Biology subjects

Atsukawa, M.

Publications and source records attributed to Atsukawa, M..

3 recordsLinked to original sources

bioRxiv2022

Prediction of elimination of intrahepatic cccDNA in hepatitis B virus-infected patients by a combination of noninvasive viral markers

Evaluation of intrahepatic covalently closed circular DNA (cccDNA) is a key for searching an elimination of hepatitis B virus (HBV) infection. HBV RNA and HBV core-related antigen have been proposed as surrogate markers for evaluating cccDNA activity, although they do not necessarily estimate the amount of cccDNA. Here, we developed a novel multiscale mathematical model describing intra- and inter-cellular viral propagation, based on the experimental quantification data in both HBV-infected cell culture and humanized mouse models. We applied it to HBV-infected patients under treatment and developed a model which can predict intracellular HBV dynamics only by use of noninvasive extracellular surrogate biomarkers. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well-correlated with the liver biopsy data. Thus, our noninvasive method enables to predict the amount of cccDNA in patients and contributes to determining the treatment endpoint required for elimination of intrahepatic cccDNA.

microbiology↗

bioRxiv2021

The impact of PNPLA3 and TM6SF2 in cirrhosis related complications

Patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6-superfamily member 2 (TM6SF2) polymorphisms have major impact for fibrosis due to steatohepatitis. However, there are scant data about correlations between cirrhosis-related complications and the polymorphisms of these genes. Therefore, we aimed to determine the role of the PNPLA3 and TM6SF2 polymorphisms in fibrosis progression for patients with liver cirrhosis. A multicenter study was performed at six hospitals in Japan enrolling 400 patients with liver cirrhosis caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33). These cirrhotic patients included those with complications of variceal bleeding, hepatic ascites, and/or hepatic encephalopathy and those without. To assess the role of the PNPLA3 and TM6SF2 polymorphisms in patients with cirrhosis related complications, we calculated the odds ratio and relative risk for the rs738409 and rs58542926 polymorphisms. We also accessed whether or not the interaction between these two polymorphisms contributed to cirrhosis related complications. As a result, the odds ratio for complications in the NAFLD group significantly increased in the presence of the rs738409 GG genotype when the CC genotype was used as the reference. There were no significant risks between complications and the presence of the rs738409 G allele in the virus or alcohol groups. There were no significant risks of complications in the frequency of the rs58542926 T polymorphism regardless of the etiology of liver cirrhosis. The interaction between the rs738409 and rs58542926 polymorphisms had the highest odds ratio of 2.415 for complications in the rs738409 GG + rs58542926 (CT+TT) group when rs738409 (CC+CG) + TM6SF2 CC was used as the reference in the NAFLD group although there was no statistically interaction between these gene polymorphisms (P=0.085).

genetics↗

bioRxiv2018

Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

BackgroundBecause human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2.\n\nMethodsWe examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro.\n\nResultsSupplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fc{gamma}-RIIIA polymorphism. NK cells with Fc{gamma}-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fc{gamma}-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fc{gamma}-RIIIA polymorphism.\n\nConclusionsThese results demonstrated that in Fc{gamma}-RIIIA-VV/VF-carrying hosts, trastuzumab plus CD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cells. This also indicates the therapeutic potential for unresectable human pancreatic cancer, in which HER-2 expression is generally low.

immunology↗