Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c-Met to up-regulate angiogenesis and lung adenocarcinoma growth.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A165 (VEGFA165 ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1-/- and Ptprz1+/+ mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1-/- lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1+/+ LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1-/- compared with Ptprz1+/+ mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (ß3 ) integrin is decreased in Ptprz1-/- LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1-/- mice. A selective PTPRZ1 TP inhibitor, VEGFA165 and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN.

On the role of pleiotrophin and its receptors in development and angiogenesis.

The secreted growth factor pleiotrophin (PTN) is expressed in all species and is evolutionarily highly conserved, suggesting that it plays a significant role in the regulation of important processes. The observation that it is highly expressed at early stages during development and in embryonic progenitor cells highlights a potentially important contribution to development. There is ample evidence of the role of PTN in the development of the nervous system and hematopoiesis, some, albeit inconclusive, evidence of its role in the skeletomuscular system, and limited evidence of its role in the development of other organs. Studies on its role in the cardiovascular system and angiogenesis suggest that PTN has a significant regulatory effect by acting on endothelial cells, while its role in the functions of smooth or cardiac muscle cells has not been studied. This review highlights what is known to date regarding the role of PTN in the development of various organs and in angiogenesis. Wherever possible, evidence on the crosstalk between the receptors that mediate PTN's functions is also quoted, highlighting the complex regulatory pathways that affect development and angiogenesis.

Assessment and Optimization of the Pediatric Parenteral Nutrition Preparation Process in a Hospital Pharmacy.

BACKGROUND: Parenteral nutrition (PN) is associated with risks that could threaten the clinical condition of premature neonates hospitalized in the neonatal intensive care unit. In this work, risk-analysis methodology was implemented to contain the risks associated with the PN production process and improve PN safety. METHODS: The Failure Modes, Effects, and Criticality Analysis was performed by a multidisciplinary team. All potential failure modes of the PN preparation process were recorded, and associated risks were scored based on their severity, occurrence, and detectability, with a risk priority number (RPN). All identified failure scenarios and the respective work stages were ranked in descending order of criticality. Corrective actions were proposed to address critical points, and the safety of the process was reassessed by the same method in a prospective manner. RESULTS: The highest RPN scores were obtained with the PN composition calculation performed manually (RPN: 530) or electronically (RPN: 478), completion of the PN medical order form (RPN: 354), manual compounding of PN admixtures (RPN: 258), and the structure/organization/maintenance of the PN preparation unit (RPN: 133). The quality and safety of PN admixtures could be compromised by many critical factors, such as the increased particle-microbial load in the unit and the inadequate training/experience of the involved health professionals and their incompliance with the given instructions. The implementation of the proposed corrective measures is expected to reduce the risks of the overall PN production process by 67.5%. CONCLUSIONS: Improvement of the PN production process through risk-analysis methodologies enhances safety for premature neonates.