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.
Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis (LAM), a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogeneic growth factor VEGF-D are elevated significantly in LAM. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in LAM. Here we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from LAM patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent anti-proliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of LAM. In TSC2-deficient cells, Syk signaling increased expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated production of VEGF-D. In clinical isolates of PBMC from LAM patients, VEGF-D expression was elevated. Further, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for LAM growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation.
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%. The majority of patients seeking care for influenza and other respiratory viruses present to episodic outpatient care settings, such as emergency departments (EDs) or other urgent or primary care settings, where rapid diagnosis and treatment are critical (1). Due to nonspecific symptoms, a provider's clinical diagnosis of influenza has low sensitivity, leading providers to rely on diagnostic testing for an accurate influenza diagnosis (2). Most commercially available real-time PCR (rt-PCR) tests are typically run in batches and require separate nucleic acid extraction, which significantly delays the results. The current antigen detection tests are rapid but have poor-to-moderate sensitivities, ranging from 10% to 70% (3). Rapid random-access PCR-based influenza tests, such as the GeneXpert Xpert Flu assay (Cepheid, Sunnyvale, CA, USA), may have clinical utility in filling this diagnostic gap, since it has a reported time to result of approximately 80 min and has a significantly higher sensitivity than rapid antigen detection tests (4).Prior to integration into routine clinical use, the clinical performance of Xpert Flu in the target population requires evaluation. Although clinicians in the outpatient episodic care setting may test an array of patients, accurate and rapid influenza testing with Xpert Flu would be most important in patients for whom the test result would impact clinical management, namely, those who meet the Centers for Disease Control and Prevention (CDC) criteria for antiviral therapy and are at risk for potential influenza-related complications. Several of these conditions, such as advanced age and pneumonia, have been associated with the decreased sensitivity of rapid antigen-based testing, highlighting the importance of evaluating Xpert Flu in this population (5). In order to fully translate rapid PCR-based testing into clinical practice, we prospectively evaluated the sensitivity and specificity of Xpert Flu in adult ED patients with an acute undifferentiated respiratory illness who met CDC criteria for recommended antiviral treatment.Adult ED patients with an undifferentiated acute respiratory illness who met CDC criteria for recommended influenza antiviral treatment at an urban university-affiliated tertiary-care ED were prospectively enrolled between December 2012 and March 2013. After written consent was obtained, as approved by the Johns Hopkins University institutional review board (IRB), a nasopharyngeal swab was collected from each patient and placed in 3 ml of viral transport medium (MicroTest M4RT; Remel, Lenexa, KS, USA). All the samples were aliquoted, stored at Ϫ70°C until com...
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