Search

Supplementary methods. Supplementary Figure S1. R406 and rapamycin induce G1 cell cycle arrest in TSC2- cells. Supplementary Figure S2. Densitometric analysis of phospho-Syk and Syk, related to Fig. 4D. Supplementary Figure S3. TSC2 deficiency leads to upregulation of MCP-1 gene expression in vitro. Supplementary Table S1. Characteristics of subjects who were part of the longitudinal studies, related to Fig.6B. Supplementary Table S2. Characteristics of healthy volunteers and LAM subjects whose PBMCs were studied, related to Fig.6C. Supplementary Table S3. siRNA sequences. Supplementary Table S4. Complete list of antibodies. Supplementary Table S5. Real-time PCR primer sequences.

Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.

Endostatin is a naturally occurring collagen fragment with anti-angiogenic properties. We investigated the association between serum endostatin levels and DLCO in a cohort of patients with lymphangioleiomyomatosis (LAM). Associations of endostatin levels to clinical features of LAM were explored using logistic regression models. Endostatin levels were associated with DLCO and were higher in subjects with TSC-associated LAM compared to sporadic LAM. These data suggest that endostatin could be a predictive biomarker of decline in DLCO and that germline mutational inactivation of the TSC1 or TSC2 gene is associated with higher endostatin levels. These findings could offer novel insights into the pathogenesis of LAM.

Advances in our ability to identify lymphatic endothelial cells and differentiate them from blood endothelial cells have led to important progress in the study of lymphatic biology. Over the past decade, preclinical and clinical studies have shown that there are changes to the lymphatic vasculature in nearly all lung diseases. Efforts to understand the contribution of lymphatics and their growth factors to disease initiation, progression, and resolution have led to seminal findings establishing critical roles for lymphatics in lung biology spanning from the first breath after birth to asthma, tuberculosis, and lung transplantation. However, in other diseases, it remains unclear if lymphatics are part of the overall lung remodeling process or real contributors to disease pathogenesis. The goal of this Translational Review is to highlight some of the advances in our understanding of the role(s) of lymphatics in lung disease and shed light on the critical needs and unanswered questions that might lead to novel translational applications.

We prospectively evaluated the performance of Cepheid's GeneXpert Xpert Flu assay in a target population of 281 adults presenting to the emergency department with an acute respiratory illness who met Centers for Disease Control and Prevention (CDC) criteria for recommended antiviral treatment. Compared with the Prodesse ProFlu+ assay, Xpert Flu had an overall sensitivity of 95.3% and specificity of 99.2%.

Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.