N. Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease.
Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-β, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. α-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in mice. pSmad3L expression was increased in mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in mice. Smad3 knockout/ double-mutant mice revealed amelioration of abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-β/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention.
Langerhans cell histiocytosis (LCH) is the most frequent type of histiocytosis and is characterized by both “inflammation/immune dysregulation” and “neoplastic disorder.” Although overall survival has remarkably improved through consecutive previous studies, the relapse-free survival rate is still only 60% to 70%, even in the latest clinical trials. Relapse of LCH is the most significant risk factor for permanent consequences in the central nervous system, such as diabetes insipidus, anterior pituitary hormone deficiency, and neurodegenerative diseases. In this trial, we evaluated the safety and effectiveness of hydroxyurea and methotrexate in recurrent LCH. Treatments in this study consisted of only orally administered drugs and not intravascularly administered drugs. Hydroxyurea therapy for patients with LCH is expected to be safer, less painful, and more cost-effective than other treatments for LCH. The results of this study could provide new therapeutic alternatives for recurrent LCH.
Methods and analysis:
This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH.
In the Results subsection of the abstract, the sentence BFifty percent relapse-free survival in patients without a history of SRNS was 615 days, longer than that of patients with one relapse (393 days) (p=0.005).^should have read BFifty percent relapse-free survival in patients without a history of SRNS was 615 days, longer than that of patients with a history of SRNS (393 days) (p=0.005).^. The authors apologize for this error and any inconvenience caused.The online version of the original article can be found at http://dx
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