Cisplatin-induced vestibular hair cell lesion-less damage at high doses

Cisplatin, a widely used anticancer drug, damages hair cells in cochlear organotypic cultures at low doses, but paradoxically causes little damage at high doses resulting in a U-shaped dose-response function. To determine if the cisplatin dose-response function for vestibular hair cells follows a similar pattern, we treated vestibular organotypic cultures with doses of cisplatin ranging from 10 to 1000 μM. Vestibular hair cell lesions progressively increased as the dose of cisplatin increased with maximum damage occurring around 50-100 μM, but the lesions progressively decreased at higher doses resulting in little hair cell loss at 1000 μM. The U-shaped doseresponse function for cisplatin-treated vestibular hair cells in culture appears to be regulated by copper transporters, Ctrl, ATP7A and ATP7B, that dose-dependently regulate the uptake, sequestration and extrusion of cisplatin.

MicroRNA-21, 204 and 125b Play Potential Roles in Tumorigenesis of Melanoma

Aim: The high mortality rate of melanoma is due to partially the lack of good diagnostic markers and treatment strategies. Over the past several years, several microRNA (miRNA) profiling studies have been performed on melanoma tissues, but with extremely inconsistency, the diagnostic value of miRNA candidates in melanoma remains under debate. Thus, this study aims to systematically evaluate the consistency of miRNAs tissue in multiple independent studies in melanoma. Method: Eligible studies were screened and selected from the PubMed, EMBASE, and Web of Science. A systematic analysis of published miRNA expression studies that compared the miRNA expression profiles between melanoma tissues and normal skin tissue was conducted. A vote-counting strategy was followed with the collection of information. Real time PCRs were employed to validate miRNA candidates with high consistency. Targets of consistent miRNAs were predicted by online programs (like miRTarBase, microRNA.org and TargetScanHuman 6.2). Enrichment analyses for gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways were carried out with Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results: A total of 303 differentially expressed miRNAs were reported in the 10 miRNA-profiling studies during comparison of melanoma tissues with normal tissues;132 were up-regulated in melanoma, and 171 were down-regulated. However, in the group of consistently reported miRNAs (cutoff > 3 times), only moderate numbers of consistent and differentially expressed miRNAs were selected. miRNA-21 was found increased in 5 different studies, miRNA-146b, miRNA-17 and miRNA-18a were reported up-regulated in 4 profiling studies. Meanwhile, miRNA-204 and miRNA-125b were found down-regulated in 5 studies, miRNA-141, miRNA-149, miRNA-224, miRNA-200b, miRNA-200c were consistently decreased in just 4 out of 10 profiling studies in total. The directions of differential expression of these miRNA candidates were confirmed by real time PCRs. Enrichment analyses demonstrated that programmed cell death and transcription regulation played very important roles in the involvement of miRNAs in tumorigenesis of melanoma. Conclusion: This systematic study of melanoma miRNA profiling studies would provide rich information on miRNAs with potential role as the biomarkers and therapeutic agents with high consistency in melanoma.

A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis,with high mortality and no proven therapy.Here,we reported a severe uremic calciphylaxis patient with progressive skin ischemia,large areas of painful malodorous ulcers,and mummified legs.Because of the worsening symptoms and signs refractory to conventional therapies,treatment with human amnion-derived mesenchymal stem cells(hAMSCs)was approved.Preclinical release inspections of hAMSCs,efficacy,and safety assessment,including cytokine secretory ability,immunocompetence,tumorigenicity,and genetics analysis in vitro,were introduced.We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats,abnormal immune response tests in C57BL/6 mice,and tumorigenicity tests in neonatal Balbc-nu nude mice.After the preclinical research,the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers.When followed up to 15 months,the blood-based markers of bone and mineral metabolism improved,with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells.Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis,and 20 months later,the re-epithelialization restored the integrity of the damaged site.No infusion or local treatment-related adverse events occurred.Thus,this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification,stimulating angiogenesis and myogenesis,anti-inflammatory and immune modulation,multidifferentiation,re-epithelialization,and restoration of integrity.