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OTOTOXIC EFFECTS OF CARBOPLATIN IN ORGANOTYPIC CULTURES IN CHINCHILLAS AND RATS

Journal of Otology 2012年第2期7卷 92-101页

作者： DING Dalian JIANG Haiyan FU Yong Richard SALVI shinichi someya Masaru TANOKURA Center for Hearing and Deafness State University of New York at Buffalo Graduate School of Agricultural and Life Sciences University of Tokyo Departments of Aging and Geriatric Research Division of Biology of Aging University of Florida

Carboplatin, a second-generation platinum chemotherapeutic drug, is considerably less ototoxic than cisplatin. While common laboratory species such as mice, guinea pigs and rats are highly resistant to carboplatin ototoxicity, the chinchilla stands out as highly susceptible. Moreover, carboplatin causes an unusual gradient of cell death in chinchillas. Moderate doses selectively damage type I spiral ganglion neurons (SGN) and inner hair cells (IHC) and the lesion tends to be relatively uniform along the length of the cochlea. Higher doses eventually damage outer hair cells (OHC), but the lesion follows the traditional gradient in which damage is more severe in the base than the apex. While carboplatin ototoxicity has been well documented in adult animals in vivo, little is known about its in vitro toxicity. To elucidate the ototoxic effects of carboplatin in vitro, we prepared cochlear and vestibular organotypic cultures from postnatal day 3 rats and adult chinchillas. Chinchilla cochlear and vestibular cultures were treated with carboplatin concentrations ranging from 50 μM to 10 mM for 48 h. Consistent with in vivo data, carboplatin selectively damaged IHC at low concentrations (50-100 μM). Surprisingly, IHC loss decreased at higher doses and IHC were intact at doses exceeding 500 μM. The mechanisms underlying this nonlinear response are unclear but could be related to a decrease in carboplatin uptake via active transport mechanisms (e.g., copper). Unlike the cochlea, the carboplatin dose-response function increased with dose with the highest dose destroying all chinchilla vestibular hair cells. Cochlear hair cells and auditory nerve fibers in rat cochlear organotypic cultures were unaffected by carboplatin concentrations <10 μM; however, the damage in OHC were more severe than IHC once the dose reached 100 μM. A dose at 500 μM destroyed all the cochlear hair cells, but hair cell loss decreased at high concentrations and nearly all the cochlear hair cells were pre

关键词： Carboplatin ototoxicity organotypic culture

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OTOTOXIC MODEL OF OXALIPLATIN AND PROTECTION FROM NICOTINAMIDE ADENINE DINUCLEOTIDE

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Journal of Otology 2013年第1期8卷 63-71页

作者： DING Dalian JIANG Haiyan FU Yong LI Yongqi Richard Salvi shinichi someya Masaru Tanokura Center for Hearing and Deafness State University of New York at Buffalo Sixth People’s Hospital Shanghai Oriental Otolaryngology InstituteShanghai Jiao Tong University Xiangya Hospital Central South University Department of Applied Biological Chemistry University of Tokyo The First Officiated Hospital College of MedicineZhejiang University The Third Affiliated Hospital of Sun Yat-Sen University University of Florida

Oxaliplatin, an anticancer drug commonly used to treat colorectal cancer and other tumors, has a number of serious side effects, most notably neuropathy and ototoxicity. To gain insights into its ototoxic profile, oxaliplatin was applied to rat cochlear organ cultures. Consistent with it neurotoxic propensity, oxaliplatin selectively damaged nerve fibers at a very low dose 1 μM. In contrast, the dose required to damage hair cells and spiral ganglion neurons was 50 fold higher (50 μM). Oxailiplatin-induced cochlear lesions initial-ly increased with dose, but unexpectedly decreased at very high doses. This non-linear dose response could be related to depressed oxaliplatin uptake via active transport mechanisms. Previous studies have demon-strated that axonal degeneration involves biologically active processes which can be greatly attenuated by nicotinamide adenine dinucleotide (NAD+). To determine if NAD+would protect spiral ganglion axons and the hair cells from oxaliplatin damage, cochlear cultures were treated with oxaliplatin alone at doses of 10 μM or 50 μM respectively as controls or combined with 20 mM NAD+. Treatment with 10 μM oxaliplatin for 48 hours resulted in minor damage to auditory nerve fibers, but spared cochlear hair cells. However, when cochlear cultures were treated with 10 μM oxaliplatin plus 20 mM NAD+, most auditory nerve fibers were intact. 50 μM oxaliplatin destroyed most of spiral ganglion neurons and cochlear hair cells with apop-totic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+treatment great-ly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+provides signifi-cant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply.

关键词： oxaliplatin apoptosis copper transporter nicotinamide adenine dinucleotide

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Detection of apoptosis by RT-PCR array in mefloquine-induced cochlear damage

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Journal of Otology 2011年第1期6卷 1-9页

作者： DING Da-lian someya shinichi JIANG Hai-yan QI Wei-dong YU Dong-zhen Center for Hearing and Deafness State University of New York at Buffalo Departments of Aging and Geriatric Research Division of Biology of Aging University of Florida Department of Otolaryngology Head and Neck Surgery Huashan Hospital Affiliated Fudan University Department of Otolaryngology Head and Neck Surgery Six People＇s Hospital of Shanghai Jiao Tong University Graduate School of Agricultural and Life Sciences University of Tokyo Department of Otolaryngology Head and Neck Surgery Xiangya Hospital of Central South University

Objective To investigate the occurrence and possible mechanisms of apoptosis in cochlear epithelium and spiral ganglion neurons after mefloquine treatment. Methods We used quantitative RT-PCR apoptosis-focused gene arrays （96-well, 84 apoptosis related genes） to assess changes of gene expression in the cochlear basilar membrane （hair cells-supporting cells） and spiral ganglion neurons of rat cochlear organotypic cultures treated with 100 IxM mefloquine for 3 h. Results Significant up-or down-regulation in gene expression was detected in 23 genes in the cochlear basilar membrane, and in 32 genes in the spiral ganglion neurons compared with time-matched controls. The responding genes could be classified as pro-or anti-apoptotic, and were mainly implicated in the Bcl-2, Caspase, Card, IAP, TNF ligand / TNF receptor, Death domain / Death effector domain, DNA damage / p53, and NF-kappa B families. Synthetic analysis suggested that these families could be revised to two major pathways mainly involved in t]he death receptor-mediated signaling pathway and apoptotic mitochondrial pathway. In addition, it was found that numerous anti-apoptotic genes such as Bcl2al, Birclb, Birc3, Birc4, Bnipl, Cflar, II10, Lhx4, Mcll, Nfkbl, Prlr, Prok2, and TNF were greatly up-regulated in the cochlear tissue, which might imply the co-existence of protective response in the ceils at the early stage of mefloquine-induced damage.

关键词： mefloquine ototoxicity apoptosis cochlea spiral ganglion neurons hair cells gene expression

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Identification of advanced spin-driven thermoelectric materials via interpretable machine learning

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npj Computational Materials 2019年第1期5卷 232-237页

作者： Yuma Iwasaki Ryohto Sawada Valentin Stanev Masahiko Ishida Akihiro Kirihara Yasutomo Omori Hiroko someya Ichiro Takeuchi Eiji Saitoh shinichi Yorozu Central Research Laboratories NEC CorporationTsukuba 305-8501Japan PREST JSTSaitama 322-0012Japan Department of Materials Science and Engineering University of MarylandCollege ParkMD 20742USA Center for Nanophysics and Advanced Materials University of MarylandCollege ParkMD 20742USA Joint Quantum Institute University of MarylandCollege ParkMD 20742USA Institute for Materials Research Tohoku UniversitySendai 908-8577Japan WPI Advanced Institute for Materials Research Tohoku UniversitySendai 908-8577Japan Advanced Science Research Center Japan Atomic Energy AgencyTokai 319-1195Japan RIKEN Center for Emergent Matter Science Wako 351-0198Japan

Machine learning is becoming a valuable tool for scientific *** attractive is the application of machine learning methods to the field of materials development,which enables innovations by discovering new and better functional *** apply machine learning to actual materials development,close collaboration between scientists and machine learning tools is ***,such collaboration has been so far impeded by the black box nature of many machine learning *** is often difficult for scientists to interpret the data-driven models from the viewpoint of material science and ***,we demonstrate the development of spin-driven thermoelectric materials with anomalous Nernst effect by using an interpretable machine learning method called factorized asymptotic Bayesian inference hierarchical mixture of experts(FAB/HMEs).Based on prior knowledge of material science and physics,we were able to extract from the interpretable machine learning some surprising correlations and new knowledge about spin-driven thermoelectric *** by this,we carried out an actual material synthesis that led to the identification of a novel spin-driven thermoelectric *** material shows the largest thermopower to date.

关键词： becoming learning attractive

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