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Aim To investigate the therapeutic effect of lenvatinib (LEN) in liver disease etiology, especially nonviral hepatocellular carcinoma (HCC). Methods and Results Sixty‐seven patients with unresectable advanced HCC (u‐HCC) treated with LEN and consisting of 26 hepatitis C virus (HCV), 19 hepatitis B virus (HBV), 11 alcohol, and 11 nonalcoholic steatohepatitis (NASH) cases were retrospectively recruited. Univariate and multivariate Cox proportional hazard models were used to determine predictive factors for survival. The objective response rate in the nonviral (alcohol and NASH) group was higher than that in the viral group (59.1% [13/22] vs. 46.7% [21/45]). Progression‐free survival was significantly longer in the nonviral group than in the viral group (13.7 vs. 6.6 months; hazard ratio [HR] 0.324; 95% confidence interval [CI] 0.174–0.602; P, Kaplan–Meier analysis of progression‐free survival among patients with unresectable advanced hepatocellular carcinoma treated with lenvatinib according to etiology. The PFS in the non‐viral group was significantly longer than that in the viral group. Our results suggest that LEN is more effective against non‐viral u‐HCC than against viral u‐HCC.

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group (p < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC50 of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.

Background & AimsThe efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line treatment of LEN, investigated the sensitivity of SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and their signal transduction pathway by protein array analysis.MethodsWe retrospectively enrolled 57 unresectable HCC patients. Radiologic responses in 53 patients were evaluated by modified Response Evaluation Criteria in Solid Tumors. Active signal transduction pathways in cells were identified by protein array analysis, including 1205 proteins.ResultsPatients comprised 34 tyrosine kinase inhibitor (TKI)-naive (first-line), nine SOR-intolerant (second-line), and ten resistant to regorafenib (third-line). Objective response rates (ORRs) were 61.8% (21/34) in TKI-naive, 33.3% (3/9) in second-line, and 20.0% (2/10) in third-line groups. The overall survival (OS) and the progression free survival (PFS) in the first-line was significantly longer than those in third-line group (p50 value of LEN against PLC/PRF5-R2 cells (30 μM) was significantly higher than that against PLC/PRF5 cells (6.4 μM). LEN inhibited significantly more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than PLC/PRF5-R2 cells.ConclusionsLEN was active and safe as a second/third-line treatment for unresectable HCC. LEN seems to be more effective for HCC patients with better hepatic reserve function or before TKI-resistance is acquired because of partial cross-resistance to SOR.

The mechanism of resistance to sorafenib in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the miRNAs responsible for resistance. Drug sensitivity, migration/invasion capabilities, and epithelial-mesenchymal transition (EMT) properties were analyzed by biochemical methods. The clinical relevance of the target genes to survival in HCC patients were assessed using a public database. Four miRNAs were significantly upregulated in PLC/PRF5-R1/-R2 compared with PLC/PRF5. Among them, miR-125b-5p mimic-transfected PLC/PRF5 cells (PLC/PRF5-miR125b) and showed a significantly higher IC50 for sorafenib compared with controls, while the other miRNA mimics did not. PLC/PRF5-miR125b showed lower E-cadherin and higher Snail and vimentin expression—findings similar to those for PLC/PRF5-R2—which suggests the induction of EMT in those cells. PLC/PRF5-miR125b exhibited significantly higher migration and invasion capabilities and induced sorafenib resistance in an in vivo mouse model. Bioinformatic analysis revealed ataxin-1 as a target gene of miR-125b-5p. PLC/PRF5 cells transfected with ataxin-1 siRNA showed a significantly higher IC50, higher migration/invasion capability, higher cancer stem cell population, and an EMT phenotype. Median overall survival in the low-ataxin-1 patient group was significantly shorter than in the high-ataxin-1 group. In conclusion, miR-125b-5p suppressed ataxin-1 and consequently induced Snail-mediated EMT and stemness, leading to a poor prognosis in HCC patients., The mechanism of resistance to multikinase inhibitors in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the responsible miRNAs and target genes involved in the mechanism of resistance. Four miRNAs were significantly upregulated. Among them, we found that miR-125-5p induced sorafenib resistance in HCC cells and in a mouse model. We also revealed that miR-125-5p suppressed ataxin-1 as a target gene and consequently induced Snail-mediated epithelial-mesenchymal transition (EMT) and cancer stemness. Moreover, we demonstrated that ataxin-1 expression has an impact on the prognosis of patients with HCCs. In the future, by comparing the expression status of miR-125b-5p/ataxin-1 and the effect of sorafenib in the clinical setting, it is expected that miR-125b-5p will be established as an effective drug selection marker for treatment selection in patients with HCC.

BackgroundThe prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels.ObjectiveTo measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT.MethodsAmong 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS.ResultsThe prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p ConclusionsAlthough NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.

485 Background: No information is available on the efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy. We evaluated the characteristics and the therapeutic efficacy and safety of LEN as a second- and third-line treatment as well as first- treatment for unresectable HCC patients in clinical settings. Moreover, to rationalize these clinical findings in vitro, we assessed the anti-tumor activity of LEN on SOR-resistant cell line and performed a comprehensive phosphorylated protein array analysis associated with 377 signal transduction pathways using SOR-resistant and parental HCC cells. Methods: We retrospectively enrolled 51 unresectable HCC patients. Radiologic responses in 41 patients were evaluated by modified RECIST. Active signal transduction pathways in the cells were identified by protein array analysis, including 1205 proteins. Results: The evaluated patients comprised 25 TKI-naive (first- line), 7 intolerant to SOR (second-line), and 9 patients resistant to regorafenib (third-line). The ORRs were 64% in first-line, 42.8% in second-line, and 22.2% in third-line groups (first-line vs. third-line p< 0.05). The OS in the first-line was significantly longer than that in third-line group ( p< 0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated in the second/third-line treatment. The IC50 value of LEN against PLC/PRF5-R2 (30 μM) was significantly higher than that against PLC/PRF5 (6.4 μM). LEN significantly inhibited more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than in PLC/PRF5-R2 cells. Conclusions: Our study indicates that LEN was active and safe in the second/third-line treatment for unresectable HCC. LEN seems more effective for HCC patients with better hepatic reserve function, or before TKI-resistance is acquired because of the partial cross-resistance to SOR.

Background Although many patients still have anxiety about upper gastrointestinal (GI) endoscopy, there have been few reports on the influence of distractions for a person who is going to undergo upper GI endoscopy soon. This study was a prospective randomized controlled study investigating the influence of distractions, such as auditive and visual distractions using subjective and objective assessments including autonomic nervous function prior to upper GI endoscopy. Methods 206 subjects who underwent upper GI endoscopy as regular health check-ups were divided randomly into 4 groups prior to upper GI endoscopy; group 1 (control group), group 2 (auditive group), group 3 (visual group), and group 4 (combination group). We measured vital signs, autonomic nervous function, profile of mood state (POMS), and the impression for upper GI endoscopy pre- and post-distraction in the 4 groups. Results There was no significant difference in vital signs between 5 and 15 min after sitting in group 1, however, several vital signs in all distraction groups improved significantly after distraction (Pulse rate (P): p

A renal subcapsular hematoma rarely occurs without a history of trauma. It has been reported as a complication of urological interventions and also reported to occur spontaneously in patients with renal malignancies. However, there are no previous reports of renal subcapsular hematomas occurring in connection with abdominal angiography. We report here a case of a renal subcapsular hematoma that developed and was recognized during abdominal angiography for treatment of hepatocellular carcinoma (HCC). An 80-year-old male was referred to our hospital for transarterial embolization for multiple HCCs. His past medical history included hypertension. His laboratory data showed slightly decreased number of platelets and hepaplastin test due to liver cirrhosis. When computed tomography angiography was performed, a 7-cm subcapsular hematoma developed and was recognized over the right kidney during the procedure. He was successfully managed supportively with blood transfusion, tranexamic acid and antibiotics. Since thrombocytopenia and hypertension are reportedly risk factors for hematoma formation, careful manipulation is required during angiography in HCC patients with liver cirrhosis and hypertension. It must be kept in mind that rare complications, such as a renal subcapsular hematoma, can happen during abdominal angiography for diagnostic and interventional treatment of HCC.

This paper discusses various design aspects and experimental results regarding the selection of bearing materials in combination with different shaft materials utilized by electric water pumps. Acceleration tests have been conducted prior to endurance life tests which simulate actual automotive applications. The potential dangers of severe wear in certain material combinations is also discussed.

For efficient antibacterial photodynamic therapy for wounds, information on the distribution of a photosensitizer in tissue is important, but conventional fluorescence measurement does not provide depth-resolved information. We previously proposed in vivo photoacoustic (PA) depth profiling of a photosensitizer, but the contrast of PA signals was not sufficiently high, mainly due to light absorption by blood in tissue. In this study, we performed dual-wavelength PA measurement; green light and red light were used to excite blood and photosensitzer, respectively, and the former signal was subtracted from the latter signal to compensate a blood-associated component. Methylene blue or porfimer sodium solution was injected into subcutaneous tissue in rats with deep dermal burn and two-dimensional PA measurement was performed. The signal subtraction diminished not only the signal originating from blood but also the signal originating from the stratum corneum and acoustic reflection noise, creating a high-contrast PA image. The distribution of PA signals was confirmed to coincide well with the distribution of photosensitizer-originating fluorescence measured for tissue biopsied after the PA measurement, demonstrating the validity of this method for in vivo photosensitizer dosimetry. On the basis of this method, temporal behaviors of two photosensitizers were compared.

Control of infection in wounds is critically important to avoid transition to sepsis; however, recent rise of drug-resistant bacteria makes it difficult. Thus, antimicrobial photodynamic therapy (APDT) has recently received considerable attention. In this study, we examined methylene blue (MB)-mediated photodynamic inactivation of Psuedomonas aeruginosa in rat burned skin. Two days after infection, the wound surface was contacted with a MB solution at different concentrations, and thereafter the wound was irradiated with cw 665-nm light at a constant power density of 250 mW/cm 2 for different time durations. We obtained a two orders of magnitude decrease in the number of bacteria by PDT with a 2-h contact of 0.5-mM MB solution and a illumination of 480 J/cm 2 , demonstrating the efficacy of PDT against infection with Ps. aeruginosa in burns.

This study proposes a modular design method that considers defense from leakage of the synthetic function. Today’s modular design method might lead to an increase in of the leakage of intellectual property. If the modular design were able to conceal the structure of the interactions of product components which realize the product functions, the competitive value of synthetic function might be protected and its life might be extended in the market. The proposed method was implemented to a prototype system (the paper feeder on a photocopier). The result showed the Pareto solution for the trade-offs of manufacturing cost reduction through outsourcing and the defense against the leakage of synthetic function value, indicating a module division plan with both aspects balanced at a high level. The comprehensive evaluation confirmed that the proposed balanced plan accounted for a more satisfactory evaluation value than the other two plans. Specifically, the study recommended the module division plan that enables around a 74% reduction of risk of leakage of synthetic function and about a 43% overall loss, even though the manufacturing cost worsened by approximately 42% when compared to the plan emphasizing manufacturing cost reduction. These application results support the hypothesis that modular design can conceal the structure of functional interactions. Therefore, it was concluded that the proposed module design method was more effective than the existing method, which does not consider the hiding and concealing of the functional interactions of the synthetic value.Copyright © 2010 by ASME

To obtain efficient antibacterial photodynamic effect in traumatic injuries such as burns, depth-resolved dosimetry of photosensitizer is required. In this study, we performed dual-wavelength photoacoustic (PA) measurement for rat burned skins injected with a photosensitizer. As a photosensitizer, methylene blue (MB) or porfimer sodium was injected into the subcutaneous tissue in rats with deep dermal burn. The wound was irradiated with red (665 nm or 630 nm) pulsed light to excite photosensitizers and green (532 nm) pulsed light to excite blood in the tissue; the latter signal was used to eliminate blood-associated component involved in the former signal. Acoustic attenuation was also compensated from the photosensitizer-associated PA signals. These signal processing was effective to obtain high-contrast image of a photosensitizer in the tissue. Behaviors of MB and porfimer sodium in the tissue were compared.