Masami Minemura

Analysis of the epitope and neutralizing capacity of human monoclonal antibodies induced by hepatitis B vaccine.

Hepatitis B virus (HBV) is an infectious agent that is a significant worldwide public health issue. However, the mechanism by which vaccination-induced antibodies prevent HBV infection remains unclear. To investigate the mechanism by which antibodies induced by hepatitis B surface Ag (HBsAg)-vaccination prevent HBV infection in humans, we prepared human monoclonal antibodies (mAbs) against HBsAg using a novel cell-microarray system from peripheral blood B-lymphocytes from vaccinated individuals. We then characterized the IgG subclass, L-chain subtype, and V-gene repertoire of the H/L-chain, as well as affinities of each of these mAbs. We also determined the epitopes of the individual mAbs using synthesized peptides, and the HBV-neutralizing activities of mAbs using the hepatocyte cell line HepaRG. Consequently, IgG1 and kappa chain was mainly used as the mAbs for HBsAg. Seventy percent of the mAbs bound to the loop domain of the small-HBsAg and showed greater neutralizing activities. There were no relationships between their affinities and neutralization activities. A combination of mAbs recognizing the first loop domain showed a synergistic effect on HBV-neutralizing activity that surpassed conventional hepatitis B-Ig (HBIG) in the HepaRG cell line assay. These results may contribute to the development of effective mAb treatment against HBV infection replacing conventional HBIG administration.

Ultrasound-Induced New Cellular Mechanism Involved in Drug Resistance

The acoustic effects in a biological milieu offer several scenarios for the reversal of multidrug resistance. In this study, we have observed higher sensitivity of doxorubicin-resistant uterine sarcoma MES-SA/DX5 cells to ultrasound exposure compared to its parent counterpart MES-SA cells; however, the results showed that the acoustic irradiation was genotoxic and could promote neotic division in exposed cells that was more pronounced in the resistant variant. The neotic progeny, imaged microscopically 24 hr post sonication, could contribute in modulating the final cell survival when an apoptotic dose of doxorubicin was combined with ultrasound applied either simultaneously or sequentially in dual-treatment protocols. Depending on the time and order of application of ultrasound and doxorubicin in combination treatments, there was either desensitization of the parent cells or sensitization of the resistant cells to doxorubicin action.

Neutrophil/lymphocyte ratio as a prognostic indicator of hepatic arterial infusion chemotherapy with arterial cisplatin plus continuous 5-fluorouracil.

Hepatic arterial infusion (HAIC) therapy may be a therapeutic option for advanced hepatocellular carcinoma (HCC) in addition to administration of sorafenib, which is the only currently established standard regimen for this disease. Survival benefit of HAIC has been reported in patients positive for antitumor response. Therefore, the prediction of antitumor response is important in decision‐making for HAIC treatment.

A case of primary biliary cirrhosis that progressed rapidly after treatment involving rituximab.

Primary biliary cirrhosis (PBC) is a progressive liver disease for which limited therapies are recommended. Rituximab, an anti-CD20 monoclonal antibody, is expected to be a useful therapeutic regimen for PBC. Previous studies indicated biochemical and immunological improvement in PBC after rituximab treatment. Although rituximab shows therapeutic potential for PBC, few cases have been reported and histological improvement and long-term outcome remain uncertain. Here, we report a case of PBC in a 66-year-old Japanese female patient who presented with a gastric lymphoma and who had been treated with a regimen containing rituximab for incidental malignant lymphoma. She showed biochemical and immunological improvements, and liver histology before and after rituximab treatment confirmed a decrease in liver inflammation. However, she developed liver cirrhosis a short time after rituximab treatment without biochemical or immunological worsening. Rituximab treatment for PBC might be considered and careful observation is required after treatment.

Neutrophil-to-lymphocyte ratio predicts recurrence after radiofrequency ablation in hepatitis B virus infection

Radiofrequency ablation (RFA) is an established treatment for small hepatocellular carcinoma (HCC) wherein non‐recurrence is essential for long‐term survival. Recently, neutrophil‐to‐lymphocyte ratio (NLR), a marker of systemic inflammation that is associated with tumor‐associated macrophages (TAMs), was suggested to be a prognostic marker of HCC treated with RFA. Therefore, we evaluated predictive factors, including NLR, associated with recurrence after curative RFA.

Differential cytotoxicity and sonosensitization by sanazole: effect of cell type and acoustic parameters.

PurposeAlthough sanazole has been used as a hypoxic radiosensitizer, we recently reported on its ability to sensitize U937 cells to hyperthermia and X-irradiation under aerobic conditions, enhancing apoptotic cell death following the combined treatment. The current study was undertaken to evaluate the effect of sanazole as a sonosensitizer under previously studied acoustic conditions of different pulse repetition frequencies, using two cell lines representative of solid tumours and haematopoietic cancers.MethodsCells were treated with different doses of sanazole. Flow-cytometric analysis and DNA fragmentation assay were carried out at different times, and morphological features were also inspected. For ultrasound treatment, cells were pre-incubated with a non-cytotoxic dose of sanazole for 30xa0min before exposure. Evaluation of cell killing and a parallel examination of intracellular oxidative stress levels in both cell lines were performed using flow cytometry.ResultsSanazole alone displayed selective cytotoxic effects towards solid tumour-derived cancer cells, resulting in complete cell death after 24xa0h of treatment, and enhanced the ultrasound-induced cell killing 6xa0h post-treatment. The enhancement seemed to be mediated by an additive increase in intracellular oxidative stress levels.ConclusionSanazole seems to be an efficient cytotoxic agent for the treatment of solid tumours and a promising sonosensitizer under aerobic conditions.

Docetaxel inhibits progression of human hepatoma cell line in vitro and is effective in advanced hepatocellular carcinoma

Background:u2002 Current chemotherapy for advanced hepatocellular carcinoma (HCC) is insufficient; only sorafenib has been proven to provide a modest survival benefit. A future direction of chemotherapy is to tailor treatment based on the chemosensitivity of each individual tumor. By doing so, only patients who stand to benefit from therapy will be exposed to potential side‐effects and morbidity. Although the use of docetaxel (DTX) for the treatment of lung, breast and gastric cancer has been reported, there are few reports about its use in the setting of HCC.

Serum microRNA profiles in patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, or drug-induced liver injury

PURPOSEnSome blood biomarkers or histological examination by liver biopsy are used for the diagnosis of liver diseases in clinics. However, conventional blood biomarkers show poor specificity and sensitivity, and liver biopsy is highly invasiveness. Therefore, to overcome such disadvantages, specific/sensitive and noninvasive options are desirable. In recent years, circulating microRNAs (miRNAs) have been acknowledged for their potential as disease markers. Actually, several miRNAs have been reported to be biomarker candidates of liver diseases. However, these earlier studies were performed for one disease. Therefore, the specificity as biomarkers was not guaranteed, because they didnt study for the other types of liver injury. In this study, we examined if circulating miRNA could distinguish different types of liver diseases.nnnMETHODSnSerum miRNA profiles in 28 patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis or drug-induced liver injury as well as 4 control subjects were determined by TaqMan MicroRNA Array analysis. Principal component analysis (PCA) of selected miRNAs was performed.nnnRESULTSnWe identified 37 miRNAs whose levels were significantly different between any of the groups. Although individual miRNAs could not distinguish different types of liver diseases, probably because of similar liver pathology, their profiling by PCA could classify different liver disease groups.nnnCONCLUSIONSnThe profiling of the selected miRNAs can be useful to distinguish different types of liver diseases.

Sneddon-Wilkinson disease induced by sorafenib in a patient with advanced hepatocellular carcinoma.

Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC), although it is known to cause a variety of dermatologic adverse events. Subcorneal pustular dermatosis (SCPD), also known as Sneddon-Wilkinson disease, is a rare skin eruption that accompanies various systemic disorders and may become chronically progressive. We herein describe the case of a patient who developed SCPD after sorafenib administration. The dermatologic reaction was improved by the cessation of sorafenib and worsened by its readministration. Clinicians treating HCC patients with sorafenib should be aware of the possibility of SCPD.

Effective healing of endoscopic submucosal dissection-induced ulcers by a single week of proton pump inhibitor treatment: a retrospective study

BackgroundAlthough artificial ulcers generally heal faster than Helicobacter pylori-related or nonsteroidal anti-inflammatory drug-related peptic ulcers, endoscopic submucosal dissection (ESD)-induced gastric ulcers are usually treated with a proton pump inhibitor (PPI) for 4–8 weeks. The effect of oral administration of a PPI for 1xa0week on ESD-induced gastric ulcers has not yet been evaluated. In the present study, we evaluated the efficacy of oral PPI for 1xa0week in patients with ESD-induced ulcers.MethodsWe selected 45 patients who underwent ESD for gastric mucosal tumors between June 2005 and July 2006 at Toyama University Hospital, and who met our inclusion criteria. All patients received omeprazole intravenously for 2xa0days after ESD and then orally for 1xa0week to prevent bleeding. Twenty two patients received no further omeprazole therapy (1-week group) and the rest received omeprazole orally for 7 more weeks (8-week group). Follow-up endoscopy was performed at 1xa0day, 4xa0weeks, and 8xa0weeks after ESD. We compared the ulcer healing rates between both groups.ResultsThere were no significant differences between the groups in the ulcer-healing rate, because ulcers healed in 22 (96%) and 20 (91%) patients from the 8-week and 1-week groups, respectively.ConclusionsIn our study, oral administration of omeprazole for 1xa0week was sufficient to achieve healing of ESD-induced artificial gastric ulcers. A larger prospective trial will be required to confirm these findings.