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1.  A genetic screen identifies an LKB1/PAR1 signaling axis controlling the Hippo/YAP pathway 
Nature cell biology  2013;16(1):108-117.
The Hippo/YAP pathway is an emerging signaling cascade involved in the regulation of stem cell activity and organ size. Alterations in Hippo signaling are also a common feature of human epithelial malignancies, although the molecular bases for this misregulation are unclear. As most of the current knowledge has been derived from work in the fruit fly, our understanding of mammalian Hippo/YAP signaling is still incomplete. To identify novel components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signaling that strongly regulate the activity of the Hippo transducer YAP. Some of these kinases control processes such as response to stress, boundary formation, cell cycle and adhesion, and reflect novel inputs that may impinge on Hippo signaling and growth control. One of the hits, LKB1 (also known as Stk11), is a common tumor suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the PAR-1 family (MARK1-4) to regulate the localization of the baso-lateral polarity complex and the activity of the core Hippo kinases. Murine and human LKB1-deficient tumors exhibit mislocalization of the basolateral determinant Scribble, reduced Hippo kinase activity, and enhanced YAP-driven transcription. Using xenograft assays and genetic analysis, we demonstrate that YAP is functionally important for the tumor suppressive effects of LKB1. Our results identify an important signaling axis that links YAP activation with LKB1 mutations, and have significant implications for the treatment of LKB1-mutant human malignancies. Additionally, our findings provide novel insight into the nature of inputs that speak to the Hippo/YAP signaling cascade.
PMCID: PMC4159053  PMID: 24362629
Background & Aims
Juvenile polyps are the most common type of pediatric gastrointestinal polyp and are typically characterized as hamartomatous overgrowths. Juvenile polyps are highly vascularized tissues and display a markedly increased mucosal microcirculation. Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that play an essential role in: the physiologic degradation of the extracellular matrix in normal development, tumor invasion and metastasis, as well as angiogenesis. We hypothesized that the presence of these enzymes in urine may serve as clinical biomarkers of juvenile polyps.
Patients and Methods
In this preliminary study, we analyzed 32 urine samples collected prospectively from 16 subjects with known or suspected juvenile polyps who presented to the endoscopy unit for colonoscopic evaluation and 16 age and sex-matched controls. Urinary MMPs were analyzed by zymography and their localized tissue expression was assayed via immunohistochemistry of tissue sections.
MMPs were detected in the urine of patients with juvenile polyps with significantly higher frequency when compared to urine of controls subjects. In addition, immunohistochemistry demonstrated that high levels of MMPs were localized in the epithelium and lamina propria of polyp tissue when compared to colonic tissue collected from healthy control subjects.
These data are the first to demonstrate that MMPs are present in the urine and tissue of patients with juvenile polyps, and these enzymes have the potential to serve as surrogate markers for the presence of polyps.
PMCID: PMC3715034  PMID: 19330927
Matrix Metalloproteinases; biomarkers; polyps; juvenile polyps; juvenile polyposis syndrome
3.  A Pilot Study of Ketamine versus Midazolam/Fentanyl Sedation in Children Undergoing GI Endoscopy 
Background. Ketamine sedation has been found superior by physician report to traditional sedation regimens for pediatric endoscopy. Goal. To objectively compare sedation with ketamine versus midazolam/fentanyl for children undergoing gastrointestinal endoscopy. Study. Patients received one of two regimens and were independently monitored using a standardized rating scale. Results. There were 2 episodes of laryngospasm during ketamine sedation. Univariate analyses showed patients sedated with ketamine (n = 17) moved more (median 25% of procedure time versus 8%, P = .03) and required similar low levels of restraint (0.83% versus 0.25%, P = .4) as patients sedated with midazolam/fentanyl (n = 20). Age-adjusted analyses suggested that patients sedated with ketamine were comparably more quiet (P = .002). Conclusions. A pilot trial of ketamine at our institution was associated with episodes of laryngospasm. In addition, children sedated with ketamine moved and required restraint similarly to patients sedated with midazolam/fentanyl. Physician perceptions may be affected by the fact that children who received ketamine were less likely to vocalize distress.
PMCID: PMC3133434  PMID: 21760813

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