Anthony M Lamattina1, Angelo Taveira-Dasilva2, Hilary J Goldberg1, Shefali Bagwe1, Ye Cui1, Ivan O Rosas1, Joel Moss2, Elizabeth P Henske1, Souheil El-Chemaly3. 1. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 2. Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. 3. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address: sel-chemaly@partners.org.
Abstract
BACKGROUND: We have previously conducted the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, a phase 1 dose-escalation study of the combination of sirolimus and hydroxychloroquine in patients with lymphangioleiomyomatosis (LAM). The goal of the present study was to analyze sera from the SAIL trial to identify novel biomarkers that could shed light into disease pathogenesis and response to therapy. METHODS: We used the DiscoveryMAP platform from Rules Based Medicine to simultaneously measure 279 analytes in sera collected at each visit from subjects enrolled in the SAIL trial. We used longitudinal regression and pathway analysis to examine analyte rate of change and corresponding effect on lung function and to identify networks and potential nodes of interest. RESULTS: A total of 222 analytes were included in the analysis. We identified 32 analytes that changed over the treatment period of the study. Pathway analysis revealed enrichment in cytokine-receptor interaction and mechanistic/mammalian target of rapamycin-related pathways, in addition to seemingly unrelated processes such as rheumatoid arthritis. Search Tool for the Retrieval of Interacting Genes/Proteins analysis identified two hubs centered around acetyl-CoA carboxylase alpha and beta and coagulation factor II. In addition, we identified vascular endothelial growth factor receptor-3 and CCL21 as molecules significantly associated with changes in FEV1 during the study period. CONCLUSIONS: We performed a large-scale analyte study in sera of women with LAM and identified potential markers that could be linked to disease pathogenesis, lung injury, and therapeutic response. These data will enable future investigation into the specific roles of these molecules in LAM. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01687179; URL: www.clinicaltrials.gov).
BACKGROUND: We have previously conducted the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, a phase 1 dose-escalation study of the combination of sirolimus and hydroxychloroquine in patients with lymphangioleiomyomatosis (LAM). The goal of the present study was to analyze sera from the SAIL trial to identify novel biomarkers that could shed light into disease pathogenesis and response to therapy. METHODS: We used the DiscoveryMAP platform from Rules Based Medicine to simultaneously measure 279 analytes in sera collected at each visit from subjects enrolled in the SAIL trial. We used longitudinal regression and pathway analysis to examine analyte rate of change and corresponding effect on lung function and to identify networks and potential nodes of interest. RESULTS: A total of 222 analytes were included in the analysis. We identified 32 analytes that changed over the treatment period of the study. Pathway analysis revealed enrichment in cytokine-receptor interaction and mechanistic/mammalian target of rapamycin-related pathways, in addition to seemingly unrelated processes such as rheumatoid arthritis. Search Tool for the Retrieval of Interacting Genes/Proteins analysis identified two hubs centered around acetyl-CoA carboxylase alpha and beta and coagulation factor II. In addition, we identified vascular endothelial growth factor receptor-3 and CCL21 as molecules significantly associated with changes in FEV1 during the study period. CONCLUSIONS: We performed a large-scale analyte study in sera of women with LAM and identified potential markers that could be linked to disease pathogenesis, lung injury, and therapeutic response. These data will enable future investigation into the specific roles of these molecules in LAM. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01687179; URL: www.clinicaltrials.gov).
Authors: Andrey Parkhitko; Faina Myachina; Tasha A Morrison; Khadijah M Hindi; Neil Auricchio; Magdalena Karbowniczek; J Julia Wu; Toren Finkel; David J Kwiatkowski; Jane J Yu; Elizabeth Petri Henske Journal: Proc Natl Acad Sci U S A Date: 2011-07-11 Impact factor: 11.205
Authors: Jennifer M Davis; Elizabeth Hyjek; Aliya N Husain; Le Shen; Jennifer Jones; Lucia A Schuger Journal: J Histochem Cytochem Date: 2013-04-22 Impact factor: 2.479
Authors: Chuan Wang; Lin Hu; Lei Zhao; Ping Yang; John F Moorhead; Zac Varghese; Yaxi Chen; Xiong Z Ruan Journal: PLoS One Date: 2014-07-21 Impact factor: 3.240
Authors: Damian Szklarczyk; John H Morris; Helen Cook; Michael Kuhn; Stefan Wyder; Milan Simonovic; Alberto Santos; Nadezhda T Doncheva; Alexander Roth; Peer Bork; Lars J Jensen; Christian von Mering Journal: Nucleic Acids Res Date: 2016-10-18 Impact factor: 16.971
Authors: Yan Tang; Souheil El-Chemaly; Angelo Taveira-Dasilva; Hilary J Goldberg; Shefali Bagwe; Ivan O Rosas; Joel Moss; Carmen Priolo; Elizabeth P Henske Journal: Chest Date: 2019-07-09 Impact factor: 9.410
Authors: Jesse D Kirkpatrick; Ava P Soleimany; Jaideep S Dudani; Heng-Jia Liu; Hilaire C Lam; Carmen Priolo; Elizabeth P Henske; Sangeeta N Bhatia Journal: Eur Respir J Date: 2022-04-14 Impact factor: 33.795
Authors: Anthony M Lamattina; Sergio Poli; Pranav Kidambi; Shefali Bagwe; Andrew Courtwright; Pierce H Louis; Shikshya Shrestha; Benjamin Stump; Hilary J Goldberg; Elizabeth A Thiele; Ivan Rosas; Elizabeth P Henske; Souheil El-Chemaly Journal: Orphanet J Rare Dis Date: 2019-03-29 Impact factor: 4.123
Authors: Carmen Herranz; Francesca Mateo; Alexandra Baiges; Gorka Ruiz de Garibay; Alexandra Junza; Simon R Johnson; Suzanne Miller; Nadia García; Jordi Capellades; Antonio Gómez; August Vidal; Luis Palomero; Roderic Espín; Ana I Extremera; Eline Blommaert; Eva Revilla-López; Berta Saez; Susana Gómez-Ollés; Julio Ancochea; Claudia Valenzuela; Tamara Alonso; Piedad Ussetti; Rosalía Laporta; Antoni Xaubet; José A Rodríguez-Portal; Ana Montes-Worboys; Carlos Machahua; Jaume Bordas; Javier A Menendez; Josep M Cruzado; Roser Guiteras; Christophe Bontoux; Concettina La Motta; Aleix Noguera-Castells; Mario Mancino; Enrique Lastra; Raúl Rigo-Bonnin; Jose C Perales; Francesc Viñals; Alvaro Lahiguera; Xiaohu Zhang; Daniel Cuadras; Coline H M van Moorsel; Joanne J van der Vis; Marian J R Quanjel; Harilaos Filippakis; Razq Hakem; Chiara Gorrini; Marc Ferrer; Aslihan Ugun-Klusek; Ellen Billett; Elżbieta Radzikowska; Álvaro Casanova; María Molina-Molina; Antonio Roman; Oscar Yanes; Miquel A Pujana Journal: EMBO Mol Med Date: 2021-08-11 Impact factor: 12.137