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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 < 0.01) in a small sample of LM subtypes. Functional analyses on the differentially expressed gene sets showed that microcystic LM gene expression favors a prooncogenic profile with upregulation of MYC target genes and cell cycle proteins, whereas macrocystic expression demonstrates hypoxic events that lead to angiogenesis and cell proliferation. Therefore, microcystic and macrocystic LMs, although histologically and physiologically similar, may occur under the influence of vastly different biological pathways and mechanisms of action.

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:BackgroundPediatric nurses care for some of the most vulnerable patients in our healthcare system and are vulnerable to the impact of the stress of their work on their well-being. Burnout is a potential response to chronic interpersonal stressors and a negative work outcome linked to personal and professional consequences. A thorough understanding of the experience and factors associated with burnout in this population is an important part of developing interventions to mitigate or prevent this workplace outcome. Therefore, our study objectives were to: (1) explain and expand our understanding of pediatric critical care nurses experience of burnout in relation to their work environment and work engagement; (2) provide recommendations for nursing administrators to improve nurses' work environment, work attitudes, and work outcomes.MethodsA convenience sample of pediatric critical care nurses from a large pediatric quaternary care hospital in Ontario, Canada were invited to participate in this second phase of a sequential explanatory mixed-methods study. Semi-structured interviews were conducted, with and main themes and subthemes distilled through the method of interpretive description.ResultsA total of 18 PICU/CCCU/NICU nurses participated. Derived themes included the experience and identification of burnout, including its prevalence and elusiveness. Their experiences of quality of work-life included themes such as compensation, emotional support at work, respect, their professional identity, and spill over into home life. They discussed components of work engagement, including the work itself, investment into their growth and development, and the meaning of their work. The self-care subthemes included the importance of preparation and recovery, and the use of physical and mental separation as a preservation strategy. The participants' recommendations for strategies to mitigate burnout were also summarized.ConclusionBurnout is a complex and regularly occurring experience for pediatric critical care nurses. Although the experience may be difficult to self-identify, the impacts on the individuals are profound. Further research and organizational support are needed to test practical and evidence-based interventions to improve the well-being of this population.

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.

Dataset Information

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

Publications

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

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