Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome

Introduction: Pendred syndrome is an autosomal-recessive disease characterized by congenital hearing loss and thyroid goiter. Previously, cell stress susceptibilities were shown to increase in patient-derived cells with intracellular aggregation using an in vitro acute cochlear cell model derived from patient-specific pluripotent stem (iPS) cells. Moreover, we showed that rapamycin can relieve cell death. However, studies regarding long-term cell survival without cell stressors that mimic the natural course of disease or the rational minimum concentration of rapamycin that prevents cell death are missing. Methods: In this report, we first investigated the rational minimum concentration of rapamycin using patient-specific iPS cells derived-cochlear cells with three different conditions of acute stress. We next confirmed the effects of rapamycin in long-term cell survival and phenotypes by using cochlear cells derived from three different patient-derived iPS cells. Results: We found that inner ear cells derived from Pendred syndrome patients are more vulnerable than those from healthy individuals during long-term culturing; however, this susceptibility was relieved via treatment with low-dose rapamycin. The slow progression of hearing loss in patients may be explained, in part, by the vulnerability observed in patient cells during long-term culturing. We successfully evaluated the rational minimum concentration of rapamycin for treatment of Pendred syndrome. Conclusion: Our results suggest that low-dose rapamycin not only decreases acute symptoms but may prevent progression of hearing loss in Pendred syndrome patients. Keywords: Induced pluripotent stem cell, Hereditary hearing loss, Pendred syndrom

Transient EDTA‐dependent pseudothrombocytopenia and ulcerative colitis recurrence during chemotherapy: A case of misleading platelet count results attributable to a laboratory artifact

Key Clinical Message EDTA‐dependent pseudothrombocytopenia as well as myelosuppression should be suspected when thrombocytopenia occurs in patients with autoimmune disease during chemotherapy. Abstract A patient with pancreatic cancer and ulcerative colitis developed transient ethylenediaminetetraacetic acid (EDTA)‐dependent pseudothrombocytopenia with exacerbation of ulcerative colitis during chemotherapy. Unfortunately, pseudothrombocytopenia could not be immediately detected because thrombocytopenia was masked by a reasonable time course of adverse events associated with chemotherapy and ulcerative colitis recurrence. When thrombocytopenia occurs during chemotherapy, especially in patients with autoimmune diseases, EDTA‐dependent pseudothrombocytopenia and bone marrow suppression caused by anti‐cancer agents should be suspected