Search

Background: Splenic hilar lymphadenectomy is not recommended for advanced proximal gastric cancer that does not invade the greater curvature according to the results of the previous studies. The efficacy of splenic hilar lymphadenectomy for type II and type III adenocarcinomas of the esophagogastric junction and easy spread to the greater curvature of the stomach remains unclear. This study aimed to investigate the efficacy of splenic hilar lymphadenectomy and identify the risk factors for metastasis to splenic hilar nodes., Methods: We examined patients who underwent R0/1 gastrectomy for Siewert types II and III at a single high-volume center in Japan. We analyzed the metastatic incidence, therapeutic value index, and risk factors for splenic hilar lymph node metastasis., Results: We examined 126 patients (74, type II; 52, type III). Splenectomy was performed in 76 patients. Metastatic incidence and the therapeutic value index of splenic hilar lymph nodes in patients with type II and type III tumors were 4.5% and 0, and 21.9% and 9.4, respectively. In the patients who underwent splenectomy, we identified Siewert type III tumors (odds ratio: 6.93, 95% confidence interval: 1.24-38.8, p = 0.027) and tumor location other than the lesser curvature (odds ratio: 7.36, 95% confidence interval: 1.32-41.1, p = 0.023) to be independent risk factors. The metastatic incidence (46.2%) and therapeutic value index (15.4) were high in patients with both risk factors., Conclusions: Splenic hilar lymphadenectomy may contribute to the survival of patients with Siewert type III tumors, especially when the predominant location is not the lesser curvature., Competing Interests: Declaration of competing interest Yasushi Rino has received speaker honorariums and research grants from Daiichi Sankyo, Johnson & Johnson, Otsuka, Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Abbott Nutrition, Asahi Kasei, Tsumura & Co., Covidien, Zeria Pharmaceutical and EA Pharma. The other authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Aims: Dilated cardiomyopathy (DCM) remains among the most refractory heart diseases because of its complicated pathogenesis, and the key molecules that cause it remain unclear., Main Methods: To elucidate the molecules and upstream pathways critical for DCM pathogenesis, we performed meta-analysis and co-expression analysis of RNA-sequencing (RNA-seq) datasets from publicly available databases. We analyzed three RNA-seq datasets containing comparisons of RNA expression in left ventricles between healthy controls and DCM patients. We extracted differentially expressed genes (DEGs) and clarified upstream regulators of cardiovascular disease-related DEGs by Ingenuity Pathway Analysis (IPA). Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) analysis were also used to identify the hub gene candidates strongly associated with DCM., Key Findings: In total, 406 samples (184 healthy, 222 DCM) were used in this study. Overall, 391 DEGs [absolute fold change (FC) ≥ 1.5; P < 0.01], including 221 upregulated and 170 downregulated ones in DCM, were extracted. Seven common hub genes (LUM, COL1A2, CXCL10, FMOD, COL3A1, ADAMTS4, MRC1) were finally screened. IPA showed several upstream transcriptional regulators, including activating (NFKBIA, TP73, CALR, NFKB1, KLF4) and inhibiting (CEBPA, PPARGC1A) ones. We further validated increased expression of several common hub genes in the transverse aortic constriction-induced heart failure model., Significance: In conclusion, meta-analysis and WGCNA using RNA-seq databases of DCM patients identified seven hub genes and seven upstream transcriptional regulators., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: The effectiveness of PD-1 blockade therapy in advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is limited. We investigated whether patient characteristics, PD-L1 expression, and immune cell (IC) status in the tumor microenvironment (TME) were associated with PD-1 blockade therapy outcomes., Materials and Methods: We retrospectively reviewed patients with advanced EGFR-mutant NSCLC treated with PD-1 blockade (nivolumab or pembrolizumab) between January 2016 and March 2018. The PD-L1 expression tumor proportion score (TPS) and types and distribution of ICs (CD8, PD-1, CD204, tumoral, and stromal) in the TME were analyzed., Results: Among 57 EGFR-mutant NSCLC patients treated with PD-1 blockade, 39 patients had sufficient tissues for analyzing the TME. The overall response rate (ORR) of PD-1 blockade was 12.3%. Only tumoral CD8 positive (CD8 + ) IC status was significantly associated with the response (median tumoral CD8 + ICs: 299/mm 2 vs. 115/mm 2 , P < .01). Among the 6 patients with concurrent high PD-L1 expression (TPS: ≥ 50%)/high tumoral CD8 + ICs (≥ 205/mm 2 ), 5 (83.3%) showed a response and a significantly longer progression-free survival (PFS) (PFS: 9.4M vs. 1.8M, P < .01). In contrast, none of the 7 patients with high PD-L1 expression/low tumoral CD8 + ICs (<205/mm 2 ) showed a response., Conclusion: Concurrent high PD-L1 expression and high tumoral CD8 + ICs could predict the response and longer PFS of PD-1 blockade therapy in EGFR-mutant patients., (Copyright © 2022. Published by Elsevier Inc.)

Dilated cardiomyopathy (DCM) is a refractory heart disease characterized by dilation of the left ventricle and systolic dysfunction. LMNA, the gene encoding lamin A/C (a nuclear envelope protein), is the second leading causative gene associated with familial DCM. LMNA-related DCM is likely to develop severe heart failure, various types of arrhythmias, and poor prognosis. We established a human induced pluripotent stem cell line, derived from a patient with DCM carrying a nonsense mutation in LMNA. This line should be a useful resource for elucidating disease mechanisms and developing fundamental treatments for LMNA-related DCM., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression., Methods: We retrospectively reviewed patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti-PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing., Results: Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1 High (tumor proportion score ≥ 50%)/TIL High (≥85/mm 2 ; n = 73); type II: PD-L1 Low (tumor proportion score < 50%)/TIL Low (<85/mm 2 ; n = 70); type III: PD-L1 High /TIL Low (n = 37); and type IV: PD-L1 Low /TIL High (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti-PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1 High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively., Conclusions: Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti-PD-1/PD-L1 therapy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Although a history of cancer is a poor prognostic factor in patients with acute myocardial infarction (AMI), the clinical importance of coexisting active cancer remains unclear., Methods: In this single-center retrospective study, we reviewed an AMI registry and assessed the prevalence and predictors of active cancer, 1-year incidence of cardiac death or major bleeding events (defined as a Bleeding Academy Research Consortium type 3 or 5), and the impact of coexisting active cancer on clinical outcomes. Active cancer was defined as either an already-diagnosed or undiagnosed occult cancer., Results: Between January 2012 and December 2017, 1140 AMI patients (median age, 69 years; male, 76.0%) were enrolled. Active and historical cancers were diagnosed in 63 patients (5.5%) and 50 patients (4.4%), respectively. The most common location was the urinary tract (n=21). In the Kaplan-Meier analysis, the active cancer group had a higher incidence of 1-year cardiac death (17.5% vs. 5.3%, p < 0.001) and major bleeding events (19.0% vs. 5.6%, p < 0.001) than the non-cancer group. In the multivariate Cox proportional hazards regression models, active cancer was an independent predictor of both cardiac death and major bleeding at 1 year. Specifically, gastrointestinal tract and advanced-stage cancers had the poorest outcomes. Compared to the non-cancer group, the 1-year major bleeding rate was higher for all cancer types and stages. In contrast, early-stage cancers had a weaker impact on the 1-year cardiac mortality compared to advanced-stage cancers. Similarly, cardiac death during 1-year also occurred less frequently in occult cancers than in already-known cancers., Conclusions: In patients with AMI, coexisting active cancer was rare, but it significantly impacted cardiac death and major bleeding events., (Copyright © 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

In arsenic toxicity, activation of the erythroid 2-related factor 2 (NRF2) pathway is regarded as a driver of cancer development and progression; however, the mechanisms by which NRF2 gene expression regulates cell cycle progression and mediates pathways of cellular proliferation and apoptosis in arsenic-induced lung carcinogenesis are poorly understood. In this study, we explored the regulatory functions of NRF2 expression and its target genes in immortalized human bronchial epithelial (HBE) cells continuously exposed to 1.0 μM sodium arsenite over approximately 43 passages (22 weeks). The experimental treatment induced malignant transformation in HBE cells, characterized by increased cellular proliferation and soft agar clone formation, as well as cell migration, and accelerated cell cycle progression from G0/G1 to S phase with increased levels of cyclin E-CDK2 complex,decreased cellular apoptosis rate. Moreover, we observed a sustained increase in NRF2 protein levels and those of its target gene products (NQO1, BCL-2) with concurrently decreased expression of apoptosis-related proteins (BAX, Cleaved-caspase-3/Caspase-3 and CHOP) and increased expression of the anti-apoptotic protein MCL-1. Silencing NRF2 expression with small interfering RNA (siRNA) in arsenite-transformed (T-HBE) cells was shown to reverse the malignant phenotype. Further, siRNA silencing of NQO1 significantly decreased levels of the cyclin E-CDK2 complex, inhibiting G0/G1 to S phase cell cycle progression and transformation to the T-HBE phenotypes. This study demonstrated a novel role for the NRF2/NQO1 signaling pathway in mediating arsenite-induced cell transformation by increasing the expression of cyclin E-CDK2, and accelerating the cell cycle and cell proliferation. Arsenite promotes activation of the NRF2/BCL-2 signaling pathway inhibited CHOP increasing cellular resistance to apoptosis and further promoting malignant transformation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Growth hormone (GH)/insulin-like growth factor (IGF) axis plays a critical role in fetal development. However, the effect of arsenite exposure on the GH/IGF axis and its toxic mechanism are still unclear. Zebrafish embryos were exposed to a range of NaAsO 2 concentrations (0.0-10.0 mM) between 4 and 120 h post-fertilization (hpf). Development indexes of survival, malformation, hatching rate, heart rate, body length and locomotor behavior were measured. Hormone levels, GH/IGF axis-related genes, and nerve-related genes were also tested. The results showed that survival rate, hatching rate, heart rate, body length and locomotor behavior all decreased, while deformity increased. At 120 hpf, the survival rate of zebrafish in 1.5 mM NaAsO 2 group was about 70%, the deformity rate exceeded 20%, and the body length shortened to 3.35 mm, the movement distance of zebrafish decreased approximately 63.6% under light condition and about 52.4% under dark condition. The level of GH increased and those of IGF did not change significantly, while the expression of GH/IGF axis related genes (ghra, ghrb, igf2r, igfbp3, igfbp2a, igfbp5b) and nerve related genes (dlx2, shha, ngn1, elavl3, gfap) decreased. In 1.5 mM NaAsO 2 group, the decrease of igfbp3 and igfbp5b was almost obvious, about 78.2% and 72.2%. The expression of nerve genes in 1.5 mM NaAsO 2 group all have declined by more than 50%. These findings suggested that arsenite exerted disruptive effects on the endocrine system by interfering with the GH/IGF axis, leading to zebrafish embryonic developmental toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: 99m Tc-labeled hexavalent probes can be readily synthesized by the coordination of six equivalent isocyanide ligands towards Tc I , and alkyl isocyanide ligands have been extensively used for preparing such probes. However, high ligand concentration (>1 mM) is generally required due to their insufficient coordination ability to Tc I ., Methods and Results: In this study, we revealed that aryl isocyanide ligands, which have greater π-accepting ability compared with alkyl ones, provided 99m Tc-labeled hexavalent probes in high radiochemical yields (>95%) even at low ligand concentration (50 μM). We applied this finding to the synthesis of a 99m Tc-labeled hexavalent RGD probe, targeting integrin α v β 3 . This 99m Tc-labeled probe was prepared in a 5 min reaction at ligand concentration of 50 μM, and exhibited high tumor localization in vivo without post-labeling purification., Conclusion: The present findings indicate that aryl isocyanide ligands would be a useful precursor to a variety of 99m Tc-labeled hexavalent targeting probes for molecular imaging of saturable systems., Advances in Knowledge: Aryl isocyanide is a better precursor than alkyl isocyanide for preparing 99m Tc-labeled hexavalent targeting probe., Implication for Patient Care: This work provides a straightforward method to prepare molecular imaging agents of high target uptake, which would facilitate nuclear medicine imaging in clinical settings., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cough and sputum are the major symptoms of pulmonary tuberculosis (TB). However, the relationship between these symptoms and treatment for TB is not fully understood. The aim of this prospective study was to clarify the cough- and sputum-related quality of life (QOL) in patients with pulmonary TB before and after initiation of treatment., Methods: The study included 85 patients with active pulmonary TB who were hospitalized from July 2014 to August 2015. They completed the Leicester Cough Questionnaire (LCQ: range 3-21, the higher the better) and the Cough and Sputum Assessment Questionnaire (CASA-Q: range 0-100, the higher the better) on admission and at discharge after 2 months of treatment., Results: The LCQ and CASA-Q scores were reduced on admission. A multivariate linear regression analysis revealed that younger age, more than two cavitary lesions, and the presence of bronchial TB were associated with reduced LCQ total score. However, each score significantly improved at discharge, regardless of the initial grade of the sputum smear, site of the lesion, number of cavitary lesions, and presence of bronchial TB. The change in the mean LCQ total score was 2.28 (95% confidence interval, 1.56-3.00). The changes in the mean CASA-Q cough symptoms, cough impact, sputum symptoms, and sputum impact scores were 22.84 (18.44-27.25), 10.96 (7.20-14.71), 17.25 (13.33-21.18), and 5.25 (2.49-8.00), respectively., Conclusions: Cough- and sputum-related QOL was impaired in patients with pulmonary TB before treatment but improved after initiation of treatment regardless of the clinical characteristics., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Electrocardiogram (ECG)-triggered angiography non-contrast-enhanced (TRANCE) imaging is useful for investigating peripheral vessel diseases; however, its efficacy for access route assessment in cerebral angiography has yet to be reported. Therefore we aimed to evaluate the efficacy of TRANCE imaging in the assessment of the access route before diagnostic subtraction angiography for cerebral vascular disorders., Methods: TRANCE imaging was performed in all patients undergoing catheter angiography for disease diagnosis at our institute between April 2014 and March 2015. This study included 31 patients (14 men, 17 women) and investigated potential changes in the planned puncture site before and during the procedure (including the reason for the change) as our main outcome., Results: TRANCE was successfully conducted in all of the patients recruited. TRANCE images led to an alteration in the approach vessel for 5 cases. The mean procedure time for angiography was <60 minutes. The median total number of catheters and guidewires used during catheter angiography was 1 (range: 1-3) and 1 (range: 1-2), respectively. There were no catheter angiography-related complications., Conclusions: TRANCE imaging before diagnostic angiography is useful because it allows detailed assessment of the access route. This practice may reduce procedure time, thus resulting in fewer complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: 18 F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (1), 11 C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (2), and 11 C-labeled (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)methanone (3)., Methods: [ 18 F]1 was synthesized by the 18 F-fluoroethylation; [ 11 C]2 or [ 11 C]3 was synthesized by the 11 C-methylation. Biodistribution studies and PET studies were conducted in mice., Results: We successfully radiosynthesized [ 18 F]1, [ 11 C]2, and [ 11 C]3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60min following injection, the radioactivity level of [ 18 F]1 was relatively high in the small intestine, that of [ 11 C]2 was high in the liver, and that of [ 11 C]3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30min following [ 11 C]3 injection was significantly reduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions, high radioactivity levels in the liver and pancreas were observed following [ 11 C]3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15-60min after [ 11 C]3 injection was significantly decreased to 78% of control., Conclusion: [ 11 C]3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas. [ 11 C]3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Some patients with aneurysm exhibit warning headaches without minor bleeding, and this could be caused by stretching of the aneurysm wall. Recently, our pathologic study observed subintimal fibrin deposition in a majority of the ruptured aneurysms. However, these findings also were observed in some unruptured aneurysms. In this report, 2 unruptured aneurysms exhibited subintimal fibrin, and interestingly, one of the patients experienced severe headache within 1 month before neuroimaging., Objective: We performed pathologic analysis of unruptured aneurysms and collected their various clinical variables, including severe headache, to clarify the clinical characteristics of "dangerous" unruptured aneurysms., Methods: This study included unruptured saccular aneurysm samples (n = 17) that were resected after clipping. We compared the differences in clinical variables, including warning headache, between aneurysms with and without fibrin deposition., Results: Fibrin deposition was present in the subintimal layer in 4 patients and in the periouter membrane in 4 patients. Three of the 4 former patients experienced warning headaches, and one presented aneurysm growth. Of the latter 4 patients, one exhibited aneurysm growth, whereas the others presented with relatively large aneurysms. In the remaining 9 aneurysms without fibrin deposition, monocyte infiltration was observed in one, all aneurysms were small, and no patients experienced warning headaches or aneurysm growth., Conclusions: Subintimal fibrin deposition is observed frequently in patients with aneurysm with warning headaches. These pathologic findings are clinically inspiring and may suggest that these aneurysms exhibit rapid stretching by newly formed aneurysms, which can result in rupture at an early stage., (Copyright © 2017. Published by Elsevier Inc.)

Background: Hydrocephalus is classified as noncommunicating and communicating based on whether all ventricular and subarachnoid spaces are communicating. Although the diagnosis between the two different states is crucial, it is difficult in certain conditions. In particular, communicating hydrocephalus and noncommunicating hydrocephalus owing to fourth ventricle outlet obstruction are highly misdiagnosed. We describe a case of fourth ventricle outlet obstruction of unknown origin that was initially misdiagnosed as communicating hydrocephalus., Case Description: A 66-year-old woman with gait disturbance and incontinence caused by hydrocephalus underwent ventriculoperitoneal shunt surgery. After 9 months, her fourth ventricle became enlarged and could not be controlled by lowering the shunt pressure. Magnetic resonance imaging (MRI) demonstrated obstruction at the foramen of Magendie, foramina of Luschka, and the cerebral aqueduct. Endoscopic surgery for aqueduct plasty with third ventriculostomy was planned. Because the aqueduct was observed to open spontaneously, only the standard third ventriculostomy was performed. When MRI findings were reviewed retrospectively, an unnatural space was observed between the lower cranial nerves and cerebellar hemisphere that grew along with the fourth ventricular enlargement. This space was determined by MRI cisternography to be the cystic membrane ballooning out from the foramen of Luschka. The primary hydrocephalus likely resulted from fourth ventricle outlet obstruction., Conclusions: Enlargement of the whole ventricular system with an expanded space between the lower cranial nerves and cerebellar hemisphere can be caused by fourth ventricle outlet obstruction. In such cases, preoperative evaluation of anatomic architecture and cerebrospinal fluid obstruction using MRI cisternography is essential and leads to a successful endoscopic strategy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [ 11 C]BU99008, a more potent PET probe for I 2 -imidazoline receptors (I 2 Rs) imaging, with a conventional SA (mean 76GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I 2 Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [ 11 C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I 2 Rs., Methods: [ 11 C]BU99008 was prepared by [ 11 C]methylation of N-desmethyl precursor with [ 11 C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats., Results: [ 11 C]BU99008 with ultra-high SA in the range of 5400-16,600GBq/μmol were successfully synthesized (n=7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [ 11 C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [ 11 C]BU99008 at 30min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC 30-60 min ) in the hypothalamus of rats injected with [ 11 C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [ 11 C]BU99008 with ultra-high SA (86% of total binding) for I 2 R was higher than that of conventional SA (76% of total binding)., Conclusion: A PET study using [ 11 C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with I 2 R expression and hence may be useful in elucidating new functions of I 2 R., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Although a marked rise in the prevalence of allergic diseases over the past few decades may be related to environmental factors in industrialized countries, evidence for the protective effect of humidity on the barrier function of the skin is still awaited. We asked whether an increase in the water content of stratum corneum at the site of hapten application had a strong impact on the magnitude of contact hypersensitivity (CHS). The magnitude of CHS, induced by either lipid-soluble or water-soluble hapten, was inversely correlated with the water content of stratum corneum at the hapten application site in the elicitation phase. An increase in the water content induced by exposure to high humidity for 6 hours was sufficient to ameliorate the magnitude of CHS even in mice with the genetic defect in attenuating the CHS responses, such as flaky tail mice. The reduced CHS was associated with downregulation of IL-1α, IL-4, and IFN-γ mRNA expression. Epicutaneously applied hapten can penetrate more readily through the stratum corneum with lower water content than that with higher water content, even after tape-stripping. These findings indicate that increased levels of water in the stratum corneum serve to ameliorate the CHS beyond the genetic effects., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The Bay of Quinte, a Z-shaped embayment at the northeastern end of Lake Ontario, has a long history of eutrophication problems primarily manifested as spatially extensive algal blooms and predominance of toxic cyanobacteria. The purpose of this study was to identify the structural changes of the phytoplankton community induced by two environmental alterations: point-source phosphorus (P) loading reduction in the late 1970s and establishment of dreissenid mussels in the mid-1990s. A combination of statistical techniques was used to draw inference about compositional shifts of the phytoplankton assemblage, the consistency of the seasonal succession patterns along with the mechanisms underlying the algal biovolume variability in the Bay of Quinte over the past three decades. Based on a number of diversity and similarity indices, the algal assemblages in the upper and middle segments of the Bay are distinctly different from those typically residing in the outer segments. Our analysis also identified significant differences among the phytoplankton communities, representing the pre- and post-P control as well as the pre- and post-dreissenid invasion periods. Recent shifts in phytoplankton community composition were mainly associated with increased frequency of occurrence of toxin-producing Microcystis outbreaks and reduced biovolume of N 2 fixers, such as Aphanizomenon and Anabaena. Bayesian hierarchical models were developed to elucidate the importance of different abiotic factors (light attenuation, water temperature, phosphorus, and ammonium) on total cyanobacteria, Microcystis, Aphanizomenon, and Anabaena relative biovolume. Our modelling exercise suggests that there is significant spatial heterogeneity with respect to the role of the factors examined, and thus total phosphorus alone cannot always explain the year-to-year variability of cyanobacteria succession patterns in the system. The lessons learned from the present analysis will be helpful to the water quality criteria setting process and could influence the management decisions in order to delist the system as an Area of Concern., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: This study was aimed to determine what preoperative profiles were associated with seizure remission after corpus callosotomy and whether such seizure outcome was associated with the postoperative developmental outcome., Methods: This retrospective study included 26 consecutive patients with childhood onset epilepsy who underwent one-stage total corpus callosotomy at our institution and were followed up for a minimum of 1 year. The age at surgery ranged from 13 months to 32 years (median 6 years). The association between postoperative seizure freedom and preoperative profiles, post-operative developmental gains was examined., Results: Five patients achieved seizure freedom (Engel class I), and 10 patients achieved worthwhile reduction of seizures (class III), whereas the remaining patients had a class IV outcome. All five seizure-free patients had "lack of abnormal magnetic resonance imaging findings", "lack of proven etiology of seizures", and underwent "surgery at age 6 years or younger". These three factors were associated with seizure freedom (p<0.05, Fisher exact test). Post-operative gains in developmental quotient were significantly better in patients with seizure freedom than in those without (p<0.05, Mann Whitney U test)., Conclusion: Our study replicated the notion that seizure remission can be achieved after total corpus callosotomy in subsets of patients with medically-uncontrolled epilepsy, and suggested that a better developmental outcome can be expected in patients benefiting from seizure freedom., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Introduction: The functions of I₂-imidazoline receptors (I₂Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I₂R ligands have been developed, of which [(11)C]FTIMD and [(11)C]BU99008 were evaluated as PET I₂R imaging ligands in monkeys, no human PET imaging study using an I₂R-selective PET ligand has been conducted yet. Thus, we synthesized an (18)F-labeled I₂R-selective ligand (BU99018 or FEBU, Ki for I₂Rs=2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I₂R PET imaging ligand., Methods: [(18)F]FEBU was synthesized by the reaction of its precursor and [(18)F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively., Results: [(18)F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n=10) based on (18)F(-)). The specific activity at end of synthesis (EOS) was 40-147 TBq/mmol (n=10). The radiochemical purity was >99% at EOS and remained >99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I₂R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I₂R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection., Conclusion: [(18)F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I₂Rs in rats and mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Organ functions are altered and impaired during aging, thereby resulting in increased morbidity of age-related diseases such as Alzheimer's disease, diabetes, and heart failure in the elderly. Angiogenesis plays a crucial role in the maintenance of tissue homeostasis, and aging is known to reduce the angiogenic capacity in many tissues. Here, we report the differential effects of aging on the expression of angiogenic factors in different tissues, representing a potentially causes for age-related metabolic disorders. PCR-array analysis revealed that many of angiogenic genes were down-regulated in the white adipose tissue (WAT) of aged mice, whereas they were largely up-regulated in the skeletal muscle (SM) of aged mice compared to that in young mice. Consistently, blood vessel density was substantially reduced and hypoxia was exacerbated in WAT of aged mice compared to that in young mice. In contrast, blood vessel density in SM of aged mice was well preserved and was not different from that in young mice. Moreover, we identified that endoplasmic reticulum (ER) stress was strongly induced in both WAT and SM during aging in vivo. We also found that ER stress significantly reduced the expression of angiogenic genes in 3T3-L1 adipocytes, whereas it increased their expression in C2C12 myotubes in vitro. These results collectively indicate that aging differentially affects the expression of angiogenic genes in different tissues, and that aging-associated down-regulation of angiogenic genes in WAT, at least in part through ER stress, is potentially involved in the age-related adipose tissue dysfunction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: [(11)C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [(11)C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[(11)C]ABP688 on the synthesis of [(11)C]ABP688 to be used for binding (E)-[(11)C]ABP688 in the brain., Methods: We synthesized and separated (E)- and (Z)-[(11)C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[(11)C]ABP688., Results: (E)- and (Z)-[(11)C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the Kd value of (E)-[(11)C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[(11)C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[(11)C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[(11)C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BPND in the striatum and hippocampus was highly correlated (R(2) = 0.99) with the percentage of (E)-[(11)C]ABP688 of the total radioactivity of (E)- and (Z)-[(11)C]ABP688 in the injection., Conclusion: We demonstrated that including (Z)-[(11)C]ABP688 in the [(11)C]ABP688 injection can decrease BPND in regions rich in mGlu5 receptors. Routine production of (E)-[(11)C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies., (© 2013.)

Differentiation into osteoclasts is induced by a macrophage colony-stimulating factor and receptor activator of nuclear-factor κB ligand. The macrophage-like cell line, C7 has the potential to differentiate into osteoclasts when it is cultured with both factors for 6 days. Although C7 is an established cell line, the frequency of differentiation into this lineage was less than 10%, and the ratio was maintained at a constant level, even after repeated cloning. In this study, to increase the differentiation of C7 cells to osteoclasts, C7 derivative treatments with several activators and/or inhibitors were performed for 3 days prior to setting osteoclast induction analysis; however, a reagent to significantly up-regulate the frequency of differentiation was not found. Only extended cultures for osteoclastogenesis exponentially increased the frequency of osteoclast precursors. It is likely that C7 cell differentiation into committed osteoclast precursors is on 'autopilot' rather than requiring specific signals to drive this process., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Vascular calcification is a major risk factor for the cardiovascular disease, yet its underlying molecular mechanisms remain to be elucidated. Recently, we identified that osteogenic signals via bone morphogenetic protein (BMP)-2 exerted by vascular smooth muscle cells (VSMCs) play a crucial role in the formation of atherosclerotic plaque calcification. Here we report a synergistic interaction between macrophages and VSMCs with respect to plaque calcification. Treatment with conditioned medium (CM) of macrophages dramatically enhanced BMP-2 expression in VSMCs, while it substantially reduced the expression of matrix Gla-protein (MGP) that inhibits the BMP-2 osteogenic signaling. As a result, macrophages significantly accelerated the osteoblastic differentiation of C2C12 cells induced by VSMC-CM. In contrast, macrophage-CM did not enhance the osteoblastic gene expressions in VSMCs, indicating that macrophages unlikely induced the osteoblastic trans-differentiation of VSMCs. We then examined the effect of recombinant TNF-α and IL-1β on the VSMC-derived osteogenic signals. Similar to the macrophage-CM, both cytokines enhanced BMP-2 expression and reduced MGP expression in VSMCs. Nevertheless, only the neutralization of TNF-α but not IL-1β attenuated the effect of macrophage-CM on the expression of these genes in VSMCs, due to the very low concentration of IL-1β in the macrophage-CM. On the other hand, VSMCs significantly enhanced IL-1β expression in macrophages, which might in turn accelerate the VSMC-mediated osteogenic signals. Together, we identified a unique role of macrophages in the formation of plaque calcification in coordination with VSMCs. This interaction between macrophages and VSMCs is a potential therapeutic target to treat and prevent the atherosclerotic plaque calcification., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We performed dynamic linear modeling analysis on fish contaminant data collected from the Ontario Ministry of the Environment and Environment Canada to examine long-term trends of total mercury (THg) and polychlorinated biphenyls (PCBs) in Lake Erie. Several sport fish species (walleye, smallmouth bass, rainbow trout) with differences in their diet habits, food competition strategies and foraging patterns are characterized by weakly increasing trends of their THg levels in Lake Erie after the mid- or late 1990s. Similarly, our analysis shows that the decline rates of the PCB body burdens in white bass, smallmouth bass, freshwater drum and whitefish have slowed down or have switched to weakly increasing rates over the last decade. Our analysis also provides evidence that the rainbow trout and coho salmon PCB concentrations have been decreasing steadily but the associated rates were fairly weak. The systematic shifts in energy trophodynamics along with the food web alterations induced from the introduction of non-native species, the new role of the sediments as a net contaminant source, and the potentially significant fluxes from the atmosphere stand out as some of the hypotheses proposed to explain the limited Lake Erie response in recent years to the various contamination mitigation strategies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dynamic linear modeling (DLM) analysis was performed to identify the long-term temporal trends of two toxic components of the technical chlordane pesticide, α- and γ-chlordane, in skinless-boneless muscle tissues of a number of sport fish species in Lake Erie. Our analysis considers the fish length as a covariate of the chlordane concentrations. The α-chlordane models for the coho salmon, channel catfish, rainbow trout, and common carp showed continuously decreasing trends during the entire 30+ year survey period (1976-2007). The γ-chlordane models demonstrated similar trends for the coho salmon, channel catfish, and common carp. These fish species had higher levels of α- and γ-chlordane in their muscle tissues. The α- and γ-chlordane levels in freshwater drum, smallmouth bass, walleye, white bass, whitefish, and yellow perch decreased until the mid-1980s and hovered at levels around the detection limits for the remaining period. The pesticide biotransformation process, the reduction of contaminant emissions to the environment, the feeding habits of the different fish species, and the food-web alterations induced by the introduction of aquatic invasive species are some of the hypotheses proposed to explain the observed temporal trends in different fish species in Lake Erie., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Visual input in the critical period is an important determinant of the functions of the visual system, affecting for example the formation of the ocular dominance column in the visual cortex. The final map of columnar organization is usually determined by plastic changes in the critical period, but organization is distorted without adequate visual input. Here, we examined whether formation of the OFF-pathway dominance of P2X(2)-purinoceptor signaling in the mouse retina is the result of visual experience. The P2X(2)-purinoceptor signaling pathway developed during the critical period. However, visual experience in this period produced no plastic change in the formation of the OFF-pathway dominance of P2X(2)-purinoceptor signaling. Our findings suggest that the OFF-pathway dominance of P2X(2)-signaling in the mouse retina is intrinsically programmed., (Copyright 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Neural recognition molecule NB-2/contactin 5 is expressed transiently during the first postnatal week in glutamatergic neurons of the central auditory system. Here, we investigated the effect of NB-2 deficiency on the auditory brainstem in mouse. While almost all principal neurons are wrapped with the calyces of Held in the medial nucleus of the trapezoid body (MNTB) in wild type, 8% of principal neurons in NB-2 knockout (KO) mice lack the calyces of Held at postnatal day (P) 6. At P10 and P15, apoptotic principal neurons were detected in NB-2 KO mice, but not in wild type. Apoptotic cells were also increased in the ventral cochlear nucleus (VCN) of NB-2 KO mice, which contains bushy neurons projecting to the MNTB and the lateral superior olive (LSO). At the age of 1 month, the number of principal neurons in the MNTB and of glutamatergic synapses in the LSO was reduced in NB-2 KO mice. Finally, interpeak latencies for auditory brainstem response waves II-III and III-IV were significantly increased in NB-2 KO mice. Together, these findings suggest that NB-2 deficiency causes a deficit in synapse formation and then induces apoptosis in MNTB and VCN neurons, affecting auditory brainstem function.

This report presents results of investigations of the influence of anthropogenic heat release in Japanese megacity (Keihanshin district) upon the urban climate, using the energy database [Shimoda et al., 1999. Estimation and evaluation of artificial waste heat in urban area. Selected Papers from the Conference ICB-ICUC'99 WCASP-50 WMO/TD no. 1026] as a part of the land-surface boundary conditions of a mesoscale meteorological simulation model. The calculated results related to atmospheric temperature distribution were similar to observed values not only for daily averages but also for amplitudes and phases of diurnal change. To reproduce accurately, it is essential to reproduce urban characteristics such as an urban canopy and anthropogenic heat release in a fine resolution mesh. We attempted an analysis using current data for anthropogenic heat and under uniform heat release conditions, to investigate temporal and spatial characteristics in relation to the influence of anthropogenic heat release on the urban climate. The results of investigation into the influence of anthropogenic heat release on atmospheric temperature using current data indicate that the amount of heat released is lower at night than during the day, but the temperature rise is nearly 3 times greater. Results of investigation into the influence of anthropogenic heat release on wind systems using current data indicate that the onset of land breezes is delayed, particularly in a coastal area. Investigation into the temporal characteristics related to the influence of anthropogenic heat release under uniform heat release conditions showed a maximum influence on temperature during the predawn period.

Introduction: Circulating endothelial cells (CECs) increase in cancer patients and play an important role in tumor neovascularization., Methods: This study was designed to investigate the role of CEC as a marker for predicting the effectiveness of a carboplatin plus paclitaxel based first line chemotherapy in advanced non-small cell lung cancer (NSCLC)., Results: The CEC count in 4 ml of peripheral blood before starting chemotherapy (baseline value) was significantly higher in NSCLC patients, ranging from 32 to 4501/4 ml (n = 31, mean +/- SD = 595 +/- 832), than in healthy volunteers (n = 53, 46.2 +/- 86.3). We did not detect a significant correlation between the CEC count and estimated tumor volume. CECs were significantly decreased by chemotherapy as compared with pretreatment values (175.6 +/- 24 and 173.0 +/- 24, day +8, +22, respectively). We investigated the correlation between baseline CEC and the clinical effectiveness of chemotherapy. CEC values are significantly higher in patients with clinical benefit (partial response and stable disease, 516 +/- 458, 870.8 +/- 1215, respectively) than in progressive disease patients (211 +/- 150). Furthermore, a statistically significant decrease in CECs, on day 22, was observed only in patients with partial response. Patients who had a baseline CEC count greater than 400/4 ml showed a longer progression-free survival (>400, 271 days [range: 181-361] versus <400, 34 [range: 81-186], p = 0.019)., Conclusion: CEC is suggested to be a promising predictive marker of the clinical efficacy of the CBDCA plus paclitaxel regimen in patients with NSCLC.

The standard biogenic volatile organic compound (BVOC) emissions from 10 Japanese plant species (Quercus serrata, Quercus crispula, Fagus crenata, Quercus acutissima Carruthers, Quercus glauca, Quercus myrsinaefolia, Cryptomeria japonica, Chamaecyparis obtusa, Pinus densiflora, and rice [Oryza sativa]) were measured. These species were selected due to their abundance in the estimated domain (47,000 km(2)) of the Kinki region. BVOC emission experiments were conducted in a growth chamber where temperature and light intensity can be controlled. Temperature was set at the average summer temperature in Osaka and at 5 degrees C above average. Light intensity was set at 1000, 335, and 0 micromol m(-2)s(-1) during day time. The amount of BVOC emission was high around noon due to the rise of ambient temperature. It was also found that the total emission rates and compositions of BVOC varied significantly among the plant species. Q. serrata, Q. crispula, F. crenata, Q. acutissima Carruthers, Q. glauca, and Q. myrsinaefolia emitted isoprene and showed emission dependence on light intensity and temperature. C. japonica, P. densiflora, C. obtusa, and O. sativa emitted monoterpenes and also showed emission dependence on temperature; however, only C. japonica and P. densiflora showed emission dependence on light intensity. Using BVOC emissions data from 10 plant species and forest data, BVOC emission potential maps were made. The emission of isoprene and monoterpenes from the Kinki region were estimated to be 596 and 54 ton h(-1), respectively. Seasonal and diurnal variations of BVOC emissions potential were also estimated. Of note, though the amount of monoterpenes from O. sativa is small, it contributes approximately 5% to the total monoterpene emissions due to the huge land area covered by paddy fields.

Obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. We have provided in vitro evidence that saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 (TLR4) to induce the inflammatory changes in macrophages. Here we show the attenuation of adipose tissue inflammation in C3H/HeJ mice carrying a functional mutation in the TLR4 gene relative to control C3H/HeN mice during a 16-week high-fat diet. We also find that adiponectin mRNA expression is significantly reduced by co-culture of hypertrophied 3T3-L1 adipocytes and C3H/HeN peritoneal macrophages, which is reversed, when co-cultured with C3H/HeJ peritoneal macrophages. This study provides in vivo evidence that TLR4 plays a role in obesity-related adipose tissue inflammation and thus helps to identify the therapeutic targets that may reduce obesity-induced inflammation and the metabolic syndrome.

Peripheral monocytosis may affect the development of heart failure (HF) after acute myocardial infarction (AMI). Activated toll-like receptor (TLR) 4 in monocytes plays an important role in the synthesis of proinflammatory cytokines. We examined TLR4 expression in monocytes, which may be a possible source of proinflammatory cytokines in AMI. Sixty-five patients with AMI and 20 healthy subjects (HS) were studied. Monocytes were isolated from peripheral blood on days 1 and 14 after the onset of AMI. TLR4 levels in monocytes were measured using real-time RT-PCR and flow cytometry. Generation capacity was evaluated by TLR4 levels and cytokine concentrations in the culture medium with lipopolysaccharide (LPS) stimulation. On day 1 after onset, baseline levels of TLR4 and plasma proinflammatory cytokines, notably IL-6 and TNF-alpha, were higher in AMI patients than in HS. These levels remained elevated in AMI patients 14 days after onset. Generation capacities of TLR4 and proinflammatory cytokines (IL-2, IL-6, IL-8, IL-10, GM-CSF and TNF-alpha) were increased in AMI patients compared to HS. LPS-stimulated TLR4 levels were positively correlated with IL-6 and TNF-alpha levels in AMI patients. Baseline TLR4 levels and plasma proinflammatory cytokine (IL-6, GM-CSF and TNF-alpha) levels were higher in AMI patients with HF (n = 22) than in those without HF. Generation capacities of TLR4 and proinflammatory cytokines (IL-6, GM-CSF and TNF-alpha) were greater in AMI patients with HF than in those without HF. Activation of TLR4 through a myocytic inflammatory reaction is associated with HF after AMI. These observations suggest that TLR4 signaling in monocytes may play a role in the development of HF after AMI.

HNK-1 epitope is a cell-surface carbohydrate mediating various cell-cell or cell-substrate interactions. We found HNK-1 epitope in longitudinally arrayed fibers in the subpopulation of the epaxial myotome, and hypaxial myoblasts migrating into the limb bud in the rat embryo. We next investigated the expression patterns of genes encoding two glucuronyltransferases (GlcAT-P, GlcAT-D) and sulfotransferase (Sul-T), which are required for biosynthesis of HNK-1 epitope. GlcAT-P gene was expressed in the non-migrating longitudinal fibers, whereas GlcAT-D gene was expressed in the migrating myoblasts in the limb bud. Sul-T gene expression was ubiquitously observed in all these myogenic populations. Thus, differential expression of GlcAT genes may relate to the epaxial/hypaxial or migrating/non-migrating myoblast lineages.

Cytochrome P450IID6 (CYP2D6) plays an important role in the hepatic metabolism of various psychotropic drugs. We detected a mutation of the CYP2D6 gene in two patients who previously had episodes of neuroleptic malignant syndrome (NMS). They were homozygous for a mutated CYP2D6J allele conferring a poor-metabolizer phenotype. Possession of this trait may contribute to susceptibility to NMS.