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The purpose of this review was to establish what cancer education programs have been carried out aimed at adolescents and young adults (AYAs) and what outcomes they achieved. The databases used were MEDLINE, CINAHL, and Web of Science, and the search period was set as 2011-2020. The extracted literature was evaluated for quality using the Joanna Briggs Institute's critical appraisal tools. The subjects of the analysis were 29 studies: 10 randomized controlled trials and 19 quasi-experimental designs. Regarding the varieties of cancers found in the data, in descending order, 10 documents looked at cervical cancer, 9 looked at cancer in general, and 4 looked at breast cancer. Most studies focused on AYAs exclusively, with just three studies involving their parents simultaneously. Many studies used lecture-based intervention, with information technology-based interventions using websites and cell phones. Topics included in the program were cancer epidemiology, cancer risk factors, cancer warning signs and symptoms, prevention methods, and screening methods. After the intervention, all studies showed statistically significant improvements in at least one outcome measure, which included knowledge and awareness of cancer, health beliefs, and intent to take preventive action, demonstrating a basis for educational intervention. Educating AYAs about cancer at a time when their ways of life are becoming more concrete can be expected to have a positive impact on cancer preventing behaviors in adulthood, increase their parents' awareness of cancer, and have a positive impact on behavior around screening.

Aim The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB). Methods In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks. Results A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient. Conclusion The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

Non-alcoholic fatty liver disease (NAFLD) occurs in patients with components of metabolic syndrome such as type 2 diabetes mellitus (T2DM). At present, the central pathophysiological problem in patients afflicted with NAFLD is insulin resistance. In this study, we aimed to determine the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, teneligliptin, on the development of NAFLD in ob/ob mice. Five-week-old male ob/ob mice were divided into 4 experimental groups as follows: a group in which they were fed a high carbohydrate diet (HCD) for 8 weeks (n=8) as controls (control group 1), a group in which they were fed HCD supplemented with 0.018% teneligliptin for 8 weeks (n=8) (teneligliptin group 1), a group in which they were fed HCD for 12 weeks (n=8) as controls (control group 2), and another group in which they were fed only HCD for 4 weeks, and the HCD was then supplemented with 0.018% teneligliptin for 8 weeks (n=8) (teligliptin group 2). Hepatic steatosis was observed in all mice in the control group fed the HCD, but only mild hepatic steatosis was observed in teneligliptin group 1. Mice in teneligliptin group 1 fed the diet containing teneligliptin had lower hepatic triglyceride (TG) and free fatty acid (FFA) levels. Mice in teneligliptin group 1 exhibited improvement of insulin resistance; however, those in teneligliptin group 2 did not show any improvement of insulin resistance. Our results thus suggest that teneligliptin may be used as a preventative, but not as a treatment drug for the development of NAFLD.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) represents approximately 85% of all primary liver cancer cases. Non-alcoholic fatty liver disease (NAFLD) is one of the risk factors for HCC. NAFLD occurs in patients with components of metabolic syndrome, such as type 2 diabetes mellitus, obesity, hypertension and hyperlipidemia. Therefore, hyperlipidemia also represents a patient population at risk for HCC that can readily be identified. Rosuvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has exhibited a more potent affinity for the active site of HMG-CoA reductase than other statins. In addition, the hepatic uptake of rosuvastatin in rats has been found to be more selective and efficient than that with other drugs. Furthermore, the cytoprotective effects of rosuvastatin against ischemic injury have been clearly reported. Thus, in this study, we aimed to determine the role of rosuvastatin as a preventive drug in HCC associated with NAFLD. STAM mice, which developed HCC from NAFLD by being fed a high-fat diet (HFD), were divided into a group in which a HFD was given to the mice for 15 weeks (n=8) and another in which a HFD supplemented with 0.00125% rosuvastatin was given to the mice for 15 weeks (n=8). Rosuvastatin inhibited the development of hepatic tumors in the mice with NAFLD induced by a specific diet both macroscopically and histologically. Rosuvastatin significantly decreased the expression levels of pro-inflammatry cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β1. Tumor aggressiveness is mediated by angiogenic factors. Therefore, we examined the hepatic mRNA expression of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF). The hepatic expression of these factors significantly decreased in the rousvastin-fed mice. Our results thus suggest rosuvastatin that prevents carcinogenesis and improves the hepatic background. Our data suggest that rosuvastatin has potential for use as a preventive drug for the development of HCC associated with NAFLD in mice.

Pseudomyxoma peritonei (PMP) is characterized by extensive mucinous ascites following rupture of mucinous neoplasms of an intra-abdominal origin, and contain secreted gel-forming mucins such as MUC2 and MUC5AC. We encountered a 66-year-old Japanese man complaining of abdominal distension. Ascites at the site was gelatinous upon gross examination, and needle aspirate smears showed histiocytes and many mucinous balls wrapped in spindle cells, which were positive for vimentin, pan-cytokeratin, and podoplanin. The cell block showed several adenocarcinoma clusters, which were positive for MUC2, MUC5AC, CK20, and CDX-2, and negative for CK7. From these findings, a diagnosis of PMP arising from colon cancer was indicated. Cytoreductive surgery was performed, and the cystic diverticulum was found to be infiltrated by tumor cells in the sigmoid colon that caused PMP. Mucinous balls surrounded by mesothelial cells and MUC2-positive adenocarcinoma cells are useful clues in the diagnosis of PMP. Diagn. Cytopathol. 2016;44:628-631. © 2016 Wiley Periodicals, Inc.

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγnull mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12+IL-10−CD163−CD14+ cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1+CD163+CD14+ cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12−IL-10−CCL1−CD163−CD14+ cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.

Two hepatic macrophage (MΦ) populations have been described in the inflamed liver: F4/80+CD11b+ cells and F4/80+CD68+ cells. In normal conditions, hepatic F4/80+CD11b+ cells are involved in host antibacterial resistance. However, these cells in total body irradiated mice (TBI mice) are unfunctional for the elimination of bacteria translocated from intestinal tracts. In this study, the properties of hepatic MΦ populations in TBI mice were characterized. Normal mice and mice 7 days after exposure to 4 Gy of X-rays were infected i.v. with 107 CFU/mouse of Enterococcus faecalis (E. faecalis). Three day after infection, F4/80+CD11b+ cells and F4/80+CD68+ cells isolated from the liver of these mice were cultured for 24 hrs, and culture fluids were assayed for IL-12, IL-10 and CCL1 by ELISA. NSG mice were inoculated i.v. with these MΦ preparations (2 × 105 cells/mouse), then infected i.v. with 5 × 104 CFU/mouse of E. faecalis. In the results, all TBI mice died within 2 weeks, while all normal mice survived. IL-12 was produced by F4/80+CD11b+ cells from normal mice, but not by both MΦ preparations from TBI mice. IL-10 was produced by F4/80+CD68+ cells from TBI mice (529.9 ± 272.6 pg/ml) and normal mice (445.8 ± 147.7 pg/ml). Large amounts of IL-10 (912.1 ± 103.7 pg/ml) was produced by F4/80+CD11b+ cells from TBI mice, and these cells produced CCL1 (327.5 ± 9.1 pg/ml), while other MΦ preparations did not. NSG mice inoculated with F4/80+CD11b+ cells from normal mice were resistant to infection; however, NSG mice inoculated with F4/80+CD11b+ cells from TBI mice did not. These results indicate hepatic F4/80+CD11b+ cells are polarized to M2bMΦ in response to total body irradiation, and these MΦ are involved in the decreased host antibacterial resistance in TBI mice.

Purpose This study's primary goal was to evaluate the safety profile, tolerability, pharmacokinetics, and dose proportionality of BI 425809, a potent and selective inhibitor of glycine transporter 1, in healthy Chinese and Japanese subjects. Methods This single center, double-blind, single-rising dose study conducted in Korea randomly assigned (3:1) subjects within each ethnic subgroup (Chinese and Japanese) to receive a single dose of BI 425809 (10, 25, or 50 mg) or placebo. The primary end point was number (%) of subjects with drug-related adverse events (AEs). Secondary end points included AUC, Cmax, tmax, and t½ for BI 425809 in plasma. The CL/F and volume of distribution (Vz/F) were also measured. Findings Of the 49 subjects enrolled into the study (24 Chinese, 25 Japanese), 36 were randomly assigned to receive BI 425809 (12 per dose group) and 13 to receive placebo. All subjects were analyzed for the primary end point and completed the study. Overall, 4 of 49 subjects (8.2%) reported ≥1 AE (placebo: n = 1, BI 425809: n = 3). One drug-related AE of moderate somnolence was reported by a Japanese subject who received placebo. In both subgroups, slightly lower than dose-proportional increases in exposure (AUC and Cmax) were observed with increasing dose. In addition, median tmax was 3.5–4.0 h, with a geometric mean t½ of 29.0–41.2 h. CL/F was similar between Chinese and Japanese subjects and increased with increasing dose (10–50 mg: 68.1–111 mL/min). Vz/F was 209–315 L and similar between the subgroups. Implications BI 425809 was generally well tolerated in healthy Chinese and Japanese subjects with no significant findings for tolerability. No apparent difference in the pharmacokinetic variables of BI 425809 was observed between Chinese and Japanese subjects. The safety profile results and pharmacokinetic exposure levels are consistent with previous trials in Caucasian subjects. ClinicalTrials.gov identifier: NCT02383888 .

Background/Aims: Diagnostic miss rate and time consumption are the two challenging limitations of small-bowel capsule endoscopy (SBCE). In this study, we aimed to know whether using of the blue mode (BM) combined with QuickView (QV) at a high reviewing speed could influence SBCE interpretation and accuracy. Materials and Methods: Seventy CE procedures were totally reviewed in four different ways; (1) using the conventional white light, (2) using the BM, [on a viewing speed at 10 frames per second (fps)], (3) using white light, and (4) using the BM (on a viewing speed at 20 fps). In study A, the results of (1) were compared with those of (2), and in study B, the results of (3) and (4) were separately compared with those of (1). Results: In study A, the total number of the vascular (P < 0.001) and the inflammatory lesions (P = 0.005) detected by BM was significantly higher than that detected by the white light. No lesion was found using the white light that was not detected by the BM. Moreover, the BM highly improved the image quality of all the vascular lesions and the erythematous ones from the nonvascular lesions. In study B, the total number of only the vascular lesions, detected by the BM on a rapid speed of viewing at 20 fps was significantly higher than that detected by the white light (P = 0.035). However, the true miss rate for the BM was 4%. Conclusion: BM imaging is a new method that improved the detection and visualization of the vascular and erythematous nonvascular lesions of SB as compared with the conventional white light imaging. Using of the BM at a slow viewing speed, markedly reduced the diagnostic miss rate of CE.

The beneficial effect of dipeptidyl peptidase-4 inhibition on diet-induced extra-pancreatic effects, especially on liver tissue remains poorly understood. Thus, we made the experimental designs as follows; five-week-old male ob/ob mice, which develop type 2 diabetic mellitus and nonalcoholic fatty liver disease by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks as control, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks. Hepatic steatosis was seen in all mice, but the mean grade of steatosis in the sitagliptin-administrated mice was significantly decreased. The acetyl-CoA concentrations were lower in sitagliptin-administrated mice, although the differences were not significant. However, the malonyl-CoA concentrations were significantly lower in sitagliptin-administrated mice. The expression of acetyl-CoA carboxylase 1 was inhibited in sitagliptin-administrated mice, irrespective of expressions of carbohydrate responsive element-binding protein (ChREBP) or sterol regulatory element-binding protein (SREBP)-1c. In conclusion, sitagliptin may affect the development of nonalcoholic fatty liver disease by inhibiting the production of malonyl-CoA and thus synthesis of fatty acids in the liver.

The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB).In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks.A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient.The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

Despite major advances in curative and palliative approaches, hepatocellular carcinoma (HCC) is still the third leading cause of cancer-related death worldwide. M1 macrophages (Mϕ) play a key role in host antitumor defenses in HCC. In our study, CD14+ cells were isolated from the peripheral blood of four groups of HCC patients (group-1, patients with stage 0 HCC; group-2, patients with stage A HCC; group-3, patients with stage B HCC; and group-4, patients with stage C HCC) and characterized phenotypically. Then, CD14+ cells from group-2 and group-3 HCC patients were induced to polarize and tested for their antitumor abilities in a chimera model of HCC patients. Human HCCs (HepG2 solid tumors) grew in a chimera model of group-3 patients (group-3 HCC chimeras) but not in a chimera model of group-2 patients (group-2 HCC chimeras). In response to HCC antigens, the majority of CD14+ cells from group-2 patients (group-2 CD14+ cells) switched to the M1 phenotype (IL-12+IL-10-iNOS+cells), whereas the majority of CD14+ cells from group-3 patients (group-3 CD14+ cells) did not switch to the M1 phenotype and continued to express M2b phenotypic properties (IL-12-IL-10+CCL1+iNOS-cells). Group-3 CD14+ cells showed M1Mϕ polarization after treatment with CCL1 antisense oligodeoxynucleotide (ODN). Therefore, our study indicates that anti-HCC defenses of group-3 HCC chimeras are improved after CCL1 antisense ODN treatment.

The relationships between the serum mineral concentrations and the endoscopic findings of esophageal varices have been poorly investigated. In this study, we investigated hepatitis virus-positive patients who had undergone a liver biopsy (n = 576) and 75 patients with compensated cirrhosis in order to evaluate the association of the zinc value with the severity of liver fibrosis and esophageal varices. The mean zinc values decreased with the progression of fibrosis (METAVIR score; F0-1: 71.3 ± 11.3, F2: 68.9 ± 11.7, F3: 66.3 ± 11.8, F4: 63.9 ± 15.0). In the hepatitis virus-related compensated cirrhosis, the mean zinc value decreased with the severity of varices (patients without varices: 66.3 ± 12.6, patients with low-risk varices: 62.5 ± 13.7, patients with high-risk varices: 55.6 ± 13.0). The zinc value was significantly lower in patients with varices than in those without varices (59.3 ± 13.6 vs 66.3 ± 12.6, p

Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumin levels despite 3 months of BCAA granule administration, they were administered 50 g of a flavored BCAA-enriched enteral nutrient twice daily, i.e., during the daytime and late evening. Serum albumin levels and major cirrhotic symptoms were examined 1, 3, and 5 months after treatment initiation. Serum albumin levels improved significantly 3 months after treatment initiation (3.14 ± 0.32 g/dl vs 3.5 ± 0.31 g/dl, p

Pseudomyxoma peritonei (PMP) is characterized by extensive mucinous ascites following rupture of mucinous neoplasms of an intra-abdominal origin, and contain secreted gel-forming mucins such as MUC2 and MUC5AC. We encountered a 66-year-old Japanese man complaining of abdominal distension. Ascites at the site was gelatinous upon gross examination, and needle aspirate smears showed histiocytes and many mucinous balls wrapped in spindle cells, which were positive for vimentin, pan-cytokeratin, and podoplanin. The cell block showed several adenocarcinoma clusters, which were positive for MUC2, MUC5AC, CK20, and CDX-2, and negative for CK7. From these findings, a diagnosis of PMP arising from colon cancer was indicated. Cytoreductive surgery was performed, and the cystic diverticulum was found to be infiltrated by tumor cells in the sigmoid colon that caused PMP. Mucinous balls surrounded by mesothelial cells and MUC2-positive adenocarcinoma cells are useful clues in the diagnosis of PMP. Diagn. Cytopathol. 2016;44:628-631. © 2016 Wiley Periodicals, Inc.

An 82-year-old woman with autoimmune hepatitis had been treated with 5 mg prednisolone (PSL) orally to maintain normal transaminase levels. The subsequent transaminase levels were elevated and remained unchanged despite increasing the dose of PSL to 20 mg and introducing ursodeoxycholic acid (UDCA) at a dose of 900 mg. This combined treatment with UDCA was, however, ineffective. Treatment with Saireito at a dose of 9.0 g in conjunction with PSL was then initiated, which led to the subsequent normalization of her transaminase levels. Oral administration of PSL was discontinued eight weeks after the co-administration of Saireito. The patient had a significant response to this treatment.

症例は80歳女性．近医で肝機能障害を指摘され，当科受診．AST 423 IU/l ， ALT 222 IU/l ，ALP 481 IU/l ，T-Bil 6.7 mg/dl と上昇，抗核抗体が160倍と陽性，IgGが3238 mg/dl と上昇し，またIgM-HA抗体が陽性であった．自己免疫性肝炎（AIH）の国際診断基準によるスコアが12点疑診であることから，背景にAIHの存在が示唆された．またRT-PCR法で血清HAV-RNAが検出されたことよりA型肝炎ウイルス（HAV）感染の存在も示唆された．安静にて経過観察を行ったが，AST，ALTの上昇が持続していたため，肝生検施行した．結果，AIHと矛盾しない組織所見であった．その後，プレドニゾロンの内服を開始し，速やかに肝機能の改善を認めた．背景に存在したAIHの急性増悪にHAV感染が併存したと考えられる高齢女性の一例を経験したので報告する．

AIM To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.

p59fyn, a protein tyrosine kinase belonging to the src-family, is involved in the regulatory mechanism of acute response to ethanol in the central nervous system. A previous report showed an association between src-family kinase activity and fatty acid oxidation, and it also reported that hepatic free fatty acid levels were low in Fyn−/− mice. We examined, using Fyn−/− mice whether Fyn is also involved in fatty acid metabolism and the development of pathological changes in the liver in response to chronic ethanol consumption. C57BL/6J Fyn−/− and Fyn+/+ mice were fed for 8 weeks with either a liquid diet comprising ethanol or one in which the calories from ethanol were replaced with carbohydrates. Chronic ethanol consumption for 8 weeks resulted in remarkable hepatic steatosis in Fyn+/+ mice but not in Fyn−/− mice. Chronic ethanol consumption induced a significant decrease in hepatic FFA and triglyceride levels in Fyn−/− mice. Levels of interleukin-6, which is associated with the enhancement of fatty acid oxidation, was also increased significantly in the livers of ethanol-fed Fyn−/− mice. The results suggest that Fyn is involved in the enhancement of fatty acid oxidation and the development of hepatic steatosis caused by chronic ethanol consumption.

Hepatocellular carcinoma (HCC) is the fifth common cancer in the world. In previous study, we reported that M2b monocytes which predominately generated in advanced-stage HCC patients were important target for HCC immunotherapy. Recently, an anti-PD-1 antibody has been approved for the treatment against HCC. In this study, we tried to analyzed for immunological characters of monocytes isolated from patients with several stages of HCC. From 2017 August to 2017 December, nine patients diagnosed as advanced-stage HCC patients and five patients diagnosed as early-stage HCC patients were enrolled in this study. Monocytes from peripheral blood of these patients were stained for anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody. These cells were analyzed for flow cytometry. Furthermore, five healthy donors were used for the control groups. In the results, a majority of monocytes from advanced-stage HCC patients were expressed PD-L1 (81.5 ± 14.7%) and PD-L2 (71.6 ± 18.5%), but not PD-1(20.2 ± 18.6%). And, monocytes from early-stage HCC patients were expressed PD-L1 (9.9 ± 4.1%), PD-L2 (38.74 ± 9.9%) and PD-1 (23.5 ± 9.8%). As the contorls, monocytes from healthy donors were not expressed PD-L1 (21.7 ± 5.5%), PD-L2 (31.7 ± 23.8%) and PD-1 (11.6 ± 6.4%). The PD-L1 expression in monocytes was increased as HCC progressed. These results indicate the PD-L1 expression may be used as a new marker for the classification of the cancer progression. And, PD-1−PD-L1+PD-L2+ monocytes which were predominantly generated in advanced-stage HCC patients, may target for the treatment of anti-PD-L1 antibody.

AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults.

There is limited data about the mucosal lesions of portal hypertensive enteropathy (PHE) detected by capsule endoscopy, and there is no scoring system to evaluate their severity. Our aim is to create a reliable scoring system for PHE, and to explore the possible usefulness of using transient elastograhy (TE) in that field. We compared the medical records of 31 patients with liver cirrhosis and portal hypertension with 29 control patients. We found that the mucosal lesions compatible with PHE were significantly more common in cirrhotic patients than in control patients (67.7% vs 6.9%, p

The susceptibility of mice to infectious complications is dramatically increased in an accompaniment with systemic inflammatory response syndrome (SIRS). Polymorphonuclear neutrophils with immunosuppressive ability (PMN-II) that appear in response to SIRS have been classified as one of the cells responsible for the increased susceptibility of mice with SIRS (SIRS mice) to sepsis induced by cecal-ligation and puncture (CLP). Since a high level of norepinephrine (NE) is demonstrated in the plasma of SIRS mice, in the present study, the role of NE on the appearance of PMN-II in SIRS mice was studied. Similar to SIRS mice, normal mice became susceptible to CLP-induced infectious complications after inoculation with NE-treated PMN. CCL2 and IL-10 (biomarkers for PMN-II) were equally produced by PMN-II prepared from SIRS mice and NE-treated PMN. However, CCL3 and IL-12 (biomarkers for immunostimulatory PMN, PMN-I) were not detected in culture fluids from either PMN preparation. These results indicate that NE mass-produced in association with SIRS development plays a role on the generation of PMN-II and the appearing PMN-II are responsible, in part, for increased susceptibility of SIRS mice to CLP-induced infectious complications.

Thermally injured mice are susceptible to Enterococcus faecalis translocation. In this study, the role of polymorphonuclear neutrophils (PMN) on the development of sepsis stemming from E. faecalis translocation was studied in SCID-beige (SCIDbg) mice depleted of PMN (SCIDbgN mice) or macrophages (Mφ) and PMN (SCIDbgMN mice). Sepsis was not developed in SCIDbgN mice orally infected with E. faecalis, while the orally infected pathogen spread systemically in the same mice inoculated with PMN from thermally injured mice (TI-PMN). SCIDbgMN mice were shown to be greatly susceptible to sepsis caused by E. faecalis translocation, while orally infected E. faecalis did not spread into sepsis in the same mice that were previously inoculated with Mφ from unburned SCIDbg mice (resident Mφ). In contrast, orally infected E. faecalis spread systemically in SCIDbgMN mice inoculated with resident Mφ and TI-PMN, while all SCIDbgMN mice inoculated in combination with resident Mφ and PMN from unburned SCIDbg mice survived after the infection. After cultivation with TI-PMN in a dual-chamber transwell, resident Mφ converted to alternatively activated Mφ, which are inhibitory on the generation of classically activated Mφ (typical effector cells in host antibacterial innate immunities). TI-PMN were characterized as immunosuppressive PMN (PMN-II) with abilities to produce cc-chemokine ligand-2 and IL-10. These results indicate that PMN-II appearing in response to burn injury impair host antibacterial resistance against sepsis stemming from E. faecalis translocation through the conversion of resident Mφ to alternatively activated Mφ.

Bombyx mori bidensovirus (BmBDV), which causes fatal flacherie disease in the silkworm, replicates only in midgut columnar cells. The viral resistance expressed by some silkworm strains, which is characterized as non-susceptibility irrespective of the viral dose, is determined by a single gene, nsd-2. We previously identified nsd-2 by positional cloning and found that this gene encodes a putative amino acid transporter that might function as a receptor for BmBDV. In this study, we investigated the relationship between the part of the midgut expressing nsd-2 (resistance gene), +(nsd-2) (susceptibility gene) and BmBDV propagation. Quantitative RT-PCR (qRT-PCR) analysis using total RNA isolated from the anterior, middle, and posterior parts of the midgut showed that nsd-2 and +(nsd-2) were strongly expressed in the posterior part of the midgut. The expression levels of both genes were very low in the anterior and middle parts. The qRT-PCR analysis showed that the expression levels of BmBDV-derived transcripts were correlated with the levels of +(nsd-2) expression. However, BmBDV-derived transcripts were clearly detected in all parts of the midgut. These results suggest that the infectivity of BmBDV depends mainly on the expression level of +(nsd-2) in the midgut and that viral infection is supported even by very faint expression of +(nsd-2). By contrast, the expression levels of +(nsd-2) were exceedingly low or undetectable in the middle part of the midgut, indicating that BmBDV infection might occur via another mechanism, independent of +(nsd-2), in the middle part of the midgut.

Smoking status, n (%) Never smoked 1 (12.5) 1 (20.0) 5 (83.3) 1 (14.3) 3 (50.0) 2 (28.6) 4 (66.7) 4 (80.0) 3 (50.0) 4 (66.7) 4 (66.7) 28 (45.2) Ex-smoker 1 (12.5) 1 (20.0) 1 (16.7) 1 (14.3) 0 (0.0) 2 (28.6) 2 (33.3) 1 (20.0) 2 (33.3) 1 (16.7) 1 (16.7) 12 (19.4) Currently smokes 6 (75.0) 3 (60.0) 0 (0.0) 5 (71.4) 3 (50.0) 3 (42.9) 0 (0.0) 0 (0.0) 1 (16.7) 1 (16.7) 1 (16.7) 22 (35.5) Alcohol status, n (%) Non-drinker 4 (50.0) 3 (60.0) 5 (83.3) 1 (14.3) 4 (66.7) 2 (28.6) 3 (50.0) 2 (40.0) 1 (16.7) 4 (66.7) 4 (66.7) 29 (46.8) Drinks, no interference 4 (50.0) 2 (40.0) 1 (16.7) 6 (85.7) 2 (33.3) 5 (71.4) 3 (50.0) 3 (60.0) 5 (83.3) 2 (33.3) 2 (33.3) 33 (53.2) Drinks, possible interference 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) *Treated set included all randomized subjects who received ≥1 dose of study medication. 1 Identical subjects consecutively received SD and MD treatment. BMI, body mass index; EM, extensive metabolizers; MD, multiple dose; PM, poor metabolizers; SD, single dose

Patients with severe burn injuries are extremely susceptible to infection, and the host's antibacterial responses are frequently suppressed by alternatively activated macrophages (M2Mphi), commonly demonstrated in these patients. An immunosuppressive subset of neutrophils (PMN-II), demonstrated in the peripheral blood of thermally injured patients, has been described as an inducer of M2Mphi. In the present studies, the inhibitory effect of glycyrrhizin (GL) on M2Mphi generation stimulated by PMN-II was examined. M2Mphi were generated from resident Mphi (R-Mphi, lower chamber) after cultivation with PMN-II (upper chamber) in a dual-chamber transwell. However, M2Mphi were not generated from R-Mphi when the same transwell cultures were performed in the presence of GL. M2Mphi were not generated from R-Mphi after cultivation with PMN-II previously treated with GL, while R-Mphi previously treated with GL converted to M2Mphi after they were cultured with PMN-II in transwells. Interleukin-10 and CCL2 released from PMN-II were shown to be effector molecules responsible for the generation of M2Mphi. However, these soluble factors were not produced by PMN-II treated with GL. These results indicate that GL inhibits PMN-II-stimulated M2Mphi generation through the inhibition of CCL2/interleukin-10 production by PMN-II.

DNA rich in non-methylated CG motifs (CpGs) enhances induction of immune responses against co-administered antigen encoding genes. CpGs are therefore among the promising adjuvants known to date. However, naked plasmid DNA, even which contains CpG motifs, are taken up by antigen presenting cells via the endocytosis pathway. Endocytosed DNAs are thus degraded and their gene expression levels are inefficient. In this context, an effective plasmid delivery carrier is required for DNA vaccine development. We show in the present study that packaging plasmids containing CpGs into fusogenic liposomes (FL) derived from conventional liposomes and Sendai virus-derived active accessory proteins is an attractive method for enhancing the efficacy of a DNA vaccine. These CpG-enhanced plasmids (possessing 16 CpG repeats) that were packaged into FL, enhanced ovalbumin (OVA)-specific T cell proliferation and cytotoxic T cell activity after immunization. In fact, vaccination with CpG enhanced plasmid-loaded FL induced effective prophylactic effects compared with 13 repeats CpG containing plasmid in a tumor challenge experiment. Thus, the development of a CpG-enhanced DNA-FL genetic immunization system represents a promising tool for developing candidate vaccines against some of the more difficult infectious, parasitic, and oncologic disease targets.

Previously, we have reported that the susceptibility of burned patients to infectious complications is increased when the production of CC-chemokine ligand 3 (CCL3) is impaired. In this study, the role of the sympathetic nervous system on impaired CCL3 production and antibacterial resistance following burn injuries was investigated. Normal mice were resistant (65% survival) to cecal ligation and puncture (CLP)-induced sepsis, while the same CLP killed 90% of thermally injured mice (TI-mice). However, TI-mice resisted CLP-induced sepsis (60% survival) when they were previously treated with CCL3 or sympathectomized with 6-hydroxydopamine (6-OHDA). Augmentation of host resistance against CLP-induced sepsis by 6-OHDA was abrogated by anti-CCL3 mAb treatment. Norepinephrine (NE) production was increased in circulation of TI-mice, and treatment of TI-mice with 6-OHDA resulted in the inhibition of NE secretion. CCL3 production was impaired in cultures of T cells from TI-mice or normal T cells treated with NE, even when stimulated with anti-CD3 mAb. However, CCL3 was produced by mAb-stimulated T cells from TI-mice previously treated with 6-OHDA. These results indicated that by inhibiting CCL3 production the sympathetic nervous system contributes to the increased susceptibility of TI-mice to sepsis.

Aims Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H1 receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children. Methods A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling. Results The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V1/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V1/F, volume of distribution of the peripheral compartment (V2/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V2/F and Ka; body weight on V2/F) were not statistically significant. No effect of age on CL/F, V1/F or V2/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90–117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the Cmax and AUC (25.6 ± 6.9 ng ml−1 and 246.8 ± 68.2 ng h ml−1) were almost same levels with those of adults after administration of 20 mg (26.9 ± 9.1 ng ml−1 and 281.6 ± 90.5 ng h ml−1). Conclusions A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults.

As Screening markers for hepatocellular Carcinoma (HCC), alpha-fetoprotein (AFP) and protein induced by an absence of vitamin K or antagonist-II (PIVKA-II) are widely used, but the sensitivity and specificity are not satisfactory enough. Neopterin is a biological marker for increased cell-mediated immunity, but has not been fully studied on HCC. To assess the clinical significance of serum neopterin as a screening marker for HCC, fifty-six HCC patients with liver cirrhosis (LC) and thirty-two LC patients without HCC as controls were studied. Serum neopterin level (n mol/L) was determined by immunoenzymatic assay. The sensitivity and specificity were analyzed by using ROC analysis. The mean level oi neopterin in HCC was significantly higher than that in LC (20.4 YS. 7.7 nmol/L, P

Neutrophils (PMN) have been described as critical effector cells in the host's antibacterial innate immunities. However, the classification of murine PMNs remains unclear. Here, we show that in addition to normal PMN (PMN-N), there are at least two distinct subsets of PMNs (PMN-I and PMN-II) distinguished as follows: (1) cytokine and chemokine production (PMN-I, IL-12/CCL3; PMN-II, IL-10/CCL2; PMN-N, no cytokine/chemokine production), (2) macrophage activation (PMN-I, classically activated macrophages; PMN-II, alternatively activated macrophages; PMN-N, no effect on macrophage activation), (3) Toll-like receptor (TLR) expression (PMN-I, TLR2/TLR4/TLR5/TLR8; PMN-II, TLR2/TLR4/TLR7/TLR9; PMN-N, TLR2/TLR4/TLR9), and (4) surface antigen expression (PMN-I, CD49d + CD11b − ; PMN-II, CD49d − CD11b + ; PMN-N, CD49d − CD11b − ). PMN-I was obtained from MRSA (methicillin-resistant Staphylococcus aureus )-resistant hosts, while MRSA-sensitive hosts were a source of PMN-II. PMN-N was obtained from naive mice. Anti-MRSA innate immunities might be influenced differently by these biochemically and physically distinguished PMNs. PMN-N may convert to PMN-I or PMN-II in response to host circumstance.