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Cincinnati, OH, United States

Hamajima Y.,University of Minnesota | Hamajima Y.,Nagoya City University | Komori M.,University of Minnesota | Preciado D.A.,University of Minnesota | And 5 more authors.
Cell Proliferation | Year: 2010

Objectives: A hallmark of cholesteatoma is hyperproliferation of keratinocytes with abundant production of keratins in the middle ear under chronic inflammatory conditions. However, little is known about the driving force of cellular proliferation and keratin production of cholesteatomal matrix. The purpose of this study was to investigate the cellular proliferation and keratin production of keratinocytes under the influence of Id1, a candidate transcription factor to cell proliferation. Materials and methods: Keratinocytes were transfected with Id1 and the responses of keratinocytes to Id1 were studied by using cellular and molecular biologic methods. Results: Id1 positively contributed to the cell cycle progression and negatively to the p16Ink4a downregulation via the nuclear factor-kappa B (NF-κB)/cyclin D1 pathway. Id1 significantly increased the promoter activity of NF-κB which, in turn, up-regulated the expression of cyclin D1 and keratin 10 in keratinocytes. Specific NF-κB inhibitors (pyrrolidine dithiocarbamate, PDTC), or dominant-negative inhibitor (I kappa B alpha mutant, IκBαM) abrogated the Id1-induced cell proliferation and keratin 10 production whereas p65, a subunit of the NF-κB heterodimer and an enhancer of the NF-κB activity, strengthened the Id1-induced cell proliferation and keratin 10 production. Conclusions: Id1 contributed to hyperproliferation of keratinocytes via enhancement of cell cycle progression, removal of cell cycle inhibition, and simultaneously increased keratin production. © 2010 Blackwell Publishing Ltd. Source


Tang X.,A-Life Medical | Li R.,Center for Hearing and Deafness Research | Zheng J.,A-Life Medical | Cai Q.,A-Life Medical | And 13 more authors.
Molecular Genetics and Metabolism | Year: 2010

Mutations in mitochondrial DNA (mtDNA) have been found to be one of the most important causes of sensorineural hearing loss. We report here a clinical, genetic, molecular and biochemical characterization of a Han Chinese pedigree with maternally transmitted nonsyndromic hearing impairment. Seven of nine matrilineal relatives exhibited a variable severity and age-at-onset (8 years old) of hearing loss. Mutational analysis of mtDNA identified the novel homoplasmic tRNASer(UCN) 7505T>C mutation and other 37 variants belonging to haplogroup F1. The 7505T>C mutation, which is absent in 449 Chinese controls, is located at a highly conserved base-pairing (10A-20U) of tRNASer(UCN). The abolishment of 10A-20U base-pairing likely alters the tRNASer(UCN) metabolism. Functional significant of this mutation was supported by ∼65% reductions in the level of tRNASer(UCN) observed in the lymphoblastoid cell lines carrying the 7505T>C mutation, compared with the wild-type cell lines. This reduced tRNA level is below the proposed threshold to support a normal respiration in lymphoblastoid cells. Furthermore, the highly conserved tRNAAla 5587T>C and Cytb C93Y variants may have a modifying role of deafness expression associated with the 7505T>C mutation. However, genotyping analysis of nuclear modifier gene TRMU and the prominent deafness-cause gene GJB2 failed to detect any mutations in the member of this family. These data strongly indicate that the novel tRNASer(UCN) 7505T>C mutation is involved in maternally transmitted hearing loss. However, other genetic, epigenetic or environmental factors may contribute to the phenotypic variability of this family. Our findings will be helpful for counseling families of maternally inherited hearing loss. © 2010 Elsevier Inc. All rights reserved. Source


Lu J.,A-Life Medical | Qian Y.,Center for Hearing and Deafness Research | Li Z.,Wenzhou Medical College | Yang A.,A-Life Medical | And 20 more authors.
Mitochondrion | Year: 2010

Mitochondrial 12S rRNA 1555A>G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic deafness. Our previous investigations showed that the A1555G mutation was a primary factor underlying the development of deafness but was insufficient to produce deafness phenotype. However, it has been proposed that mitochondrial haplotypes modulate the phenotypic manifestation of the 1555A>G mutation. Here, we performed systematic and extended mutational screening of 12S rRNA gene in a cohort of 1742 hearing-impaired Han Chinese pediatric subjects from Zhejiang Province, China. Among these, 69 subjects with aminoglycoside-induced and nonsyndromic deafness harbored the homoplasmic 1555A>G mutation. These translated to a frequency of ∼3.96% for the 1555A>G mutation in this hearing-impaired population. Clinical and genetic characterizations of 69 Chinese families carrying the 1555A>G mutation exhibited a wide range of penetrance and expressivity of hearing impairment. The average penetrances of deafness were 29.5% and 17.6%, respectively, when aminoglycoside-induced hearing loss was included or excluded. Furthermore, the average age-of-onset for deafness without aminoglycoside exposure ranged from 5 and 30 years old, with the average of 14.5 years. Their mitochondrial genomes exhibited distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups A, B, C, D, F, G, M, N, R and Y, respectively. These indicated that the 1555A>G mutation occurred through recurrent origins and founder events. The haplogroup D accounted for 40.6% of the patient's mtDNA samples but only 25.8% of the Chinese control mtDNA samples. Strikingly, these Chinese families carrying mitochondrial haplogroup B exhibited higher penetrance and expressivity of hearing loss. In addition, the mitochondrial haplogroup specific variants: 15927G>A of haplogroup B5b, 12338T>C of haplogroup F2, 7444G>A of haplogroup B4, 5802T>C, 10454T>C, 12224C>T and 11696G>A of D4 haplogroup, 5821G>A of haplogroup C, 14693A>G of haplogroups Y2 and F, and 15908T>C of Y2 may enhance the penetrace of hearing loss in these Chinese families. Moreover, the absence of mutation in nuclear modifier gene TRMU suggested that TRMU may not be a modifier for the phenotypic expression of the 1555A>G mutation in these Chinese families. These observations suggested that mitochondrial haplotypes modulate the variable penetrance and expressivity of deafness among these Chinese families. © 2009 Mitochondria Research Society. Source


Smith N.,Center for Hearing and Deafness Research | Greinwald J.,Center for Hearing and Deafness Research
Current Opinion in Otolaryngology and Head and Neck Surgery | Year: 2011

In children, indicator guideline changes have been shown to not affect speech, language, and cognitive development, but further study is needed to find the right balance of observation, antibiotics, and myringotomy with tube placement for otitis media. Future vaccines may further decrease the number of children requiring myringotomy with tube placement for otitis media. © 2011 Wolters Kluwer Health. Source

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