👤 Kazuyuki Narimatsu

Paneth cell metaplasia (PCM), a metaplastic change associated with chronic inflammation in ulcerative colitis (UC), may be linked to UC-associated neoplasia (UCAN). However, no endoscopic method currently exists for detecting PCM. This study aimed to develop and validate a novel endoscopic staining technique-CV-SCAN-for identifying PCM and UCAN, and to explore the molecular characteristics of the stained areas. This retrospective observational study included 131 patients with UC undergoing surveillance colonoscopy. CV-SCAN involved spraying an ultra-diluted solution (0.006%) of crystal violet from the descending colon to the rectum. Biopsies were obtained from stained and non-stained areas and evaluated histologically and molecularly. RNA expression profiles were analyzed via microarray and real-time RT-PCR. The diagnostic performance of CV-SCAN for detecting PCM was assessed, along with its correlation with UCAN history. CV-SCAN visualized sharply demarcated, purple-stained areas corresponding to PCM or UCAN. PCM was significantly associated with a history of UCAN. Uniform, dark staining was characteristic of PCM, while UCAN showed heterogeneous staining with small round pits. CV-SCAN achieved a sensitivity of 81.3% and a specificity of 84.9% for PCM detection. Molecular analysis revealed upregulation of Paneth cell-specific (DEFA5, DEFA6), small intestinal (CCL25, APOC3), and UCAN-associated (IL17RC) genes, along with downregulation of SATB2 in stained areas. CV-SCAN is a novel and effective endoscopic staining method for detecting PCM and UCAN in patients with UC. It enables risk stratification through direct visualization of precancerous changes and may facilitate early detection and targeted surveillance. Show less

We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-β-induced activation in vivo and in vitro. Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH. Show less

Multiple osteochondroma (MO) is an autosomal dominant skeletal disorder characterized by the formation of multiple osteochondromas, and exostosin-1 (EXT1) and exostosin-2 (EXT2) are major causative genes in MO. In this study, we evaluated the genetic backgrounds and mutational patterns in Japanese families with MO. We evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. The exons and exon/intron junctions of EXT1 and EXT2 were directly sequenced after PCR amplification. Fifty-two mutations in 47 families with MO in either EXT1 or EXT2, and 42.3% (22/52) of mutations were novel mutations. Twenty-nine families (40.8%) had mutations in EXT1, and 15 families (21.1%) had mutations in EXT2. Interestingly, three families (4.2%) had mutations in both EXT1 and EXT2. Twenty-four families (33.8%) did not exhibit mutations in either EXT1 or EXT2. With regard to the types of mutations identified, 59.6% of mutations were inactivating mutations, and 38.5% of mutations were missense mutations. We found that the prevalence of EXT1 mutations was greater than that of EXT2 mutations in Japanese MO families. Additionally, we identified 22 novel EXT1 and EXT2 mutations in this Japanese MO cohort. This study represents the variety of genotype in MO. Show less