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Alzheimer's disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5-trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ1-42 (Aβ1-42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ1-42 treatment in rat primary hippocampal neuron cultures. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.

This study aims to provide a clear relationship of how the storage status and duration of the urea affect the efficiency and performance of the SCR system. Focusing on the marine environment, the research compares NOx emissions using new urea solution versus urea solution stored for 5 years on ships. The results indicate that using new urea solution reduces NOx emissions by an average of 30%. Additionally, the study confirms that the impact of the SCR system on the combustion process is negligible. These findings the importance of regular urea solution replacement to optimize the performance of SCR systems installed to meet environmental regulations. Currently, there are no detailed procedures or regulatory standards for urea management and replacement on ships. Considering the strict NOx emission regulations and harsh storage conditions in ship, the study proposes the establishment of effective urea replacement cycles and management procedures.

IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses . We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4 T cells producing IFN-γ with maintenance of HBV-specific CD8 T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8 T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment. ClinicalTrials.gov NCT01204762.

Although several studies have confirmed the clinical significance of the systemic inflammation markers in hepatocellular carcinoma (HCC), evaluating the clinical significance of each blood cell remains to be conducted. We aimed to evaluate the clinical importance of absolute counts of blood cells in the overall survival (OS) of patients with newly diagnosed HCC. We recruited patient cohorts from the prospective registry of newly diagnosed and previously untreated HCC at Samsung Medical Center, which included a training set of 6619 patients (2005–2013) and a validation set of 2084 patients (2014–2016). More than three-quarters of all patients had hepatitis B virus (HBV)-related HCC in both training and validation sets. The optimal cutoff values of the absolute counts of neutrophils, lymphocytes, monocytes, and platelets were 3917, 488, 1379, and 22,100, respectively, which correlated significantly with OS. The absolute blood cell counts categorized by each optimal cutoff value significantly correlated with liver function status determined by Child–Pugh class/albumin-bilirubin (ALBI) grade and the HCC burden determined by several staging systems/portal vein tumor thrombosis. Although the prognostic model based on these blood cells (ABC model) showed a lower prognostic ability than the Japan Integrated Staging or ALBI-T staging systems, it provided significant discrimination of survival in the subgroups of ALBI-T and showed the highest prognostic ability in the present study in the training and validation sets. Absolute counts of blood cells are independently associated with OS, though it is also significantly associated with liver function and tumor burden in newly diagnosed HCC.

In this paper, the formability of E-FORM magnesium alloy sheet (as one of recent alloys for automotive magnesium sheets) is analyzed based on the comparison between the results of actual magnesium (Mg) roof forming and those of finite element (FE) simulations. The FE model considers anisotropic mechanical properties and forming limit diagram (FLD) of the investigated magnesium alloy sheet. Through the coupled experimental and numerical procedure, the dominating factors for improving the accuracy of the numerical simulations are further studied. A commercial finite element analysis program, AUTOFORM®, is used for the simulations, in which identified mechanical properties and forming limit criteria are implemented as functions of temperature and strain rate. The improvement in the prediction of formability during the warm forming of the E-FORM magnesium alloy sheet can be obtained by considering a modified hardening law at large strain region, sheet anisotropy, and the properly measured forming limit curve.

We report the results of radiotherapy for abdominal lymph node metastasis from hepatocellular carcinoma (HCC). From 1998 to 2004, 45 cases were treated with radiotherapy (RT), with a dose between 30 and 55 Gy. The radiation response, overall survival, prognostic factors, and complications were evaluated. Thirty-nine cases were able to be evaluated for response: 10 cases showed complete response; 21 cases showed a partial response; and 8 cases showed stable disease. The overall response rate was 79.5%. The response rate was 87.5% for patients receiving >or=40 Gy(10) (biologically effective dose, alpha/beta = 10) and 42.9% for patients receiving <40 Gy(10) (P = 0.02). The median survival time was 10 months for responders and 6 months for nonresponders (P = 0.01). The absence of other concurrent distant metastasis and controllable primary HCC were significant prognostic factors. RT induced gastric or duodenal ulcer development in nine patients. All of these patients had received more than 50 Gy(10), and these complications were not detected among patients receiving <50 Gy(10) (0% vs 37.5%, P < 0.01). RT was an effective treatment modality, and the absence of concurrent distant metastasis and controllable primary tumor were significant prognostic factors. However, considering the high rate of RT-induced morbidity, 40 Gy(10) to 50 Gy(10) might be the optimal RT dose.

Given the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT improves patient outcome is limited. We performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396). In the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval [CI]; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR [95% CI] = 0.67 [0.56-0.80]). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml). MDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations.

Hepatocellular carcinoma (HCC) patients usually achieve a complete response after treatment. This study was aimed to assess the clinical outcome of HCC patients who had achieved a complete response but later presented with elevated tumor marker levels without an identifiable recurrent tumor on gadoxetic acid-enhanced magnetic resonance imaging (MRI). We retrospectively reviewed the clinical outcome of 58 HCC treated patients who had achieved a complete response but later was referred to our institution's multidisciplinary tumor board for a clinically suspected hidden HCC recurrence based on elevated tumor marker levels but negative gadoxetic acid-enhanced MRI. The imaging studies, tumor markers, and clinical information were reviewed. The total follow-up period was at least 15 months after the initial negative gadoxetic acid-enhanced MRI. Follow-up imaging studies detected an HCC lesion in 89.7% (n = 52/58) of the patients within the study period, and approximately half of the tumors (46.2%, n = 24/52) developed within 3 months. The most frequent site of recurrence was the liver (86.5%; n = 45/52), but extra-hepatic metastasis was also common (19.2%; n = 10/52). In 5.8% (n = 3/52), HCC reoccurred in the combined form of intra-hepatic and extra-hepatic recurrence. Extra-hepatic metastasis alone occurred in 13.5% (n = 7/52) of patients. HCC frequently recurred within a short interval in patients who achieved a complete response to treatment in the presence of increased tumor marker levels, even if gadoxetic acid-enhanced MRI was negative. Under such circumstances, we suggest a short-term follow-up including, but not limited to, gadoxetic acid-enhanced MRI along with systemic evaluation.

Background A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. Methods Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. Results The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI , 2.4–17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Conclusions Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. Trial registration NCT#03163992 (first posted: May 23, 2017)

Background/Aims: Although hepatocellular carcinoma (HCC) is notorious for its high recurrence rate, some patients do not experience recurrence for more than 5 years after resection or radiofrequency ablation for early-stage HCC. For those with five recurrence-free period, the risk of HCC recurrence within the next 5 years remains unknown.Methods: A total of 1,451 consecutive patients (median, 55 years old; males, 79.0%; hepatitis B virus-related, 79.3%) with good liver function (Child-Pugh class A) diagnosed with early-stage HCC by Barcelona Clinic Liver Cancer Staging and received radiofrequency ablation or resection as an initial treatment between 2005 and 2010 were analyzed.Results: During a median follow-up period of 8.1 years, 961 patients (66.2%) experienced HCC recurrence. The cumulative recurrence rates increased to 39.7%, 60.3%, and 71.0% at 2, 5, and 10 years, respectively, and did not reach a plateau. Five years after HCC diagnosis, 487 patients were alive without experiencing a recurrence. Among them, during a median of 3.9 additional years of follow-up (range, 0.1–9.0 years), 127 patients (26.1%) experienced recurrence. The next 5-year cumulative recurrence rate (5–10 years from initial diagnosis) was 27.0%. Male sex, higher fibrosis-4 scores, and alpha-fetoprotein levels at 5 years were associated with later HCC recurrence among patients who did not experience recurrence for more than 5 years.Conclusions: The HCC recurrence rate following 5 recurrence-free years after HCC treatment was high, indicating that HCC patients warrant continued HCC surveillance, even after 5 recurrence-free years.