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1. Fibrotic cocktail treated human precision lung slices replicate the cellular diversity of the IPF lung

Author

Justet, A., primary, Pineda, H.R., additional, Adams, T., additional, Balayev, A., additional, Mitash, N., additional, Ishizuka, M., additional, Kim, H., additional, Khoury, J., additional, Cala-García, J.D., additional, Flint, J., additional, Schupp, J., additional, Ahangari, F., additional, Yan, X., additional, Rosas, I., additional, Kaminski, N., additional, and Königshoff, M., additional

Published
2024
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2. Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

Author

Abe, S., Aburto, M., Acosta, O., Andrews, C., Antin-Ozerkis, D., Arce, G., Arias, M., Avdeev, S., Barczyk, A., Bascom, R., Bazdyrev, E., Beirne, P., Belloli, E., Bergna, M.A., Bergot, E., Bhatt, N., Blaas, S., Bondue, B., Bonella, F., Britt, E., Buch, K., Burk, J., Cai, H., Cantin, A., Castillo Villegas, D.M., Cazaux, A., Cerri, S., Chaaban, S., Chaudhuri, N., Cottin, V., Crestani, B., Criner, G., Dahlqvist, C., Danoff, S., Dematte D'Amico, J., Dilling, D., Elias, P., Ettinger, N., Falk, J., Fernández Pérez, E.R., Gamez-Dubuis, A., Giessel, G., Gifford, A., Glassberg, M., Glazer, C., Golden, J., Gómez Carrera, L., Guiot, J., Hallowell, R., Hayashi, H., Hetzel, J., Hirani, N., Homik, L., Hope-Gill, B., Hotchkin, D., Ichikado, K., Ilkovich, M., Inoue, Y., Izumi, S., Jassem, E., Jones, L., Jouneau, S., Kaner, R., Kang, J., Kawamura, T., Kessler, R., Kim, Y., Kishi, K., Kitamura, H., Kolb, M., Kondoh, Y., Kono, C., Koschel, D., Kreuter, M., Kulkarni, T., Kus, J., Lebargy, F., León Jiménez, A., Luo, Q., Mageto, Y., Maher, T.M., Makino, S., Marchand-Adam, S., Marquette, C., Martinez, R., Martínez, M., Maturana Rozas, R., Miyazaki, Y., Moiseev, S., Molina-Molina, M., Morrison, L., Morrow, L., Moua, T., Nambiar, A., Nishioka, Y., Nunes, H., Okamoto, M., Oldham, J., Otaola, M., Padilla, M., Park, J.S., Patel, N., Pesci, A., Piotrowski, W., Pitts, L., Poonyagariyagorn, H., Prasse, A., Quadrelli, S., Randerath, W., Refini, R., Reynaud-Gaubert, M., Riviere, F., Rodríguez Portal, J.A., Rosas, I., Rossman, M., Safdar, Z., Saito, T., Sakamoto, N., Salinas Fénero, M., Sauleda, J., Schmidt, S., Scholand, M.B., Schwartz, M., Shapera, S., Shlobin, O., Sigal, B., Silva Orellana, A., Skowasch, D., Song, J.W., Stieglitz, S., Stone, H., Strek, M., Suda, T., Sugiura, H., Takahashi, H., Takaya, H., Takeuchi, T., Thavarajah, K., Tolle, L., Tomassetti, S., Tomii, K., Valenzuela, C., Vancheri, C., Varone, F., Veeraraghavan, S., Villar, A., Weigt, S., Wemeau, L., Wuyts, W., Xu, Z., Yakusevich, V., Yamada, Y., Yamauchi, H., Ziora, D., Wells, Athol U, Flaherty, Kevin R, Brown, Kevin K, Inoue, Yoshikazu, Devaraj, Anand, Richeldi, Luca, Moua, Teng, Crestani, Bruno, Wuyts, Wim A, Stowasser, Susanne, Quaresma, Manuel, Goeldner, Rainer-Georg, Schlenker-Herceg, Rozsa, and Kolb, Martin

Published
2020
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9. P-148 Denudation employing human recombinant hyaluronidase enzyme does not affect fertilization and blastocyst formation rates in sibling oocytes from patients undergoing ART: A prospective randomized study

Author

Almaguer-Fernandez, L.D, primary, Ramirez Dominguez, L.B, additional, Jimenez-Medina, I, additional, Maldonado-Rosas, I, additional, Izquierdo-Martinez, M, additional, Sanchez-Encarnacion, Y.J, additional, Villar-Muñoz, L.G, additional, Simopoulou, M, additional, and Agarwal, A, additional

Published
2022
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10. A RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED, PHASE 2 STUDY OF SAFETY, TOLERABILITY, AND EFFICACY OF PIRFENIDONE IN PATIENTS WITH RHEUMATOID ARTHRITIS INTERSTITIAL LUNG DISEASE

Author

SOLOMON, J., primary, WOODHEAD, F., additional, DANOFF, S., additional, HAYNES-HARP, S., additional, NAIK, T., additional, SPINO, C., additional, HURWITZ, S., additional, MAURER, R., additional, CHAMBERS, D., additional, KOLB, M., additional, GOLDBERG, H., additional, and ROSAS, I., additional

Published
2022
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11. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Author

Rosas, I, Bräu, N, Waters, M, Go, R, Malhotra, A, Hunter, B, Bhagani, S, Skiest, D, Savic, S, Douglas, I, Garcia-Diaz, J, Aziz, M, Cooper, N, Youngstein, T, Sorbo, L, Zerda, D, Ustianowski, A, Gracian, A, Blyth, K, Carratalà, J, François, B, Benfield, T, Haslem, D, Bonfanti, P, van der Leest, C, Rohatgi, N, Wiese, L, Luyt, C, Bauer, R, Cai, F, Lee, I, Matharu, B, Metcalf, L, Wildum, S, Graham, E, Tsai, L, Bao, M, Rosas, Ivan O, Bräu, Norbert, Waters, Michael, Go, Ronaldo C, Malhotra, Atul, Hunter, Bradley D, Bhagani, Sanjay, Skiest, Daniel, Savic, Sinisa, Douglas, Ivor S, Garcia-Diaz, Julia, Aziz, Mariam S, Cooper, Nichola, Youngstein, Taryn, Sorbo, Lorenzo Del, Zerda, David J De La, Ustianowski, Andrew, Gracian, Antonio Cubillo, Blyth, Kevin G, Carratalà, Jordi, François, Bruno, Benfield, Thomas, Haslem, Derrick, Bonfanti, Paolo, van der Leest, Cor H, Rohatgi, Nidhi, Wiese, Lothar, Luyt, Charles Edouard, Bauer, Rebecca N, Cai, Fang, Lee, Ivan T, Matharu, Balpreet, Metcalf, Louis, Wildum, Steffen, Graham, Emily, Tsai, Larry, Bao, Min, Rosas, I, Bräu, N, Waters, M, Go, R, Malhotra, A, Hunter, B, Bhagani, S, Skiest, D, Savic, S, Douglas, I, Garcia-Diaz, J, Aziz, M, Cooper, N, Youngstein, T, Sorbo, L, Zerda, D, Ustianowski, A, Gracian, A, Blyth, K, Carratalà, J, François, B, Benfield, T, Haslem, D, Bonfanti, P, van der Leest, C, Rohatgi, N, Wiese, L, Luyt, C, Bauer, R, Cai, F, Lee, I, Matharu, B, Metcalf, L, Wildum, S, Graham, E, Tsai, L, Bao, M, Rosas, Ivan O, Bräu, Norbert, Waters, Michael, Go, Ronaldo C, Malhotra, Atul, Hunter, Bradley D, Bhagani, Sanjay, Skiest, Daniel, Savic, Sinisa, Douglas, Ivor S, Garcia-Diaz, Julia, Aziz, Mariam S, Cooper, Nichola, Youngstein, Taryn, Sorbo, Lorenzo Del, Zerda, David J De La, Ustianowski, Andrew, Gracian, Antonio Cubillo, Blyth, Kevin G, Carratalà, Jordi, François, Bruno, Benfield, Thomas, Haslem, Derrick, Bonfanti, Paolo, van der Leest, Cor H, Rohatgi, Nidhi, Wiese, Lothar, Luyt, Charles Edouard, Bauer, Rebecca N, Cai, Fang, Lee, Ivan T, Matharu, Balpreet, Metcalf, Louis, Wildum, Steffen, Graham, Emily, Tsai, Larry, and Bao, Min

Abstract

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to

Published
2022

12. Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

Author

Tom, J, Bao, M, Tsai, L, Qamra, A, Summers, D, Carrasco-Triguero, M, Mcbride, J, Rosenberger, C, Lin, C, Stubbings, W, Blyth, K, Carratalà, J, François, B, Benfield, T, Haslem, D, Bonfanti, P, van der Leest, C, Rohatgi, N, Wiese, L, Luyt, C, Kheradmand, F, Rosas, I, Cai, F, Tom, Jennifer, Bao, Min, Tsai, Larry, Qamra, Aditi, Summers, David, Carrasco-Triguero, Montserrat, McBride, Jacqueline, Rosenberger, Carrie M., Lin, Celia J. F., Stubbings, William, Blyth, Kevin G., Carratalà, Jordi, François, Bruno, Benfield, Thomas, Haslem, Derrick, Bonfanti, Paolo, van der Leest, Cor H., Rohatgi, Nidhi, Wiese, Lothar, Luyt, Charles Edouard, Kheradmand, Farrah, Rosas, Ivan O., Cai, Fang, Tom, J, Bao, M, Tsai, L, Qamra, A, Summers, D, Carrasco-Triguero, M, Mcbride, J, Rosenberger, C, Lin, C, Stubbings, W, Blyth, K, Carratalà, J, François, B, Benfield, T, Haslem, D, Bonfanti, P, van der Leest, C, Rohatgi, N, Wiese, L, Luyt, C, Kheradmand, F, Rosas, I, Cai, F, Tom, Jennifer, Bao, Min, Tsai, Larry, Qamra, Aditi, Summers, David, Carrasco-Triguero, Montserrat, McBride, Jacqueline, Rosenberger, Carrie M., Lin, Celia J. F., Stubbings, William, Blyth, Kevin G., Carratalà, Jordi, François, Bruno, Benfield, Thomas, Haslem, Derrick, Bonfanti, Paolo, van der Leest, Cor H., Rohatgi, Nidhi, Wiese, Lothar, Luyt, Charles Edouard, Kheradmand, Farrah, Rosas, Ivan O., and Cai, Fang

Abstract

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predic

Published
2022

13. A biodegradable polymeric system for peptide–protein delivery assembled with porous microspheres and nanoparticles, using an adsorption/infiltration process

Author

Alcalá-Alcalá S, Urbán-Morlán Z, Aguilar-Rosas I, and Quintanar-Guerrero D

Subjects
Medicine (General), R5-920
Abstract

Sergio Alcalá-Alcalá, Zaida Urbán-Morlán, Irene Aguilar-Rosas, David Quintanar-Guerrero Laboratorio de Investigación y Posgrado en Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México Abstract: A biodegradable polymeric system is proposed for formulating peptides and proteins. The systems were assembled through the adsorption of biodegradable polymeric nanoparticles onto porous, biodegradable microspheres by an adsorption/infiltration process with the use of an immersion method. The peptide drug is not involved in the manufacturing of the nanoparticles or in obtaining the microspheres; thus, contact with the organic solvent, interfaces, and shear forces required for the process are prevented during drug loading. Leuprolide acetate was used as the model peptide, and poly(D,L-lactide-co-glycolide) (PLGA) was used as the biodegradable polymer. Leuprolide was adsorbed onto different amounts of PLGA nanoparticles (25 mg/mL, 50 mg/mL, 75 mg/mL, and 100 mg/mL) in a first stage; then, these were infiltrated into porous PLGA microspheres (100 mg) by dipping the structures into a microsphere suspension. In this way, the leuprolide was adsorbed onto both surfaces (ie, nanoparticles and microspheres). Scanning electron microscopy studies revealed the formation of a nanoparticle film on the porous microsphere surface that becomes more continuous as the amount of infiltrated nanoparticles increases. The adsorption efficiency and release rate are dependent on the amount of adsorbed nanoparticles. As expected, a greater adsorption efficiency (~95%) and a slower release rate were seen (~20% of released leuprolide in 12 hours) when a larger amount of nanoparticles was adsorbed (100 mg/mL of nanoparticles). Leuprolide acetate begins to be released immediately when there are no infiltrated nanoparticles, and 90% of the peptide is released in the first 12 hours. In contrast, the systems assembled in this study released less than 44% of the loaded drug during the same period of time. The observed release profiles denoted a Fickian diffusion that fit Higuchi's model (t1/2). The manufacturing process presented here may be useful as a potential alternative for formulating injectable depots for sensitive hydrophilic drugs such as peptides and proteins, among others. Keywords: adsorption, biodegradable polymers, controlled release, nanoparticles, porous microspheres, peptide delivery

Published
2013

14. Pulmonary Vascular Immunohistopathology and Pulmonary Hypertension in COVID-19 Lung Transplant Recipients

Author

Gekhman, D., primary, Kumar, A., additional, Pandit, L.M., additional, Ramineni, M., additional, Senussi, M.H., additional, Levett, K., additional, Garcha, P.S., additional, Li, M., additional, Liu, Z., additional, Li, G., additional, Seagraves, J., additional, Rosas, I., additional, Loor, G., additional, Shafii, A., additional, and Baz, M., additional

Published
2022
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17. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Author

Muus, C, Luecken, MD, Eraslan, G, Sikkema, L, Waghray, A, Heimberg, G, Kobayashi, Y, Vaishnav, ED, Subramanian, A, Smillie, C, Jagadeesh, KA, Duong, ET, Fiskin, E, Triglia, ET, Ansari, M, Cai, P, Lin, B, Buchanan, J, Chen, S, Shu, J, Haber, AL, Chung, H, Montoro, DT, Adams, T, Aliee, H, Allon, SJ, Andrusivova, Z, Angelidis, I, Ashenberg, O, Bassler, K, Bécavin, C, Benhar, I, Bergenstråhle, J, Bergenstråhle, L, Bolt, L, Braun, E, Bui, LT, Callori, S, Chaffin, M, Chichelnitskiy, E, Chiou, J, Conlon, TM, Cuoco, MS, Cuomo, ASE, Deprez, M, Duclos, G, Fine, D, Fischer, DS, Ghazanfar, S, Gillich, A, Giotti, B, Gould, J, Guo, M, Gutierrez, AJ, Habermann, AC, Harvey, T, He, P, Hou, X, Hu, L, Hu, Y, Jaiswal, A, Ji, L, Jiang, P, Kapellos, TS, Kuo, CS, Larsson, L, Leney-Greene, MA, Lim, K, Litviňuková, M, Ludwig, LS, Lukassen, S, Luo, W, Maatz, H, Madissoon, E, Mamanova, L, Manakongtreecheep, K, Leroy, S, Mayr, CH, Mbano, IM, McAdams, AM, Nabhan, AN, Nyquist, SK, Penland, L, Poirion, OB, Poli, S, Qi, CC, Queen, R, Reichart, D, Rosas, I, Schupp, JC, Shea, CV, Shi, X, Sinha, R, Sit, RV, Slowikowski, K, Slyper, M, Smith, NP, Sountoulidis, A, Strunz, M, Sullivan, TB, Muus, C, Luecken, MD, Eraslan, G, Sikkema, L, Waghray, A, Heimberg, G, Kobayashi, Y, Vaishnav, ED, Subramanian, A, Smillie, C, Jagadeesh, KA, Duong, ET, Fiskin, E, Triglia, ET, Ansari, M, Cai, P, Lin, B, Buchanan, J, Chen, S, Shu, J, Haber, AL, Chung, H, Montoro, DT, Adams, T, Aliee, H, Allon, SJ, Andrusivova, Z, Angelidis, I, Ashenberg, O, Bassler, K, Bécavin, C, Benhar, I, Bergenstråhle, J, Bergenstråhle, L, Bolt, L, Braun, E, Bui, LT, Callori, S, Chaffin, M, Chichelnitskiy, E, Chiou, J, Conlon, TM, Cuoco, MS, Cuomo, ASE, Deprez, M, Duclos, G, Fine, D, Fischer, DS, Ghazanfar, S, Gillich, A, Giotti, B, Gould, J, Guo, M, Gutierrez, AJ, Habermann, AC, Harvey, T, He, P, Hou, X, Hu, L, Hu, Y, Jaiswal, A, Ji, L, Jiang, P, Kapellos, TS, Kuo, CS, Larsson, L, Leney-Greene, MA, Lim, K, Litviňuková, M, Ludwig, LS, Lukassen, S, Luo, W, Maatz, H, Madissoon, E, Mamanova, L, Manakongtreecheep, K, Leroy, S, Mayr, CH, Mbano, IM, McAdams, AM, Nabhan, AN, Nyquist, SK, Penland, L, Poirion, OB, Poli, S, Qi, CC, Queen, R, Reichart, D, Rosas, I, Schupp, JC, Shea, CV, Shi, X, Sinha, R, Sit, RV, Slowikowski, K, Slyper, M, Smith, NP, Sountoulidis, A, Strunz, M, and Sullivan, TB

Abstract

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Published
2021

18. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Author

Muus, C, Luecken, MD, Eraslan, G, Sikkema, L, Waghray, A, Heimberg, G, Kobayashi, Y, Vaishnav, ED, Subramanian, A, Smillie, C, Jagadeesh, KA, Duong, ET, Fiskin, E, Triglia, ET, Ansari, M, Cai, P, Lin, B, Buchanan, J, Chen, S, Shu, J, Haber, AL, Chung, H, Montoro, DT, Adams, T, Aliee, H, Allon, SJ, Andrusivova, Z, Angelidis, I, Ashenberg, O, Bassler, K, Bécavin, C, Benhar, I, Bergenstråhle, J, Bergenstråhle, L, Bolt, L, Braun, E, Bui, LT, Callori, S, Chaffin, M, Chichelnitskiy, E, Chiou, J, Conlon, TM, Cuoco, MS, Cuomo, ASE, Deprez, M, Duclos, G, Fine, D, Fischer, DS, Ghazanfar, S, Gillich, A, Giotti, B, Gould, J, Guo, M, Gutierrez, AJ, Habermann, AC, Harvey, T, He, P, Hou, X, Hu, L, Hu, Y, Jaiswal, A, Ji, L, Jiang, P, Kapellos, TS, Kuo, CS, Larsson, L, Leney-Greene, MA, Lim, K, Litviňuková, M, Ludwig, LS, Lukassen, S, Luo, W, Maatz, H, Madissoon, E, Mamanova, L, Manakongtreecheep, K, Leroy, S, Mayr, CH, Mbano, IM, McAdams, AM, Nabhan, AN, Nyquist, SK, Penland, L, Poirion, OB, Poli, S, Qi, C, Queen, R, Reichart, D, Rosas, I, Schupp, JC, Shea, CV, Shi, X, Sinha, R, Sit, RV, Slowikowski, K, Slyper, M, Smith, NP, Sountoulidis, A, Strunz, M, Sullivan, TB, Sun, D, Talavera-López, C, Tan, P, Tantivit, J, Travaglini, KJ, Tucker, NR, Vernon, KA, Wadsworth, MH, Waldman, J, Wang, X, Xu, K, Yan, W, Zhao, W, Ziegler, CGK, NHLBI LungMap Consortium, and Human Cell Atlas Lung Biological Network

Subjects
Adult, Male, Cathepsin L, Immunology, Respiratory System, Datasets as Topic, Humans, Lung, 11 Medical and Health Sciences, Aged, Demography, Aged, 80 and over, SARS-CoV-2, Sequence Analysis, RNA, Gene Expression Profiling, Serine Endopeptidases, COVID-19, respiratory system, Middle Aged, Virus Internalization, Organ Specificity, Alveolar Epithelial Cells, Host-Pathogen Interactions, Female, Angiotensin-Converting Enzyme 2, Single-Cell Analysis
Abstract

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Published
2020

22. Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative

Author

Hunninghake, G. M., Goldin, J. G., Kadoch, M. A., Kropski, J. A., Rosas, I. O., Wells, A. U., Yadav, R., Lazarus, H. M., Abtin, F. G., Corte, T. J., de Andrade, J. A., Johannson, K. A., Kolb, M. R., Lynch, D. A., Oldham, J. M., Spagnolo, P., Strek, M. E., Tomassetti, S., Washko, G. R., White, E. S., Abtin, F., Antoniou, K., Blackwell, T., Brown, K., Chung, J., Corte, T., Crestani, B., Crossno, P., Culver, D., de Andrade, J., Deveraj, A., Flaherty, K., Gudmundsson, G., Hatabu, H., Jacob, J., Johansson, K., Kanne, J., Kazerooni, E., Kolb, M., Lynch, D., Maher, T., Martinez, F., Morais, A., Nathan, S. D., Noth, I., Oldham, J., Podolanczuk, A., Poletti, V., Ravaglia, C., Renzoni, E., Richeldi, L., Rubin, G., Ryerson, C., Sahoo, D., Suh, R., Sverzellati, N., Valeyre, D., Walsh, S., and Washko, G.

Subjects
Lung Diseases, interstitial lung disease, Male, fibrosis, Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO, X-Ray Computed, Respiratory Function Tests, CT, interstitial lung abnormalities, survey, Early Diagnosis, Pulmonologists, Surveys and Questionnaires, Radiologists, Disease Progression, Humans, Female, Interstitial, Lung Diseases, Interstitial, Tomography, X-Ray Computed, Tomography, Referral and Consultation
Abstract

Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral.Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs?Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement.Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System "S-modifier" [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD.Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA.

Published
2020

24. Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

Author

Wells, A. U., Flaherty, K. R., Brown, K. K., Inoue, Y., Devaraj, A., Richeldi, Luca, Moua, T., Crestani, B., Wuyts, W. A., Stowasser, S., Quaresma, M., Goeldner, R. -G., Schlenker-Herceg, R., Kolb, M., Abe, S., Aburto, M., Acosta, O., Andrews, C., Antin-Ozerkis, D., Arce, G., Arias, M., Avdeev, S., Barczyk, A., Bascom, R., Bazdyrev, E., Beirne, P., Belloli, E., Bergna, M. A., Bergot, E., Bhatt, N., Blaas, S., Bondue, B., Bonella, F., Britt, E., Buch, K., Burk, J., Cai, H., Cantin, A., Castillo Villegas, D. M., Cazaux, A., Cerri, S., Chaaban, S., Chaudhuri, N., Cottin, V., Criner, G., Dahlqvist, C., Danoff, S., Dematte D'Amico, J., Dilling, D., Elias, P., Ettinger, N., Falk, J., Fernandez Perez, E. R., Gamez-Dubuis, A., Giessel, G., Gifford, A., Glassberg, M., Glazer, C., Golden, J., Gomez Carrera, L., Guiot, J., Hallowell, R., Hayashi, H., Hetzel, J., Hirani, N., Homik, L., Hope-Gill, B., Hotchkin, D., Ichikado, K., Ilkovich, M., Izumi, S., Jassem, E., Jones, L., Jouneau, S., Kaner, R., Kang, J., Kawamura, T., Kessler, R., Kim, Y., Kishi, K., Kitamura, H., Kondoh, Y., Kono, C., Koschel, D., Kreuter, M., Kulkarni, T., Kus, J., Lebargy, F., Leon Jimenez, A., Luo, Q., Mageto, Y., Maher, T. M., Makino, S., Marchand-Adam, S., Marquette, C., Martinez, Sara, Martinez, M., Maturana Rozas, R., Miyazaki, Y., Moiseev, S., Molina-Molina, M., Malcolm, Joan Morrison, Morrow, L., Nambiar, A., Nishioka, Y., Nunes, H., Okamoto, M., Oldham, J., Otaola, M., Padilla, M., Park, J. S., Patel, N., Pesci, Riccardo, Piotrowski, W., Pitts, L., Poonyagariyagorn, H., Prasse, A., Quadrelli, S., Randerath, W., Refini, R., Reynaud-Gaubert, M., Riviere, F., Rodriguez Portal, J. A., Rosas, I., Rossman, M., Safdar, Z., Saito, T., Sakamoto, N., Salinas Fenero, M., Sauleda, J., Schmidt, S., Scholand, M. B., Schwartz, M., Shapera, S., Shlobin, O., Sigal, B., Silva Orellana, A., Skowasch, D., Song, J. W., Stieglitz, S., Stone, H., Strek, M., Suda, T., Sugiura, H., Takahashi, H., Takaya, H., Takeuchi, T., Thavarajah, K., Tolle, L., Tomassetti, S., Tomii, K., Valenzuela, C., Vancheri, C., Varone, Francesco, Veeraraghavan, S., Villar, A., Weigt, S., Wemeau, L., Wuyts, W., Xu, Z., Yakusevich, V., Yamada, Y., Yamauchi, H., Ziora, D., Richeldi L. (ORCID:0000-0001-8594-1448), Martinez R., Morrison L., Pesci A., Varone F., Wells, A. U., Flaherty, K. R., Brown, K. K., Inoue, Y., Devaraj, A., Richeldi, Luca, Moua, T., Crestani, B., Wuyts, W. A., Stowasser, S., Quaresma, M., Goeldner, R. -G., Schlenker-Herceg, R., Kolb, M., Abe, S., Aburto, M., Acosta, O., Andrews, C., Antin-Ozerkis, D., Arce, G., Arias, M., Avdeev, S., Barczyk, A., Bascom, R., Bazdyrev, E., Beirne, P., Belloli, E., Bergna, M. A., Bergot, E., Bhatt, N., Blaas, S., Bondue, B., Bonella, F., Britt, E., Buch, K., Burk, J., Cai, H., Cantin, A., Castillo Villegas, D. M., Cazaux, A., Cerri, S., Chaaban, S., Chaudhuri, N., Cottin, V., Criner, G., Dahlqvist, C., Danoff, S., Dematte D'Amico, J., Dilling, D., Elias, P., Ettinger, N., Falk, J., Fernandez Perez, E. R., Gamez-Dubuis, A., Giessel, G., Gifford, A., Glassberg, M., Glazer, C., Golden, J., Gomez Carrera, L., Guiot, J., Hallowell, R., Hayashi, H., Hetzel, J., Hirani, N., Homik, L., Hope-Gill, B., Hotchkin, D., Ichikado, K., Ilkovich, M., Izumi, S., Jassem, E., Jones, L., Jouneau, S., Kaner, R., Kang, J., Kawamura, T., Kessler, R., Kim, Y., Kishi, K., Kitamura, H., Kondoh, Y., Kono, C., Koschel, D., Kreuter, M., Kulkarni, T., Kus, J., Lebargy, F., Leon Jimenez, A., Luo, Q., Mageto, Y., Maher, T. M., Makino, S., Marchand-Adam, S., Marquette, C., Martinez, Sara, Martinez, M., Maturana Rozas, R., Miyazaki, Y., Moiseev, S., Molina-Molina, M., Malcolm, Joan Morrison, Morrow, L., Nambiar, A., Nishioka, Y., Nunes, H., Okamoto, M., Oldham, J., Otaola, M., Padilla, M., Park, J. S., Patel, N., Pesci, Riccardo, Piotrowski, W., Pitts, L., Poonyagariyagorn, H., Prasse, A., Quadrelli, S., Randerath, W., Refini, R., Reynaud-Gaubert, M., Riviere, F., Rodriguez Portal, J. A., Rosas, I., Rossman, M., Safdar, Z., Saito, T., Sakamoto, N., Salinas Fenero, M., Sauleda, J., Schmidt, S., Scholand, M. B., Schwartz, M., Shapera, S., Shlobin, O., Sigal, B., Silva Orellana, A., Skowasch, D., Song, J. W., Stieglitz, S., Stone, H., Strek, M., Suda, T., Sugiura, H., Takahashi, H., Takaya, H., Takeuchi, T., Thavarajah, K., Tolle, L., Tomassetti, S., Tomii, K., Valenzuela, C., Vancheri, C., Varone, Francesco, Veeraraghavan, S., Villar, A., Weigt, S., Wemeau, L., Wuyts, W., Xu, Z., Yakusevich, V., Yamada, Y., Yamauchi, H., Ziora, D., Richeldi L. (ORCID:0000-0001-8594-1448), Martinez R., Morrison L., Pesci A., and Varone F.

Abstract

Background: The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. Methods: The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Findings: Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune IL

Published
2020

31. Revisiting the UK Genetic Severity Score for NF2: a proposal for adding functional information

Author

Catasús, N., primary, García, B., additional, Galvan, I., additional, Plana, A., additional, Negro, A., additional, Rosas, I., additional, Ros, A., additional, Amilibia, E., additional, Becerra, JL., additional, Hostalot, C., additional, Roca-Ribas, F., additional, Bielsa, I., additional, Lazaro, C., additional, de Cid, R., additional, Serra, E., additional, Blanco, I., additional, and Castellanos, E., additional

Published
2020
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32. OP0036 METHOTREXATE AND RHEUMATOID ARTHRITIS ASSOCIATED INTERSTITIAL LUNG DISEASE

Author

Juge, P. A., primary, Lee, J. S., additional, Lau, J., additional, Kawano, L., additional, Rojas-Serrano, J., additional, Sebastiani, M., additional, Koduri, G., additional, Matteson, E., additional, Bonfiglioli, K., additional, Sawamura, M., additional, Kairalla, R., additional, Cavagna, L., additional, Bozzalla Cassione, E., additional, Manfredi, A., additional, Mejia, M., additional, Rodríguez Henríquez, P., additional, Gonzalez-Perez, M. I., additional, Falfan-Valencia, R., additional, Buendia-Roldan, I., additional, Perez-Rubio, G., additional, Ebstein, E., additional, Gazal, S., additional, Borie, R., additional, Ottaviani, S., additional, Kannengiesser, C., additional, Wallaert, B., additional, Uzunhan, Y., additional, Nunes, H., additional, Valeyre, D., additional, Saidenberg Kermanac’h, N., additional, Boissier, M. C., additional, Wemeau Stervinou, L., additional, Flipo, R. M., additional, Marchand-Adam, S., additional, Richette, P., additional, Allanore, Y., additional, Dromer, C., additional, Truchetet, M. E., additional, Richez, C., additional, Schaeverbeke, T., additional, Lioté, H., additional, Thabut, G., additional, Deane, K., additional, Solomon, J., additional, Doyle, T., additional, Ryu, J. H., additional, Rosas, I. O., additional, Holers, V. M., additional, Boileau, C., additional, Debray, M. P., additional, Porcher, R., additional, Schwartz, D. A., additional, Vassallo, R., additional, Crestani, B., additional, and Dieudé, P., additional

Published
2020
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33. Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

Author

Wells, Athol U, primary, Flaherty, Kevin R, additional, Brown, Kevin K, additional, Inoue, Yoshikazu, additional, Devaraj, Anand, additional, Richeldi, Luca, additional, Moua, Teng, additional, Crestani, Bruno, additional, Wuyts, Wim A, additional, Stowasser, Susanne, additional, Quaresma, Manuel, additional, Goeldner, Rainer-Georg, additional, Schlenker-Herceg, Rozsa, additional, Kolb, Martin, additional, Abe, S., additional, Aburto, M., additional, Acosta, O., additional, Andrews, C., additional, Antin-Ozerkis, D., additional, Arce, G., additional, Arias, M., additional, Avdeev, S., additional, Barczyk, A., additional, Bascom, R., additional, Bazdyrev, E., additional, Beirne, P., additional, Belloli, E., additional, Bergna, M.A., additional, Bergot, E., additional, Bhatt, N., additional, Blaas, S., additional, Bondue, B., additional, Bonella, F., additional, Britt, E., additional, Buch, K., additional, Burk, J., additional, Cai, H., additional, Cantin, A., additional, Castillo Villegas, D.M., additional, Cazaux, A., additional, Cerri, S., additional, Chaaban, S., additional, Chaudhuri, N., additional, Cottin, V., additional, Crestani, B., additional, Criner, G., additional, Dahlqvist, C., additional, Danoff, S., additional, Dematte D'Amico, J., additional, Dilling, D., additional, Elias, P., additional, Ettinger, N., additional, Falk, J., additional, Fernández Pérez, E.R., additional, Gamez-Dubuis, A., additional, Giessel, G., additional, Gifford, A., additional, Glassberg, M., additional, Glazer, C., additional, Golden, J., additional, Gómez Carrera, L., additional, Guiot, J., additional, Hallowell, R., additional, Hayashi, H., additional, Hetzel, J., additional, Hirani, N., additional, Homik, L., additional, Hope-Gill, B., additional, Hotchkin, D., additional, Ichikado, K., additional, Ilkovich, M., additional, Inoue, Y., additional, Izumi, S., additional, Jassem, E., additional, Jones, L., additional, Jouneau, S., additional, Kaner, R., additional, Kang, J., additional, Kawamura, T., additional, Kessler, R., additional, Kim, Y., additional, Kishi, K., additional, Kitamura, H., additional, Kolb, M., additional, Kondoh, Y., additional, Kono, C., additional, Koschel, D., additional, Kreuter, M., additional, Kulkarni, T., additional, Kus, J., additional, Lebargy, F., additional, León Jiménez, A., additional, Luo, Q., additional, Mageto, Y., additional, Maher, T.M., additional, Makino, S., additional, Marchand-Adam, S., additional, Marquette, C., additional, Martinez, R., additional, Martínez, M., additional, Maturana Rozas, R., additional, Miyazaki, Y., additional, Moiseev, S., additional, Molina-Molina, M., additional, Morrison, L., additional, Morrow, L., additional, Moua, T., additional, Nambiar, A., additional, Nishioka, Y., additional, Nunes, H., additional, Okamoto, M., additional, Oldham, J., additional, Otaola, M., additional, Padilla, M., additional, Park, J.S., additional, Patel, N., additional, Pesci, A., additional, Piotrowski, W., additional, Pitts, L., additional, Poonyagariyagorn, H., additional, Prasse, A., additional, Quadrelli, S., additional, Randerath, W., additional, Refini, R., additional, Reynaud-Gaubert, M., additional, Riviere, F., additional, Rodríguez Portal, J.A., additional, Rosas, I., additional, Rossman, M., additional, Safdar, Z., additional, Saito, T., additional, Sakamoto, N., additional, Salinas Fénero, M., additional, Sauleda, J., additional, Schmidt, S., additional, Scholand, M.B., additional, Schwartz, M., additional, Shapera, S., additional, Shlobin, O., additional, Sigal, B., additional, Silva Orellana, A., additional, Skowasch, D., additional, Song, J.W., additional, Stieglitz, S., additional, Stone, H., additional, Strek, M., additional, Suda, T., additional, Sugiura, H., additional, Takahashi, H., additional, Takaya, H., additional, Takeuchi, T., additional, Thavarajah, K., additional, Tolle, L., additional, Tomassetti, S., additional, Tomii, K., additional, Valenzuela, C., additional, Vancheri, C., additional, Varone, F., additional, Veeraraghavan, S., additional, Villar, A., additional, Weigt, S., additional, Wemeau, L., additional, Wuyts, W., additional, Xu, Z., additional, Yakusevich, V., additional, Yamada, Y., additional, Yamauchi, H., additional, and Ziora, D., additional

Published
2020
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35. The characterisation of interstitial lung disease multidisciplinary team meetings: A global study

Author

Richeldi, L. Launders, N. Martinez, F. Walsh, S.L.F. Myers, J. Wang, B. Jones, M. Chisholm, A. Flaherty, K.R. David-Wang, A. Morais, A. Azuma, A. Crestani, B. Vancheri, C. Youakim, C. Fell, C.D. Ryerson, C.J. Bouros, D. Bendstrup, E. Morell, F. Bonella, F. Raghu, G. Christoff, G. Ferrara, G. Glaspole, I. Rosas, I. Behr, J. DeBoer, K. Antoniou, K.M. Dheda, K. Brown, K. Planas-Cerezales, L. Sköld, M. Funke, M. Molina-Molina, M. Mazzei, M. Kolb, M. Selman, M. Rottoli, P. Spagnolo, P. Rivera-Ortega, P. Avdeev, S. Quadrelli, S. Corte, T.J. Maher, T.M. Cottin, V. Wuyts, W. Xu, Z.J.

Subjects
body regions, respiratory system
Abstract

Multidisciplinary team (MDT) diagnosis of interstitial lung disease (ILD) has been proposed as a gold standard, but there are no formal recommendations for MDT process or composition and limited knowledge regarding prevalence in routine practice. We performed a systematic evaluation of ILD diagnostic practice across a range of healthcare settings around the world. Electronic questionnaires were distributed across all global regions via society and collaborators networks. Responses from 457 unique centres across 64 countries were included in the analysis. Of the 350 (76.6%) centres holding formal meetings, the majority held face-to-face MDT meetings (80%), for a minimum of 30 min (93%), and discussed diagnosis (96.9%) and patient management (94.9%) at the meetings. Compared with non-academic and academic non-ILD centres, ILD academic centres reported a higher ILD caseload, held more formal MDT meetings, and were more likely to include histopathology and rheumatology specialists in their diagnostic team. Of the centres holding MDT meetings, 5.5% routinely discussed all new cases at such meetings. An MDT approach to ILD diagnosis is consistently interpreted and widely implemented across a range of routine care settings around the world. This observation will inform future ILD diagnostic agreement studies and diagnostic pathway recommendations. © ERS 2019.

Published
2019

37. Abundance of airborne Penicillium CFU in relation to urbanization in Mexico City

Author

Rosas, I., Calderon, C., Ulloa, M., and Lacey, J.

Subjects
Penicillin -- Analysis, Biological sciences
Abstract

Penicillum spp. is not significant outdoor aeroallergens in Mexico City, but complete exposure cannot be evaluated until the sampling of indoor environments has been done. Air sampling was concurrently done at an urbanization index and air pollution level during a period covering dry and rainy seasons. An Andersen two-stage microbial sample was used to detach culturable fungi and malt extract sugar. Seventy percent penicillum propagules were collected in the small-particle fraction of the eight species known.

Published
1993

39. Early Genetic Diagnosis of Neurofibromatosis Type 2 From Skin Plaque Plexiform Schwannomas in Childhood

Author

Castellanos E, Plana A, Carrato C, Carrio M, Rosas I, Amilibia E, Roca-Ribas F, Hostalot C, Castillo A, Ros A, Quer A, Becerra JL, Salvador-Hernandez H, Lazaro C, Blanco I, Serra E, Bielsa I, and for CSUR Phakomatoses Multidisciplinary Clinics HUGTiP-ICO-IGTP

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, otorhinolaryngologic diseases
Abstract

IMPORTANCE: Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. OBJECTIVE: To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. DESIGN, SETTING, AND PARTICIPANTS: Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. MAIN OUTCOMES AND MEASURES: Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. RESULTS: In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. CONCLUSIONS AND RELEVANCE: This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.

Published
2018

40. Early Genetic Diagnosis of Neurofibromatosis Type 2 From Skin Plaque Plexiform Schwannomas in Childhood

Author

Castellanos, E, Plana, A, Carrato, C, Carrio, M, Rosas, I, Amilibia, E, Roca-Ribas, F, Hostalot, C, Castillo, A, Ros, A, Quer, A, Becerra, JL, Salvador, H, Lazaro, C, Blanco, I, Serra, E, and Bielsa, I

Abstract

IMPORTANCE Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. OBJECTIVE To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. DESIGN, SETTING AND PARTICIPANTS Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NE2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. MAIN OUTCOMES AND MEASURES Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. RESULTS In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. CONCLUSIONS AND RELEVANCE This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.

Published
2018

44. Antennas Design for UHF Passive RFID Tags

Author

Teran Guerra, J. D., primary, Martinez-Castillo, J., additional, Lopez-Leal, R., additional, Arceo-Rosas, I., additional, Caldernn-Ramon, C., additional, Morales-Mendoza, L. J., additional, Herrera-May, A. L., additional, and Escalante-Martinez, J. E., additional

Published
2019
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