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991.
Autoantibodies to RuvBL1 and RuvBL2: A Novel Systemic Sclerosis–Related Antibody Associated With Diffuse Cutaneous and Skeletal Muscle Involvement
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992.
Simin Lu Kohsuke Kanekura Takashi Hara Jana Mahadevan Larry D. Spears Christine M. Oslowski Rita Martinez Mayu Yamazaki-Inoue Masashi Toyoda Amber Neilson Patrick Blanner Cris M. Brown Clay F. Semenkovich Bess A. Marshall Tamara Hershey Akihiro Umezawa Peter A. Greer Fumihiko Urano 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(49):E5292-E5301
Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.The endoplasmic reticulum (ER) takes center stage for protein production, redox regulation, calcium homeostasis, and cell death (1, 2). It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3, 4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5–8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies. In contrast, we reasoned that it should be possible to define the role of ER dysfunction in mechanistically homogenous patient populations, especially in rare diseases with a monogenic basis, such as Wolfram syndrome (9).Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy (7). Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7, 10, 11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12, 13). It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through ER and mitochondrial dysfunction (5, 6, 14–16). WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.Despite the underlying importance of ER malfunction in Wolfram syndrome, and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we show that the calpain protease provides a mechanistic link between the ER and death of neurons and β cells in Wolfram syndrome. 相似文献
993.
994.
Rheumatoid arthritis (RA) mainly affects various joints of the body, including the temporomandibular joint (TMJ), and it involves an infiltration of autoantibodies and inflammatory leukocytes into articular tissues and the synovium. Initially, the synovial lining tissue becomes engaged with several kinds of infiltrating cells, including osteoclasts, macrophages, lymphocytes, and plasma cells. Eventually, bone degradation occurs. In order to elucidate the best therapy for RA, a comprehensive study of RA pathogenesis needs to be completed. In this article, we discuss a Fas-deficient condition which develops into RA, with an emphasis on the role of sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling which induces the migration of osteoclast precursor cells. We describe that Fas/S1P1 signaling via NF-κB activation in osteoclasts is a key factor in TMJ-RA severity and we discuss a strategy for blocking nuclear translocation of the p50 NF-κB subunit as a potential therapy for attenuating osteoclastogenesis. 相似文献
995.
Akitoshi Kinoshita Hayato Miyachi Hiromichi Matsushita Miharu Yabe Tomohiko Taki Tomoyuki Watanabe Akiko M. Saito Daisuke Tomizawa Takashi Taga Hiroyuki Takahashi Hidemasa Matsuo Kumi Kodama Kentaro Ohki Yasuhide Hayashi Akio Tawa Keizo Horibe Souichi Adachi 《British journal of haematology》2014,167(1):80-86
The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found ‘AML with myelodysplasia‐related changes’ (AML‐MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia‐related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with ‘AML, not otherwise specified’ (AML‐NOS), patients with ‘AML‐MRC’ presented at a younger age, with a lower white blood cell count, higher incidence of 20–30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms‐like tyrosine kinase 3 internal tandem duplication (FLT3‐ITD), NPM1 and CEBPA mutations. Complete remission rate and 3‐year probability of event‐free survival were significantly worse in ‘AML‐MRC’ patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3‐year overall survival and relapse‐free survival were comparable with ‘AML‐NOS’ patients. By multivariate analysis, FLT3‐ITD was solely associated with worse overall survival. These results support the distinctive features of the category ‘AML‐MRC’ even in children. 相似文献
996.
Michinori Ogura Kiyoshi Ando Tatsuya Suzuki Kenichi Ishizawa Sung Yong Oh Kuniaki Itoh Kazuhito Yamamoto Wing Yan Au Hwei‐Fang Tien Yoshihiro Matsuno Takashi Terauchi Keiko Yamamoto Masahiko Mori Yoshinobu Tanaka Takashi Shimamoto Kensei Tobinai Won Seog Kim 《British journal of haematology》2014,165(6):768-776
Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted. 相似文献
997.
Sari ImamuraKumiko Hirata MD PhD Makoto OriiKunihiro Shimamura MD Yasutsugu ShionoKohei Ishibashi MD PhD Takashi TanimotoTakashi Yamano MD PhD Yasushi InoHironori Kitabata MD PhD Tomoyuki YamaguchiTakashi Kubo MD PhD Atsushi TanakaToshio Imanishi MD PhD Takashi Akasaka MD PhD 《The American journal of cardiology》2014
998.
999.
Honda Mika Iida Takashi Kamiyama Hirona Masuda Manabu Kawara Misao Svensson Peter Komiyama Osamu 《Clinical oral investigations》2019,23(2):757-762
Clinical Oral Investigations - The aim of this study was to compare mechanical sensitivity on the tongue using quantitative sensory testing (QST) and psychological factors using the General Health... 相似文献
1000.
Masahiro Nakamura Noriaki Kawanabe Rie Adachi Takashi Yamashiro Hiroshi Kamioka 《The Angle orthodontist》2019,89(2):333
This report illustrates successful nonsurgical orthodontic treatment of a hypodivergent adult patient with bilateral posterior scissors bite (Brodie bite) and excessive overjet. A 26-year-old woman primarily reported maxillary incisor protrusion. She was diagnosed with Class ll division 1 malocclusion with skeletal Class I, short face, low mandibular plane angle and bilateral posterior scissors bite. A lingual arch with anterior bite block and posterior miniscrews with preadjusted edgewise appliances were used to improve the bilateral scissors bite. After achieving molar occlusion, the maxillary first premolars were extracted, and six miniscrews were used to improve the anterior-posterior and vertical discrepancies. After active treatment for 56 months, the convex facial profile with excessively protruded lips was improved and good interdigitation with ideal incisor relationship was achieved. Additionally, the irregular movements of the incisal path and the bilateral condyles during lateral excursion were improved. At 13 months of retention, a satisfactory facial profile, occlusion, and jaw movements were maintained. The treatment results suggest that miniscrews and fixed bite blocks were effective and efficient to facilitate correction of the bilateral scissors bite, excessive overjet, and vertical relationship correction in this nonsurgical orthodontic treatment. 相似文献