-term estrogen exposure; epigenetic; (GGGGC)n repeat polymorphism; guanine-quadruplex; 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
8.  Haplotype-tagging single nucleotide polymorphisms in the GSTP1 gene promoter and susceptibility to lung cancer☆ 
Cancer detection and prevention  2009;32(0):403-415.
Background
Glutathione S-transferase (GST) P1 is a major phase II xenobiotic-metabolizing enzyme in the human lung. Our laboratory had previously identified nine single nucleotide polymorphisms (SNPs) in the GSTP1 gene promoter, which were then grouped into three main haplotypes (Hap1, Hap2, and Hap3) based on statistical inference. Hap3 was found to display a high expression phenotype. The main objective of the current study was to test the association between GSTP1 promoter haplotypes with the risk of lung cancer after determining the promoter haplotypes experimentally through cloning and sequencing.
Methods
We conducted a case–control analysis of 150 subjects with lung cancer and 329 controls with no personal history of the disease. The three statistically inferred GSTP1 promoter haplotypes were confirmed experimentally through cloning and sequencing. Haplotype-tagging SNPs were selected and GSTP1 haplotypes were tested for genetic association to lung cancer using unconditional logistic regression after adjusting for confounders. Statistical interaction between GSTP1 promoter haplotypes with either cigarette smoking or dietary fruit and vegetable intake were tested using the likelihood ratio test.
Results
We did not find protective effects of Hap3 against lung cancer, despite an adequately powered design for this main effect. Homozygous variants of tagSNPs –1738 T >A and –354 G > T, which tag Hap2, showed an increased (but statistically non-significant) risk of lung cancer among all subjects as well as among individuals with low fruit and vegetable intake, compared to homozygous wildtypes for these SNPs. We did not find significant interactions between Hap2 and dietary intake of fruits and vegetables.
Conclusions
Our results do not support significant main and modifying effects for GSTP1 promoter haplotypes on susceptibility to lung cancer in this population, but reinforce the protective effects of dietary intake of fruits and vegetables.
doi:10.1016/j.cdp.2009.02.004
PMCID: PMC3730463  PMID: 19282111
Lung cancer; GSTP1; Promoter polymorphisms; Gene–environment interaction
9.  High-Throughput Library Screening Identifies Two Novel NQO1 Inducers in Human Lung Cells 
Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element–mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)–specific gene expression–based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4′-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H2O2 induced nuclear translocation of nuclear factor erythroid 2–related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES.
doi:10.1165/rcmb.2011-0301OC
PMCID: PMC3326428  PMID: 22021338
GSTP1; NQO1; phytochemicals; high-throughput screening; gene expression
10.  Gene promoter methylation assayed in exhaled breath, with differences in smokers and lung cancer patients 
Respiratory Research  2009;10(1):86.
Background
There is a need for new, noninvasive risk assessment tools for use in lung cancer population screening and prevention programs.
Methods
To investigate the technical feasibility of determining DNA methylation in exhaled breath condensate, we applied our previously-developed method for tag-adapted bisulfite genomic DNA sequencing (tBGS) for mapping of DNA methylation, and adapted it to exhaled breath condensate (EBC) from lung cancer cases and non-cancer controls. Promoter methylation patterns were analyzed in DAPK, RASSF1A and PAX5β promoters in EBC samples from 54 individuals, comprised of 37 controls [current- (n = 19), former- (n = 10), and never-smokers (n = 8)] and 17 lung cancer cases [current- (n = 5), former- (n = 11), and never-smokers (n = 1)].
Results
We found: (1) Wide inter-individual variability in methylation density and spatial distribution for DAPK, PAX5β and RASSF1A. (2) Methylation patterns from paired exhaled breath condensate and mouth rinse specimens were completely divergent. (3) For smoking status, the methylation density of RASSF1A was statistically different (p = 0.0285); pair-wise comparisons showed that the former smokers had higher methylation density versus never smokers and current smokers (p = 0.019 and p = 0.031). For DAPK and PAX5β, there was no such significant smoking-related difference. Underlying lung disease did not impact on methylation density for this geneset. (4) In case-control comparisons, CpG at -63 of DAPK promoter and +52 of PAX5β promoter were significantly associated with lung cancer status (p = 0.0042 and 0.0093, respectively). After adjusting for multiple testing, both loci were of borderline significance (padj = 0.054 and 0.031). (5) The DAPK gene had a regional methylation pattern with two blocks (1)~-215~-113 and (2) -84 ~+26); while similar in block 1, there was a significant case-control difference in methylation density in block 2 (p = 0.045); (6)Tumor stage and histology did not impact on the methylation density among the cases. (7) The results of qMSP applied to EBC correlated with the corresponding tBGS sequencing map loci.
Conclusion
Our results show that DNA methylation in exhaled breath condensate is detectable and is likely of lung origin. Suggestive correlations with smoking and lung cancer case-control status depend on individual gene and CpG site examined.
doi:10.1186/1465-9921-10-86
PMCID: PMC2759916  PMID: 19781081
11.  The expression and antigenicity of a truncated spike-nucleocapsid fusion protein of severe acute respiratory syndrome-associated coronavirus 
BMC Microbiology  2008;8:207.
Background
In the absence of effective drugs, controlling SARS relies on the rapid identification of cases and appropriate management of the close contacts, or effective vaccines for SARS. Therefore, developing specific and sensitive laboratory tests for SARS as well as effective vaccines are necessary for national authorities.
Results
Genes encoding truncated nucleocapsid (N) and spike (S) proteins of SARSCoV were cloned into the expression vector pQE30 and fusionally expressed in Escherichia coli M15. The fusion protein was analyzed for reactivity with SARS patients' sera and with anti-sera against the two human coronaviruses HCoV 229E and HCoV OC43 by ELISA, IFA and immunoblot assays. Furthermore, to evaluate the antigen-specific humoral antibody and T-cell responses in mice, the fusion protein was injected into 6-week-old BALB/c mice and a neutralization test as well as a T-cell analysis was performed. To evaluate the antiviral efficacy of immunization, BALB/c mice were challenged intranasally with SARSCoV at day 33 post injection and viral loads were determined by fluorescent quantitative RT-PCR. Serological results showed that the diagnostic sensitivity and specificity of the truncated S-N fusion protein derived the SARS virus were > 99% (457/460) and 100.00% (650/650), respectively. Furthermore there was no cross-reactivity with other two human coronaviruses. High titers of antibodies to SRASCoV appeared in the immunized mice and the neutralization test showed that antibodies to the fusion protein could inhibit SARSCoV. The T cell proliferation showed that the fusion protein could induce an antigen-specific T-cell response. Fluorescent quantitative RT-PCR showed that BALB/c mice challenged intranasally with SARSCoV at day 33 post injection were completely protected from virus replication.
Conclusion
The truncated S-N fusion protein is a suitable immunodiagnostic antigen and vaccine candidate.
doi:10.1186/1471-2180-8-207
PMCID: PMC2613400  PMID: 19038059

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