Neurotrophic factors, now termed neurotrophins, which belong to a class of polypeptidyl agents, have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as ...Alzheimer’s disease, because endogenous neurotrophic factors (NGF, BDNF, NT3, NT4) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular weight proteins are unable to cross the blood–brain barrier and are easily decomposed by peptidase under physiological conditions. To address this issue, small molecules that can mimic the functions of neurotrophic factors would be promising alternatives for the treatment of neurodegenerative disease. We have continued to search for natural products having typical neurotrophic properties, which can cause neurogenesis, enhance neurite outgrowth, and protect neuronal death using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). In this review, we summarize the neurotrophic activities and synthesis of dimeric isocuparane-type sesquiterpenes from the liverwort,
Mastigophora diclados
, the mechanism of neurotrophic neolignans, magnolol, honokiol and their sesquiterpene derivatives, and introduce unique neurotrophin-mimic natural products, including
seco
-prezizaane-type sesquiterpenes from the
Illicium
species, vibsane-type diterpenes from
Viburnum awabuki
, and miscellaneous natural products with neurotrophic effects discovered by us.
Graphic abstract
A Vesical Imaging-Reporting and Data System (VI-RADS) based on multiparametric magnetic resonance imaging (mp-MRI) was developed to provide accurate information for the diagnosis of muscle-invasive ...bladder cancers (MIBCs). In this study we evaluated the interobserver agreement and diagnostic performance of VI-RADS. We retrospectively evaluated data for 74 consecutive patients with bladder cancer who had undergone mp-MRI before transurethral resection in a single institution from January 2010 to August 2018. Five readers assessed the probability of the presence of MIBC using VI-RADS scores. The interobserver agreement was assessed by measuring intraclass correlation coefficients (ICCs). Receiver operating characteristic (ROC) analysis was used to evaluate the MIBC diagnostic performance. The area under the ROC curve (AUC) was estimated for ordinal score assessments. Our study demonstrated that interobserver agreement was excellent among five readers (ICC 0.85, 95% confidence interval 0.80–0.89) and the diagnostic performance of VI-RADS was represented as a pooled AUC of 0.90 (95% confidence interval 0.87–0.93).
We evaluated the interobserver agreement and diagnostic performance of a new scoring system based on magnetic resonance imaging called a Vesical Imaging-Reporting and Data System (VI-RADS) for muscle-invasive bladder cancer. Our results indicate that VI-RADS is suitable as a comprehensive tool for appropriate treatment planning for patients with bladder cancer.
Multiparametric magnetic resonance imaging is useful for the diagnosis of muscle-invasive bladder cancers. With further efforts to refine its application and standardization, the Vesical Imaging-Reporting and Data System may become an important comprehensive tool for appropriate treatment planning for patients with bladder cancers.
The U-box type ubiquitin ligase PUB44 positively regulates pattern-triggered immunity in rice. Here, we identify PBI1, a protein that interacts with PUB44. Crystal structure analysis indicates that ...PBI1 forms a four-helix bundle structure. PBI1 also interacts with WRKY45, a master transcriptional activator of rice immunity, and negatively regulates its activity. PBI1 is degraded upon perception of chitin, and this is suppressed by silencing of PUB44 or expression of XopP, indicating that PBI1 degradation depends on PUB44. These data suggest that PBI1 suppresses WRKY45 activity when cells are in an unelicited state, and during chitin signaling, PUB44-mediated degradation of PBI1 leads to activation of WRKY45. In addition, chitin-induced MAP kinase activation is required for WRKY45 activation and PBI1 degradation. These results demonstrate that chitin-induced activation of WRKY45 is regulated by the cooperation between MAP kinase-mediated phosphorylation and PUB44-mediated PBI1 degradation.
Background
Association between systemic inflammation and clinical outcome of immune checkpoint inhibitors (ICIs) has received focus. Our objective was to evaluate the utility of the ...neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab as well as the prognostic impact of the C-reactive protein (CRP) level.
Materials and methods
Sixty-five mRCC patients treated with nivolumab were enrolled. We retrospectively investigated several factors, including the NLR and the CRP level, for their association with progression-free survival (PFS) and overall survival (OS). In addition, we evaluated their impact on the objective response.
Results
The CRP level was confirmed to be positively correlated with the NLR in a correlation analysis. An NLR ≥ 5 was significantly associated with a worse PFS (hazard ratio HR: 4.54, 95% confidence interval CI 1.93–10.7;
p
< 0.001), and an NLR ≥ 5 and a CRP ≥ 2.1 mg/dL were identified as a significant factors predicting worse OS with HRs of 4.88 (95% CI 1.35–17.7;
p
< 0.016) and 3.89 (95% CI 1.01–15.0;
p
= 0.049), respectively. In addition, patients with a ≥ 25% decrease in the NLR and CRP level showed a significantly better response to nivolumab than those without a ≥ 25% decrease in the NLR and CRP level, with odds ratios of 9.54 (95% CI 2.09–49.8,
p
= 0.001) and 4.36 (95% CI 1.03–18.9,
p
= 0.032), respectively.
Conclusion
Both the NLR and CRP levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.
Seven new vibsane-type diterpenoids, 6-O-methyl-6,7-dihydroxyvibsanin B (1), 4-hydroxyvibsanin A (2), 14(R*),15-epoxyneovibsanin B (3), 14(S*),15-epoxyneovibsanin B (4), (8Z)-neovibsanin B (5), ...18-O-methylvibsanin C (6), and (8Z)-vibsanin E (7), have been isolated from the leaves of Viburnum awabuki. Their structures have been elucidated by molecular mechanics 2 (MM2) calculations and comparison of the spectroscopic data, including 13C NMR data, with those of previously known compounds. Moreover, neovibsane-type diterpenoids 3, 4, and 5 enhanced the neurite outgrowth of NGF-mediated PC12 cells at a concentration of 40 μM.
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Immunoglobin G (IgG) 4‐related sclerosing pancreatitis and cholangitis (autoimmune pancreato‐cholangitis AIPC) are recently recognized disease entities characterized by high serum IgG4 concentrations ...and sclerosing inflammation with numerous IgG4‐positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin‐fixed (28 cases) specimens of AIPC and related extra‐pancreatobiliary lesions. Quantitative real‐time polymerase chain reaction revealed that AIPC and extra‐pancreatobiliary lesions had significantly higher ratios of interleukin (IL)‐4/interferon‐γ (IFN‐γ) (45.8‐fold), IL‐5/IFN‐γ (18.7‐fold), IL‐13/interferon (IFN)‐γ (20.7‐fold), IL‐10/CD4 (45.3‐fold), and tumor growth factor (TGF)‐β/CD4 (39.4‐fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL‐4 and IL‐10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4+CD25+ Tregs, was significantly increased in AIPC and extra‐pancreatobiliary lesions in comparison to PSC and PBC (36.4‐fold). Immunohistochemically, CD4+CD25+Foxp3+ cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over‐production of T helper (Th) 2 and regulatory cytokines. Tregs might be involved in the in situ production of IL‐10 and TGF‐β, which could be followed by IgG4 class switching and fibroplasia. Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs. (HEPATOLOGY 2007.)
Aim
We aimed to develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named nonalcoholic steatohepatitis NASH‐Scope) to screen nonalcoholic fatty liver ...disease (NAFLD) and NASH.
Methods
We enrolled 324 and 74 patients histologically diagnosed with NAFLD for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for validation study. Additionally, 48 subjects who underwent a medical health checkup and did not show fatty liver ultrasonographically and had normal serum aminotransferase levels were categorized as the non‐NAFLD group. NASH‐Scope was based on 11 clinical values: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ‐glutamyl transferase, cholesterol, triglyceride, and platelet count.
Results
The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operator characteristic curve of NASH‐Scope for distinguishing NAFLD from non‐NAFLD in the training study and validation study were 99.7% versus 97.2%, 97.8% versus 97.8%, 99.7% versus 98.6%, 97.8% versus 95.7%, and 0.999 versus 0.950, respectively. Those for distinguishing NASH with fibrosis from NAFLD without fibrosis were 99.5% versus 90.7%, 84.3% versus 93.3%, 94.2% versus 98.0%, 98.6% versus 73.7%, and 0.960 versus 0.950. These results were excellent, even when the output data were divided into two categories without any gray zone.
Conclusions
The AI/NN system, termed as NASH‐Scope, is practical and can accurately differentially diagnose between NAFLD and non‐NAFLD and between NAFLD without fibrosis and NASH with fibrosis. Thus, NASH‐Scope is useful for screening nonalcoholic fatty liver and NASH.
The usefulness of whole-body 18-fluoro-2-deoxyglucose (FDG)-fluorodeoxyglucose positron emission (PET)/computed tomography (CT) is established for assessment of disease staging, detection of early ...disease recurrence, therapeutic evaluation, and predicting prognosis in various malignancies; and for evaluating the spread of inflammation. However, the role of FDG-PET/CT for the liver is limited because CT and magnetic resonance imaging (MRI) can provide an accurate diagnosis of most tumors. In addition, in other potentially useful roles there are several pitfalls in the interpretation of FDG uptake in PET/CT imaging. Accurate evaluation demands knowledge of the FDG uptake of each lesion, including potential negative and positive uptakes, and requires an understanding of the underlying background of the molecular mechanisms. The degree of FDG uptake is dependent on cellular metabolic rate and the expression of glucose transporter, hexokinase, and glucose-6-phosphatase, which in turn are closely affected by biological characteristics such as pathological category (e.g., adenocarcinoma, squamous cell carcinoma, small cell cancer, transitional cell cancer, neuroendocrine tumor, sarcoma, lymphoma), tumor differentiation, histological behavior (e.g., solid, cystic, mucinous), and intratumoral alterations (e.g., necrosis, degeneration, hemorrhage). Correlation with the CT and MRI findings, which also precisely depict the pathological findings, is important to avoid misdiagnosis.
This study aimed to clarify the impact of proton pump inhibitors (PPIs) on oncological outcomes in patients who received pembrolizumab for advanced urothelial carcinoma (UC).
Forty advanced UC ...patients treated with pembrolizumab were retrospectively reviewed and divided into two groups (PPI: 15 patients; without PPI: 25 patients). Tumor response and survival were compared between these groups. The factors associated with survival were also investigated.
The objective response rate was significantly lower in the group with PPIs compared with the group without PPIs. Both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the group with PPIs than in the group without PPIs. The use of PPIs was a significant predictor of poor PFS and OS in multivariate analysis.
The use of PPIs was negatively associated with tumor response and survival in patients with advanced UC treated with pembrolizumab.
Primary biliary cirrhosis (PBC) primarily affects females and is rarely complicated by hepatocellular carcinoma (HCC). Although the HCC incidence in PBC patients is low, several characteristics and ...risk factors associated with its development have been reported. In this study, national data concerning the current status of carcinogenesis in PBC patients in Japan are reviewed. Using data from two national questionnaire surveys, we investigated the clinicopathological findings associated with HCC in PBC patients. According to the data of all reviewed PBC patients, the HCC incidence was 2.4% (71/2946). The HCC incidence by gender was 5.1% (19/370) in males and 2.0% (52/2576) in females, and the proportion of males was 26.7%. Prognosis was significantly poorer in the PBC patients with HCC than in those without. Multivariate analysis of risk factors associated with HCC by gender revealed histological stage at the time of PBC diagnosis as an independent risk factor associated with the development of HCC in females, but not in males. Furthermore, data from another national survey of 178 PBC patients with HCC (male/female = 49/129; proportion of males 27.5%) revealed that the duration between the diagnosis of PBC and that of HCC was significantly shorter in males than in females. In addition, histological stage at the time of HCC diagnosis was an independent risk factor for HCC in females, whereas no risk factors were identified in males. Conclusion: these data indicate that males are at risk of developing HCC at any histological stage of PBC. Therefore, male PBC patients in particular should be carefully screened for HCC from the early stages of PBC. (HEPATOLOGY 2013)
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