👤 Yoshinori Imura

Lymphoplasmacytic lymphoma (LPL) is a type of indolent B-cell lymphoma typically associated with IgM paraproteinemia and does not require immediate treatment until symptoms appear. However, non-IgM LPL has a higher frequency of extramedullary involvement and requires more aggressive therapy than IgM-LPL. A 51-year-old woman in treatment-free follow-up for LPL with IgG-κ paraproteinemia was referred to our hospital with a chief complaint of right coxalgia. A plain MRI scan showed multiple osteolytic bone lesions, including bilateral femoral incomplete fractures. Similar bone lesions were also detected in the right shoulder joint. Pathological examination of the bilateral femurs and the right shoulder revealed LPL lesions with amyloid deposits. MYD88 L265P gene mutations were confirmed by genetic analysis, and all lesions were considered identical. Ibrutinib plus rituximab therapy was administered, resulting in a partial response sustained to date. Bone involvement and amyloidosis are rare but critical extranodal manifestations of LPL, necessitating careful screening and follow-up even in asymptomatic patients. When these manifestations are suspected, prompt pathological and genetic evaluation is warranted, especially in non-IgM LPL cases. Show less

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK. Show less

Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRβ are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers. Show less

To determine the significance of anti-U1 RNP antibodies in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) who have central neuropsychiatric SLE (NPSLE). The frequency of antinuclear antibodies including anti-U1 RNP antibodies in the sera and CSF of 24 patients with SLE and 4 patients with MCTD, all of whom had neuropsychiatric syndromes, was determined using an RNA immunoprecipitation assay and an enzyme-linked immunosorbent assay. The frequency of anti-U1 RNP antibodies in the CSF of patients with central NPSLE was examined, and the anti-U1 RNP index ([CSF anti-U1 RNP antibodies/serum anti-U1 RNP antibodies]/[CSF IgG/serum IgG]) was compared with CSF interleukin-6 (IL-6) levels and the albumin quotient (Qalb, an indicator of blood-brain barrier damage). CSF and serum antibodies against U1-70K, U1-A, and U1-C, including autoantigenic regions, were examined, and the U1-70K, U1-A, and U1-C indices as well as the anti-U1 RNP index were calculated. CSF anti-U1 RNP antibodies with an increased anti-U1 RNP index showed 64.3% sensitivity and 92.9% specificity for central NPSLE. The anti-U1 RNP index did not correlate with CSF IL-6 levels or the Qalb. The anti-U1-70K index was higher than the anti-U1-A and anti-U1-C indices in the CSF of anti-U1 RNP antibody-positive patients with central NPSLE. The major autoantigenic region for CSF anti-U1-70K antibodies appeared to be localized in U1-70K amino acid 141-164 residue within the RNA-binding domain. The frequency of anti-U1 RNP antibodies in the CSF and the anti-U1 RNP index are useful indicators of central NPSLE in anti-U1 RNP antibody-positive patients. The predominance of anti-U1-70K antibodies in CSF suggests intrathecal anti-U1 RNP antibody production. Show less