Long-term deterioration of bone-conduction hearing level in patients with labyrinthine fistula.

Objective: Although many reports describe the short-term hearing outcomes of surgically managed labyrinthine fistulae, the long-term results remain unknown. We reviewed the long-term postoperative hearing outcomes of 14 ears of patients with cholesteatoma and labyrinthine fistulae.

Methods: Between 1996 and 2010, 84 patients with cholesteatoma and labyrinthine fistula underwent tympanoplasty at Hyogo College of Medicine Hospital.

Enhanced antigen retrieval of amyloid β immunohistochemistry: re-evaluation of amyloid β pathology in Alzheimer disease and its mouse model.

Senile plaques, extracellular deposits of amyloid β peptide (Aβ), are one of the pathological hallmarks of Alzheimer disease (AD). As the standard immunohistochemical detection method for Aβ deposits, anti-Aβ immunohistochemistry combined with antigen retrieval (AR) by formic acid (FA) has been generally used. Here, we present a more efficient AR for Aβ antigen.

Reduction of β-amyloid accumulation by reticulon 3 in transgenic mice.

Inhibition of the β-secretase, BACE1, which cleaves amyloid precursor protein (APP) to produce β-amyloid protein (Aβ), is thought to be a feasible therapeutic strategy for Alzheimer's disease. Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Aβ-generating activity. In this study, we investigated whether RTN3 can regulate Aβ production in vivo, using transgenic (Tg) mice expressing APP with Swedish and London mutations (APP Tg mice) and those expressing RTN3; the latter mice showed ~1.

Antitumor effect of new HER2 peptide vaccination based on B cell epitope.

Background: While the benefit of passive immunotherapy is commonly accepted, active immunization may have advantages for the patient's quality of life. We identified a new epitope of Mab CH401 against Her-2/neu extracellular domain (N: 167-175), and evaluated the effect of active immunization of the 20mer peptide containing the epitope (CH401 peptide).

Materials And Methods: Epitope-mapping was performed using ELISA with Her-2/neu-related multiple antigen peptides (MAP).

Age-dependent increase in lysosome-associated membrane protein 1 and early-onset behavioral deficits in APPSL transgenic mouse model of Alzheimer's disease.

Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for beta- and gamma-secretases, and the resulting cleaved products (amyloid-beta peptides) are capable of causing neurotoxicity. Such cleavage is promoted by the Swedish and London mutations (APPSwe/Lon) inside the APP gene.

Gender effect on the accumulation of hyperphosphorylated tau in the brain of locus-ceruleus-injured APP-transgenic mouse.

Locus ceruleus (LC) neurons are preferentially and initially affected in Alzheimer disease (AD); however, the impact of the loss of LC neurons on the pathological sequence of AD, including amyloid beta-protein (Abeta) deposition and neurofibrillary tangle formation, has not been elucidated. In this study, we chemically injured LC neurons of the brains of familial AD-related amyloid precursor protein (APP)-transgenic mice using the LC-noradrenergic neuron-selective neurotoxin, N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4). The levels of noradrenaline significantly decreased in the cerebral cortices of DSP4-treated mice.

Gangliosides determine the amyloid pathology of Alzheimer's disease.

Gangliosides, GM3 and GM1, are suggested to accelerate the deposition of the amyloid beta-protein as amyloid angiopathy and senile plaques, respectively, in the Alzheimer brain. We investigated the profile of amyloid deposition in the brains of transgenic mice expressing a mutant amyloid precursor protein with a disrupted GM2 synthase gene, in which GM3 accumulates whereas GM1 is lacking. These mice showed a significantly increased level of deposited amyloid beta-protein in the vascular tissues.

Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease.

Increasing evidence suggests that the elevation of beta-amyloid (Abeta) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Abeta-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice].

A new approach for drug discovery from glycobiology and phage-displayed peptide library technology.

Peptides which mimic functional activities of glycosphingolipids were prepared by a technology of phage-displayed peptide library using monoclonal antibodies against glycosphingolipids. These peptides were named glyco-replica peptides. Peptides prepared with anti-GD1alpha antibody by this technology were found to contain WHW as common motif, and they showed suppressive activity not only on adhesion between hepatic sinusoidal endothelial cells and lymphosarcoma RAW117-H10 cells, but also on metastasis of the tumor cell to the liver and lung.

Epithelial-myoepithelial carcinoma arising in the nasal cavity.

This study documents a case of an epithelial-myoepithelial carcinoma (EMC) in the left nasal cavity. A 70-year-old woman who presented with recurrent epistaxis of the left nasal nostril of 3 months duration was found to have a polypoid tumor in the left nasal cavity. A computed tomography (CT) scan revealed a tumor to occupy the left inferior and middle nasal cavity which had destroyed the inferior nasal turbinate, and a horizontal scan showed the tumor to occupy the middle and posterior nasal cavity.

Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer's disease and its transgenic models: a role to mediate interaction of Abeta and tau.

Abnormal accumulation of Abeta and tau in senile plaques (SP) and neurofibrillary tangles (NFTs) is a key event in Alzheimer's disease (AD). Here, we show that T668-phosphorylated cytoplasmic domain of APP (pT668-ACD) accumulates Abeta and tau in AD and its transgenic models. Anti-pT668 immunostaining of AD brain sections with hydrated autoclave enhancement identified SP neurites and NFTs in which pT668-ACD colocalizes with tau.

GD3-replica peptides selected from a phage peptide library induce a GD3 ganglioside antibody response.

GD3-replica peptides were obtained from a phage peptide library and an anti-GD3 monoclonal antibody (Mab) (4F6), and anti-GD3 Mabs were generated by immunizing a peptide GD3P4. A Mab, 3D2 was found to recognize GD3 by immunohistochemical approaches. Amino acid analysis of heavy and light chain variable regions of 4F6 and 3D2 showed that the respective chains had the same length, and only a few different amino acid substitutions were found.

Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase.

Because membrane type-1 matrix metalloproteinase (MT1-MMP) is expressed specifically on the angiogenic endothelium as well as tumor cells, an agent possessing the ability to bind to this molecule might be useful as a tool for active targeting of tumor angiogenic vessels. Based on the sequences of peptide substrates of MT1-MMP, which had been determined by using a phage-displayed peptide library, we examined the binding ability of peptide-modified liposomes for endothelial cells and targeting ability for tumor tissues by positron emission tomography (PET). Liposomes modified with stearoyl-Gly-Pro-Leu-Pro-Leu-Arg (GPLPLR-Lip) showed high binding ability to human umbilical vein endothelial cells and accumulated in the tumor about 4-fold more than did the unmodified liposomes.

Isolation of a novel peptide homing to tumor-derived neovasculature that suppresses tumor growth.

Novel peptides homing to angiogenic vessels were recently isolated from a phage-displayed random pentade-capeptide library, and peptides having WRP sequence showed tumor growth suppression. In this study, we observed that another novel sequence, PVVLFPLH, suppressed tumor growth in vivo. Through the study of tumor growth suppression by the 5-mer peptides derived from this sequence, we determined the epitope sequence to be LFPLH.

Anti-neovascular therapy by liposomal DPP-CNDAC targeted to angiogenic vessels.

We previously reported that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity.

Anti-neovascular therapy using novel peptides homing to angiogenic vessels.

Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively.

Suppression of tumor growth by novel peptides homing to tumor-derived new blood vessels.

Novel peptides homing to angiogenic vessels were recently isolated from a phage-displayed random pentadecapeptide library. One of the isolated peptides, ASSSYPLIHWRPWAR, significantly suppressed the migration of VEGF-stimulated human umbilical vein endothelial cells. Dendoric ASSSYPLIHWRPWAR-peptide suppressed the formation of new blood vessels in dorsal air sac model mice.