👤 Y Takagi

Type 2 diabetic patients exhibited an increased secretion of triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol levels with a greater amount of small dense low-density lipoprotein (LDL). Given that apolipoprotein B (apoB), a proatherogenic lipoprotein, exists at both triglyceride-rich lipoproteins and LDL particles, circulating apoB may associate with diabetic coronary atherosclerosis. The OPTIMAL study was a prospective randomized-controlled study which employed serial near-infrared spectroscopy (NIRS)/intravascular ultrasound (IVUS) imaging to evaluate the efficacy of glycemic control on coronary atherosclerosis in 94 statin-treated type 2 diabetic patients with coronary artery disease (CAD) (UMIN000036721). Of these, 78 patients with both serial apoB levels and NIRS/IVUS images at baseline and week 48 were analyzed. NIRS/IVUS-derived plaque measures were compared in those with and without any reduction of apoB levels. All of the study subjects received a statin, and 60.6% of the study subjects exhibited any reduction of apoB levels. There was no significant difference in the atheroma progression rate between the 2 groups (-0.27 ± 0.15% vs -0.33 ± 0.51%, P = .44). However, patients with any reduction of apoB levels exhibited a greater frequency of change in maximal lipid-core burden index at 4-mm segment (maxLCBI In statin-treated type 2 diabetic patients with CAD, a greater delipidation of coronary atherosclerosis was observed in association with a reduction of apoB levels. The current findings indicate a potential anti-atherosclerotic effect of lowering apoB levels, which may ultimately mitigate future coronary events risk in statin-treated type 2 diabetic patients with CAD. Show less

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-driven B-cell lymphoproliferative disease that often progresses to high-grade lymphoma. We describe a case of high-grade LYG causing Pancoast syndrome, diagnosed via transbronchial biopsy after a failed incisional biopsy. Complete remission was achieved with R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone), but 2.5 years later, the patient developed lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Despite bendamustine-rituximab improving LPL/WM, LYG recurred, underscoring its treatment challenges. This case highlights LYG's diagnostic complexity, its potential link with other hematologic malignancies, and therapeutic limitations. Further research is needed to elucidate LYG's pathogenesis and develop effective treatments for relapsed cases. Show less

Liposarcoma and lymphoma are very rare tumors, and their combination is extremely rare. Moreover, there have been no reports of liposarcoma and lymphoma occurring in the same region. A 58-year-old man presented to Kanagawa Cancer Center with a mass in his left thigh and underwent a needle biopsy. Histological analysis showed an increase in the number of small lymphocytes and plasma cells; immunohistochemical analysis showed an increase in CD20-positive cells with Lambda light-chain restriction; therefore, the diagnosis of B-cell malignancy with plasma cell differentiation was made. A bone marrow biopsy specimen showed infiltration of atypical cells of the same phenotype and increased serum IgM-M levels; therefore, a diagnosis of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (LPL) was made. The needle biopsy specimen showed scattered CDK4-positive cells in the background of the lymphoma cells and sporadic MDM2 signal amplification on fluorescence in situ hybridization, suggesting mixed well-differentiated liposarcoma (WDL). Tumor resection was performed. The tumor contained a mixture of WDL and LPL areas. RNA sequencing revealed upregulated expression of chemokine genes, including CCL5, CCL18, and CCL19, in WDL and that of the corresponding chemokine receptor genes CCR4, CCR6, and CCR7 in the lymphoma cells. Chemokine-chemokine receptor axes may be involved in the pathogenesis of LPL cell-infiltrating WDL. This is an extremely rare case, and we have reported some considerations regarding the tumorigenesis of LPL cell-infiltrating WDL. Show less

Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing. We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor-α, interferon γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-12, interleukin-13, interleukin-15, interleukin-17A, interleukin-17F, interleukin-18, interleukin-21, interleukin-22, interleukin-23, interleukin-27, and interleukin-33 was measured by quantitative real-time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission. Ten cytokines, including interleukin-2, interleukin-4, interleukin-8, interleukin-10, interleukin-12, interleukin-15, interleukin-17A, interleukin-21, interleukin-23, and interleukin-33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin-8 expression was the most useful predictor. In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin-8 expression was the most useful for predicting relapse. Show less

No therapeutic targets have been identified for lung squamous cell cancer (SqCC) which is the second most prevalent lung cancer because its molecular profiles remain unclear. This study aimed to unveil disease-related protein networks by proteomic and bioinformatic assessment of laser-microdissected cancerous cells from seven SqCCs compared with eight representative lung adenocarcinomas. We identified three network modules significant to lung SqCC using weighted gene co-expression network analysis. One module was intrinsically annotated to keratinization and cell proliferation of SqCC, accompanied by hypoxia-induced aerobic glycolysis, in which key regulators were activated (HIF1A, ROCK2, EFNA1-5) and highly suppressed (KMT2D). The other two modules were significant for translational initiation, nonsense-mediated mRNA decay, inhibited cell death, and interestingly, eIF2 signaling, in which key regulators, MYC and MLXIPL, were highly activated. Another key regulator LARP1, the master regulator in cap-dependent translation, was highly suppressed although upregulations were observed for hub proteins including EIF3F and LARP1 targeted ribosomal proteins, among which PS25 is the key ribosomal protein in IRES-dependent translation. Our results suggest an underlying progression mechanism largely caused by switching to the cap-independent, IRES-dependent translation of mRNA subsets encoding oncogenic proteins. Our findings may help to develop therapeutic strategies to improve patient outcomes. Show less

Long-term survival of patients with neonatal-onset carbamoyl-phosphate synthetase 1 deficiency (CPS1D), an autosomal recessive disorder characterized by repeated, life-threatening hyperammonemia, is rare. We describe the diagnosis and clinical management of a teenager with neonatal-onset CPS1D who did not undergo therapeutic liver transplantation. Following emergent neonatal therapy, the patient was diagnosed with CPS1D based on clinical, radiological, biochemical and genetic analyses. Her clinical course, neurobehavioral development and therapeutic interventions are presented and discussed. Born from nonconsanguineous parents, the proband underwent phototherapy for neonatal jaundice, associated with acute encephalopathy, apnea and cerebral edema. Based on blood and urinary biochemical abnormalities, neonatal-onset CPS1D was diagnosed. Her hyperammonemia was corrected by hemodialysis, followed by sodium benzoate, L-arginine, levocarnitine and protein-free diet therapy. Because of a relapse and persistent neurobehavioral regression by age 1, a planned liver transplantation was cancelled. At age 10, sodium phenylbutyrate was substituted as ammonia scavenger. Genetic testing revealed compound heterozygote c.2359C>T (R787X) and c.236+6T>C variants of CPS1, confirming her diagnosis. Despite severe neurological sequelae, the patient is 16 and in stable condition. Our case suggests that early hemodialysis and pharmacologic interventions for acute neonatal hyperammonemia can improve the prognosis of patients with neonatal-onset CPS1D. Show less

The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)-namely glucagon gene knockout (GcgKO) mice-administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg-Gipr double knockout (DKO) mice. GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival. Show less

Niemann-Pick C1-like 1 (NPC1L1), ATP-binding cassette (ABC)G5, and ABCG8 mediate intestinal cholesterol absorption. It is unclear whether pravastatin (PR) or ezetimibe (EZ) affect expression of these transporters. We examined the effects of PR and EZ on NPC1L1, ABCG5, and ABCG8 expression in human hepatoma HepG2 cells and the murine small intestine. We also assessed expression of the transcription factors liver X receptor (LXR)a, LXRb and sterol regulatory element-binding protein. Transporter mRNA levels were determined in murine small intestines 6 and 24 h after oral PR and EZ administration by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). In PR- and EZ-treated HepG2 cells, transporter and transcription factor mRNA and protein levels were examined by RT-PCR and western blot, respectively. Significant decreases in NPC1L1, ABCG5, and ABCG8 mRNA expression were observed in the duodenum, but not jejunum and ileum, of mice 24 h after treatment with PR, but not EZ. In HepG2 cells, PR but not EZ treatment for 24 h also significantly decreased NPC1L1 protein and ABCG5, and ABCG8 mRNA expression, while increasing LXRa mRNA levels. PR but not EZ treatment reduced duodenal cholesterol transporter expression in mice. PR-induced increases in LXRa mRNA levels may be involved in attenuation of NPC1L1 expression, subsequently decreasing intestinal cholesterol absorption. Show less

Activation of the Wnt signaling pathway is frequently observed in hepatocellular carcinoma (HCC), though mutation of three of its components, CTNNB1, AXIN1, and AXIN2, is observed substantially less often. We examined the relationship between Wnt signaling and epigenetic alteration of secreted frizzled-related protein (SFRP) genes in HCC. We frequently detected the active form of beta-catenin and accumulation of nuclear beta-catenin in liver cancer cell lines. We detected methylation of SFRP family genes in liver cancer cell lines (SFRP1, 9/12, 75%; SFRP2, 7/12, 58%; SFRP4, 3/12, 25%; SFRP5, 7/12, 58%) and primary HCCs (SFRP1, 9/19, 47%; SFRP2, 12/19, 63%; SFRP5, 8/19, 42%), though methylation of SFRP4 was not found in primary HCCs. SFRP methylation also was detected in hepatitis B or C virus-associated chronic hepatitis (SFRP1, 6/37, 16%; SFRP2, 14/37, 38%; SFRP5, 5/37, 14%) and liver cirrhosis (SFRP1, 10/28, 36%; SFRP2, 9/28, 32%; SFRP5, 3/28, 11%), suggesting that methylation of these genes is an early event in liver carcinogenesis. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor (TCF/LEF) transcriptional activity in liver cancer cells, while overexpression of a beta-catenin mutant and depletion of SFRP1 using siRNA synergistically upregulated TCF/LEF transcriptional activity. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in HCC, and suggest that their loss of function contributes to activation of Wnt signaling during hepatocarcinogenesis. Show less

In the yeast, Saccharomyces cerevisiae, cell size is affected by the kind of carbon source in the medium. Here, we present evidence that the Gpr1 receptor and Gpa2 Galpha subunit are required for both maintenance and modulation of cell size in response to glucose. In the presence of glucose, mutants lacking GPR1 or GPA2 gene showed smaller cells than the wild-type strain. Physiological studies revealed that protein synthesis rate was reduced in the mutant strains indicating that reduced growth rate, while the level of mRNAs for CLN1, 2 and 3 was not affected in all strains. Gene chip analysis also revealed a down-regulation in the expression of genes related to biosynthesis of not only protein but also other cellular component in the mutant strains. We also show that GPR1 and GPA2 are required for a rapid increase in cell size in response to glucose. Wild-type cells grown in ethanol quickly increased in size by addition of glucose, while little change was observed in the mutant strains, in which glucose-dependent cell cycle arrest caused by CLN1 repression was somewhat alleviated. Our study indicates that the yeast G-protein coupled receptor system consisting of Gpr1 and Gpa2 regulates cell size by affecting both growth rate and cell division. Show less