USP10 inhibits the dopamine-induced reactive oxygen species-dependent apoptosis of neuronal cells by stimulating the antioxidant Nrf2 activity.

Nrf2 is an antioxidant transcriptional activator in many types of cells, and its dysfunction plays key roles in a variety of human disorders, including Parkinson's disease (PD). PD is characterized by the selective loss of dopaminergic neurons in PD-affected brain regions. Dopamine treatment of neuronal cells stimulates the production of reactive oxygen species (ROS) and increases ROS-dependent neuronal apoptosis. In this study, we found that the ubiquitin-specific protease 10 (USP10) protein reduces dopamine-induced ROS production of neuronal cells and ROS-dependent apoptosis by stimulating the antioxidant activity of Nrf2. USP10 interacted with the Nrf2 activator p62, increased the phosphorylation of p62, increased the interaction of p62 with the Nrf2 inhibitor Keap1, and stimulated Nrf2 antioxidant transcriptional activity. In addition, USP10 augmented dopamine-induced Nrf2 translation. Taken together, these results indicate that USP10 is a key regulator of Nrf2 antioxidant activity in neuronal cells and suggest that USP10 activators are promising therapeutic agents for oxidative stress-related diseases, including PD.

P-wave terminal force in lead V1 and outcomes in patients with persistent atrial fibrillation undergoing catheter ablation.

AIMS: The P-wave terminal force in electrocardiogram lead V1 (PTFV1) correlates with outcomes in patients with paroxysmal atrial fibrillation (AF). Nevertheless, the correlation between the PTFV1 and outcomes after AF ablation in patients with persistent AF remains unclear. This study aimed to determine whether the PTFV1 at 3 months after AF ablation could predict AF recurrence and cardiovascular events in patients with persistent AF. METHODS: This historical cohort study examined 453 consecutive patients with persistent AF who underwent a first-time AF ablation. We measured the PTFV1 at 3 months after the ablation. An abnormal PTF was defined as a ≥4 mVms depression. The 3-year incidence of AF recurrence and composite cardiovascular events, including strokes, heart failure hospitalizations, and cardiovascular death, were compared between the abnormal and normal PTF groups. RESULTS: Among 434 enrolled patients, 101 had an abnormal, and 333 normal PTF at 3 months after AF ablation. Compared with the normal PTF group, the abnormal PTF group had a significantly higher incidence of AF recurrence (52.6% vs 28.1%, log-rank P < .001) and cardiovascular events (13.7% vs 2.6%, log-rank P = .005). After adjusting for the risk factors, an abnormal PTF was established as an independent predictor of AF recurrence (hazard ratio [HR] 2.12, 95% confidence interval [CI]: 1.44-3.13, P < .001) and cardiovascular events (HR 3.26, 95% CI: 1.19-8.97, P = .022). CONCLUSIONS: The PTFV1 at 3 months after AF ablation could be a valuable noninvasive predictor of both AF recurrence and cardiovascular events in patients with persistent AF.

Electron-atom Compton profiles due to the intramolecular motions of the H and D atoms in HD.

We report an atomic momentum spectroscopy (AMS) experiment on HD, performed at a scattering angle of 135° and at an incident electron energy of 2.0 keV. The electron-atom Compton profiles due to the intramolecular motions of the H and D atoms in HD were obtained. The two Compton profiles are shown to be identical with each other in both shape and intensity, proving that the experimental responses of the intramolecular atomic motions are disentangled from the effect of molecular translational motion. It is also shown that the Compton profiles are in agreement with associated quantum chemistry-based calculations, indicating that the large momentum transfer limit is achieved under the experimental conditions. These observations demonstrate the ability of AMS not only to map the intramolecular motion of each atom with different masses but also to perform elemental composition analysis of a molecular system.

Theoretical Study of Valence Shell Excitation by Electron Impact in CCl4.

This paper reports a theoretical study of valence shell excitation in CCl4 by high-energy electron impact. Generalized oscillator strengths are calculated for the molecule at the equation-of-motion coupled-cluster singles and doubles level. To elucidate the influence of nuclear dynamics on electron excitation cross-sections, the effects of molecular vibration are included in the calculation. Based on a comparison with recent experimental data, several reassignments of spectral features are made, and it is found that excitations from the Cl 3p nonbonding orbitals to σ* antibonding orbitals, 7a1 and 8t2, play dominant roles below the excitation energy of ∼9 eV. Furthermore, the calculations reveal that distortion of the molecular structure due to the asymmetric stretching vibration significantly affects the valence excitations at small momentum transfers, where contributions from dipole transitions are dominant. It indicates that vibrational effects have a considerable influence on Cl formation in the photolysis of CCl4.

[Epithelioid Hemangioendothelioma of the Upper Mediastinum:Report of a Case].

A 81-year-old woman was referred to our hospital for neck discomfort. Chest computed tomography (CT) showed a tumor in the upper mediastinum. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the mild accumulation in the tumor. Percutaneous biopsy was performed and epithelioid hemangioendothelioma was suspected, and the surgical treatment was performed. The histological study showed polygonal and irregular cells with nuclear atypia in myxoma-like substrate compatible with epithelioid hemangioendothelioma.

HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/ß-catenin signalling pathway.

BACKGROUND: This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/ß-catenin pathway in oesophageal squamous cell carcinoma (ESCC). METHODS: The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, ß-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS: The expression level of HIF-1α, ß-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and ß-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, ß-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. CONCLUSIONS: HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/ß-catenin pathway.

Metformin-Induced Heat Shock Protein Family A Member 6 Is a Promising Biomarker of Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties. METHODS: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed. RESULTS: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC. CONCLUSIONS: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment.

Asymptotic behavior of the electron-atom Compton profile due to the intramolecular H-atom motion in H2.

We report the asymptotic behavior of the electron-atom Compton profile due to the intramolecular H-atom motion in H2. The experiment has been performed at a scattering angle of 135° and at incident electron energies from 1.0 to 2.2 keV, thus covering a momentum transfer (K) range from 15.8 to 23.5 a.u. It is shown that with the increase in K, the Compton profile changes in shape and becomes more symmetric. Furthermore, it is found that the experiment reaches the limit of sufficiently large K at an incident electron energy of 2.0 keV, where the plane-wave impulse approximation is applicable to directly relate the Compton profile to the momentum distribution of the H atom.

Impact of direct oral anticoagulant use on mortality in very old patients with non-valvular atrial fibrillation.

BACKGROUND: the efficacy and safety of direct oral anticoagulants (DOACs) compared with that of warfarin in very old patients with non-valvular atrial fibrillation (NVAF) have been reported in terms of thromboembolisms and bleeding. However, the association of DOAC use and mortality in such patients remains unclear. OBJECTIVES: this study aimed to investigate the incidence of mortality, as well as thromboembolisms and major bleeding, in very old patients with NVAF using DOACs as compared with warfarin. METHODS: we conducted a single-centre historical cohort study of consecutive patients with NVAF aged ≥80 years who used oral anticoagulants. We compared the 5-year outcomes (all-cause mortality, thromboembolism, major bleeding and intracranial haemorrhage) between the DOAC and Warfarin groups. RESULTS: of 1,676 patients with atrial fibrillation aged 80 years and over, 1,208 with NVAF were included. Propensity score matching provided 461 patients in each group, and the risk of all-cause mortality, thromboembolisms, major bleeding and intracranial haemorrhages was significantly lower in the DOAC group than Warfarin group (hazard ratio [95% confidence interval] for DOAC use, 0.68 [0.54-0.87], 0.31 [0.19-0.53], 0.56 [0.36-0.88], 0.23 [0.10-0.56], log-rank P = 0.002, P < 0.001, P = 0.010, P < 0.001). The mortality rate within 1 year after major bleeding was significantly lower in the DOAC group than Warfarin group (14% versus 38%, P = 0.03), however, that after a thromboembolism was similar between the two groups (33% versus 35%). CONCLUSION: patients with NVAF aged ≥80 years and using DOACs had a lower mortality than those using warfarin.

[Primary Pericardial Malignant Mesothelioma:Report of a Case].

A 67-year-old woman was referred to our hospital for cough and fever. Chest computed tomography (CT) showed some masses showing slightly enhanced effect in the pericardium. FDG-PET showed the accumulation of FDG in the masses. Thoracoscopic surgical biopsy was performed to establish the diagnosis. The histological study showed proliferation of short spindle-shaped cells surrounded by lymphocyte, and the spindle cells were immunohistochemically positive for cytokeratin AE1/AE3, WT-1, D2-40, CAM5.2, intelectin-1 and negative for CEA, TTF-1, napsin A, claudin-4, calretinin, MUC4, PAX8, CD30. These findings were compatible with epithelial pericardial malignant mesothelioma.

Biased expression of mutant alleles in cancer-related genes in esophageal squamous cell carcinoma.

BACKGROUND: Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed. METHODS: We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA. RESULTS: The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification. CONCLUSIONS: The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways.

Lithographically Formed Fine Wavy Surface Morphology for Universal Alignment Control of Mesochannels in Mesostructured Silica Films.

In-plane orientation of mesochannels in mesostructured silica films is fully controlled by a lithographically formed anisotropic surface morphology of a substrate. The orientation is determined simply by elastic properties of a liquid crystal phase, which appears in the course of the formation of mesostructured silica films through the sol-gel process. When an array of linear microscopic grooves with a round cross section is closely formed on the substrate surface, the cylindrical mesochannels in the films are entirely aligned strictly perpendicular to the grooves, as a consequence of minimization of the total elastic energy. When the surface morphology geometrically fits to the hexagonal arrangement of the mesochannels, the orientation abruptly changes into the direction parallel to the long axis of the grooves. The alignment control based on the elastic property of the liquid crystal phase described in this report does not require any specific chemical interactions between the surfactant molecules and the substrate surface. Therefore, aligned mesostructured silica films with a large structural periodicity can successfully be formed using block copolymer surfactants, which hardly form an aligned mesostructure without the support of external fields. The vapor-phase synthesis, which enables considerable retardation of the solidification process of siliceous species, is the most favorable way, and totally aligned mesostructured silica films with significantly large thickness, more than 1 µm, can be obtained. Appropriate combination of the bottom-up and the top-down nanoprocesses reported in this paper, that is, self-assembly and photolithography, will enable the formation of highly anisotropic nanostructured materials, which will find various practical applications.

[Successful Endoscopic Submucosal Dissection of Early Gastric Cancer after Ulcer Healing Associated with a Malignant Cycle-A Case Report].

A 79-year-old man was detected with anemia on medical examination and underwent gastroscopy at the previous hospital. Gastroscopy revealed a 15-mm ulcerative lesion(Type 0-Ⅱc plus Ⅲ)on the greater curvature of the upper gastric body. Tumor biopsy showed well-differentiated adenocarcinoma. The patient was suspected of deep submucosal invasion due to poor stretching of the gastric wall and the ulcer depth; hence, he was transferred to our hospital for surgery. When gastroscopy was repeated, the ulcer was found to be scarred(Type 0-Ⅱc), thereby indicating the occurrence of intramucosal carcinoma; hence, endoscopic submucosal dissection was performed. The pathological finding showed 10×6 mm, tub1, pT1a, ly0, v0, pUL1, pHM0, pVM0, suggesting a curative resection. Early gastric cancer of the depressed type is known to develop a malignant cycle with repeated improvements and exacerbations of the ulcer. Diagnosing the depth of tumor invasion is particularly difficult when there is an active ulcer. For small lesions with active ulcers, repeating gastroscopy might allow for correct diagnosis and appropriate treatment.

Tumor-derived exosomes influence the cell cycle and cell migration of human esophageal cancer cell lines.

Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor-derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor-derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound-healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor-derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination-based cell cycle indicator expressing ESCC cells revealed that the ratio of G1-phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high-density exposure of cancer-derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high-density tumor-derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation.

Temperature-Dependent Electron Momentum Spectroscopy on the Molecular Orbitals of Dimethyl Ether.

This paper investigates vibrational excitation effects on valence electron momentum distributions of dimethyl ether. A symmetric noncoplanar (e, 2e) experiment has been performed for the molecule at a high temperature (980 K) as well as at room temperature (300 K). For comparison, theoretical calculations with vibrational effects being involved have also been carried out. Changes of the momentum profiles with the rise of temperature are observed for the 2b1 and 6a1 orbitals, indicating that distortion of these molecular orbitals is appreciably enhanced upon excitation of the methyl torsional vibrations. The present study provides a way for exploring the influence of vibrational excitation on electronic wavefunctions of molecules.

Forward-backward asymmetry in electron impact ionization of CO.

We experimentally investigate the molecular-orientation dependence of high-energy electron-impact ionization of CO. The direction of the molecular-axis with respect to the momentum transfer vector K is deduced from the angular correlation between the fragment ion and the scattered electron. The experimental results on the 3 2Π ionization reveal that at small momentum transfer, the ionization probability near the threshold is higher when K points toward the C atom along the molecular axis than when it is in the opposite direction. Such a forward-backward asymmetry does not appear in single-photon ionization and requires non-dipole contributions. It is also shown that the {4 2Σ+ + 5 2Σ+ + 6 2Σ+} ionization preferentially takes place in the vicinity of the molecular orientation parallel to K at small momentum transfer, while non-dipole contributions cause the decrease in the relative intensity of the parallel direction.

[Solitary Pulmonary Metastasis from Follicular Thyroid Carcinoma Resected 28 Years Earlier Coexisting with Early Lung Cancer;Report of a Case].

A 71-year-old woman was referred to our hospital for a round mass shadow in the right lower lung field in mass screening chest X-ray. Computed tomography (CT) of the chest showed a well-defined lobulating mass shadow measuring 2.2 cm in diameter in the lower lobe of the right lung and a ground glass opacity ( GGO) in the upper lobe of the left lung. She underwent video-assisted partial resection of right lower lobe of the lung. The pathological examinations indicated a pulmonary metastasis of follicular thyroid carcinoma. Three months later, video-assisted partial resection of left upper lobe of the lung was performed. Microscopically, 2 lesions of adenocarcinoma in situ were revealed.

[Creation of Brain Parenchymal Equivalent Phantom for Diffusion Weighted Image Using Microwave Oven: A Different Heating Method].

The acute micro cerebral infarction phantom was created to evaluate the detectability of acute micro cerebral infarction and optimize scan conditions in magnetic resonance imaging (MRI) examinations. The creation of the brain parenchyma phantom requires a hot stirrer that can be heated and stirred simultaneously. However, few hospitals and facilities have hot stirrers. The aim of our study was to use a microwave oven instead of a hot stirrer for the creation of a brain parenchyma phantom. Five phantoms using a hot stirrer and five phantoms using a microwave oven were created. The phantom creation time, T2 value, apparent diffusion coefficient (ADC) value, uniformity, and reproducibility of MR images were compared between the two creation methods. The phantom creation time, when using a microwave oven was 108±8 minutes, which was significantly shorter than that of 213± 48 minutes when using a hot stirrer. T2 values, ADC values, uniformity, and reproducibility were not significantly different. Therefore, it is easier to create an acute micro cerebral infarction phantom using a microwave oven compared to a hot stirrer.

Electron momentum spectroscopy study on the valence electronic structure of methyl formate.

We report an electron momentum spectroscopy study on methyl formate. A symmetric noncoplanar (e, 2e) experiment has been performed at an incident electron energy of 1.2 keV and electron momentum profiles of the valence orbitals have been obtained. On the basis of the result, assignments of the 10a'-1 and 1a″-1 bands have been made to resolve a contradiction between photoelectron spectroscopy and Penning ionization electron spectroscopy studies. Comparisons between experiment and theory reveal that the influence of the molecular vibration has to be taken into account for a proper understanding of the electron momentum profiles. Contributions of individual vibrational normal modes have also been investigated in detail by means of the harmonic analytical quantum mechanical approach.

[Development of TP53-Targeted Treatment in Esophageal Squamous Cell Carcinoma Using Cancer Genomic Profiling Test].

Recently, the interest in cancer genomic medicine has increased, owing to the powerful and cost-effective technology of next-generation sequencing(NGS), which allows rapid identification of a large number of gene mutations. TP53 mutations are frequently found in solid cancers, especially in esophageal squamous cell carcinoma(ESCC), wherein the frequency of TP53 mutation is considered to be 90% or more. However, there is no clinical targeted therapy as yet utilizing TP53. Here, we aimed to characterize TP53 mutations associated with ESCC, in order to assess its feasibility as a therapeutic target. We extracted DNA and RNA from specimens of ESCC patients and analyzed them using NGS, which revealed different TP53 mutations. Based on previous reports, it is considered that different TP53 mutations lead to different functions of the protein, and subsequently account for varied prognosis in squamous cell carcinoma of the head and neck. We also performed cell viability assay using ESCC cell lines with different TP53 mutations and 2 kinds of p53-targeted drug and found differences in the growth inhibition of the cell lines. Although individual treatment can be determined depending on the type of TP53 mutation, it would be necessary to further examine the interaction of TP53 with other genes to determine its therapeutic efficacy as a target.