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Benhamouche S.,Harvard University | Curto M.,Harvard University | Saotome I.,Harvard University | Gladden A.B.,Harvard University | And 3 more authors.
Genes and Development | Year: 2010

The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2-/- progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2-/- liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2-/- liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche. © 2010 by Cold Spring Harbor Laboratory Press. Source


Elberling C.,William Demant Holding A S | Don M.,House Ear Institute
Journal of the Acoustical Society of America | Year: 2010

A recent study evaluates auditory brainstem responses (ABRs) evoked by chirps of different durations (sweeping rates) [Elberling (2010). J. Acoust. Soc. Am. 128, 215-223]. The study demonstrates that shorter chirps are most efficient at higher levels of stimulation whereas longer chirps are most efficient at lower levels. Mechanisms other than the traveling wave delay, in particular, upward spread of excitation and changes in cochlear-neural delay with level, are suggested to be responsible for these findings. As a consequence, delay models based on estimates of the traveling wave delay are insufficient for the design of chirp stimuli, and another delay model based on a direct approach is therefore proposed. The direct approach uses ABR-latencies from normal-hearing subjects in response to octave-band chirps over a wide range of levels. The octave-band chirps are constructed by decomposing a broad-band chirp, and constitute a subset of the chirp. The delay compensations of the proposed model are similar to those found in the previous experimental study, which thus verifies the results of the proposed model. © 2010 Acoustical Society of America. Source


Niparko J.K.,Johns Hopkins University | Tobey E.A.,University of Texas at Dallas | Thal D.J.,University of California at San Diego | Eisenberg L.S.,House Ear Institute | And 2 more authors.
JAMA - Journal of the American Medical Association | Year: 2010

Context: Cochlear implantation is a surgical alternative to traditional amplification (hearing aids) that can facilitate spoken language development in young children with severe to profound sensorineural hearing loss (SNHL). Objective: To prospectively assess spoken language acquisition following cochlear implantation in young children. Design, Setting, and Participants: Prospective, longitudinal, and multidimensional assessment of spoken language development over a 3-year period in children who underwent cochlear implantation before 5 years of age (n=188) from 6 US centers and hearing children of similar ages (n=97) from 2 preschools recruited between November 2002 and December 2004. Follow-up completed between November 2005 and May 2008. Main Outcome Measures: Performance on measures of spoken language comprehension and expression (Reynell Developmental Language Scales). Results: Children undergoing cochlear implantation showed greater improvement in spoken language performance (10.4; 95% confidence interval [CI], 9.6-11.2 points per year in comprehension; 8.4; 95% CI, 7.8-9.0 in expression) than would be predicted by their preimplantation baseline scores (5.4; 95% CI, 4.1-6.7, comprehension; 5.8; 95% CI, 4.6-7.0, expression), although mean scores were not restored to age-appropriate levels after 3 years. Younger age at cochlear implantation was associated with significantly steeper rate increases in comprehension (1.1; 95% CI, 0.5-1.7 points per year younger) and expression (1.0; 95% CI, 0.6-1.5 points per year younger). Similarly, each 1-year shorter history of hearing deficit was associated with steeper rate increases in comprehension (0.8; 95% CI, 0.2-1.2 points per year shorter) and expression (0.6; 95% CI, 0.2-1.0 points per year shorter). In multivariable analyses, greater residual hearing prior to cochlear implantation, higher ratings of parent-child interactions, and higher socioeconomic status were associated with greater rates of improvement in comprehension and expression. Conclusion: The use of cochlear implants in young children was associated with better spoken language learning than would be predicted from their preimplantation scores. ©2010 American Medical Association. All rights reserved. Source


The pharmaceutical composition and a method of treatment of infectious diseases, such as otitis media, paranasal sinusitis, labyrinthitis and meningitis are described. The composition comprises EP2E or homologues thereof.


Zhang N.,Howard Hughes Medical Institute | Bai H.,Johns Hopkins University | David K.K.,Howard Hughes Medical Institute | Dong J.,Howard Hughes Medical Institute | And 6 more authors.
Developmental Cell | Year: 2010

The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2. © 2010 Elsevier Inc. Source

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