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Gene Expression Differences in Pediatric Lymphatic Malformations: Size Really Matters.

ABSTRACT: Lymphatic malformations (LMs) are congenital vascular anomalies characterized by dilated and cystic lymphatic channels. They are subdivided into macrocystic and microcystic lesions based upon the predominant size of the cysts involved. However, significant differences in clinical characteristics, treatment outcomes, and prognosis between macrocytic and microcytic disease suggest variation in underlying biologic and genetic influences. Indirect differential expression analysis revealed that 426 genes are significantly different (p?

SUBMITTER: Gomez-Acevedo H

PROVIDER: S-EPMC6104254 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Gene Expression Differences in Pediatric Lymphatic Malformations: Size Really Matters.

Gomez-Acevedo Horacio H Dornhoffer James R JR Stone Annjanette A Dai Yuemeng Y Richter Gresham T GT

Lymphatic research and biology 20180801 4

Lymphatic malformations (LMs) are congenital vascular anomalies characterized by dilated and cystic lymphatic channels. They are subdivided into macrocystic and microcystic lesions based upon the predominant size of the cysts involved. However, significant differences in clinical characteristics, treatment outcomes, and prognosis between macrocytic and microcytic disease suggest variation in underlying biologic and genetic influences. Indirect differential expression analysis revealed that 426 g ...[more]

PMID: 30130159

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Project description:Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic vessels during pre- and postnatal development. Macrocystic, microcystic and combined forms of LM are known. The cysts are lined by lymphatic endothelial cells (LECs). Resection and sclerotherapy are the most common treatment methods. Recent studies performed on LM specimens in the United States of America have identified activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but not isolated cell types were studied. Here, we studied LM tissues resected at the University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21 of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6 LM-derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A; p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived fibroblasts did not possess such mutations, showing cell-type specificity of the gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones with newly identified mutations), as compared to normal LECs. Additionally, hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one with Glu109del. In vitro, the small molecule kinase inhibitors Buparlisib/BKM-120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101 (inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of LM-derived LECs in a concentration-dependent manner, but also blocked proliferation of normal LECs. However, MK-2206 appeared to be more specific for mutated LECs, except in case of Glu109 deletion. In sum, children that are, or will be, treated with kinase inhibitors must be monitored closely.

Project description:ContextResearch environments, or cultures, are thought to be the most influential predictors of research productivity. Although several narrative and systematic reviews have begun to identify the characteristics of research-favourable environments, these reviews have ignored the contextual complexities and multiplicity of environmental characteristics.ObjectivesThe current synthesis adopts a realist approach to explore what interventions work for whom and under what circumstances.MethodsWe conducted a realist synthesis of the international literature in medical education, education and medicine from 1992 to 2016, following five stages: (i) clarifying the scope; (ii) searching for evidence; (iii) assessing quality; (iv) extracting data, and (v) synthesising data.ResultsWe identified numerous interventions relating to research strategy, people, income, infrastructure and facilities (IIF), and collaboration. These interventions resulted in positive or negative outcomes depending on the context and mechanisms fired. We identified diverse contexts at the individual and institutional levels, but found that disciplinary contexts were less influential. There were a multiplicity of positive and negative mechanisms, along with three cross-cutting mechanisms that regularly intersected: time; identity, and relationships. Outcomes varied widely and included both positive and negative outcomes across subjective (e.g. researcher identity) and objective (e.g. research quantity and quality) domains.ConclusionsThe interplay among mechanisms and contexts is central to understanding the outcomes of specific interventions, bringing novel insights to the literature. Researchers, research leaders and research organisations should prioritise the protection of time for research, enculturate researcher identities, and develop collaborative relationships to better foster successful research environments. Future research should further explore the interplay among time, identity and relationships.

Dataset Information

Gene Expression Differences in Pediatric Lymphatic Malformations: Size Really Matters.

Publications

Gene Expression Differences in Pediatric Lymphatic Malformations: Size Really Matters.

Similar Datasets

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