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It is shown that electron-atom Compton scattering has the ability not only to map the intramolecular motion of each atom with different masses but also to perform elemental composition analysis of a molecular system.

The number of elderly patients with acute decompensated heart failure (ADHF) is increasing, and it is often difficult to treat. This study aimed to evaluate the efficacy and safety of using tolvaptan early after hospitalization in elderly patients with ADHF and the prognosis one year after hospitalization. This study enrolled 185 patients with ADHF who were admitted for the first time. Tolvaptan was administered within 24 h after admission. These patients were assigned to two groups: over 80 years old (n = 109) and under 80 years old (n = 76). There were no significant differences between the two groups in the occurrence of MACCE within one year (25% vs. 20%, p = 0.59). All-cause mortality was significantly higher in the over-80 group (12% vs. 2%, p = 0.01). There were no significant differences in the incidence of worsening renal failure (11% vs. 7%, p = 0.46) and hypernatremia (5% vs. 9%, p = 1.0), and in the duration of hospitalization (19.2 days vs. 18.8 days, p = 0.8). Tolvaptan might be effective and safe in elderly patients with ADHF, and there was no difference in the incidence of MACCE within one year.

BACKGROUND: This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-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, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS: The expression level of HIF-1α, β-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 β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-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/β-catenin pathway.

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.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.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.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.

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.

How to look at the intramolecular motion of an atom – a result of the asymptotic behavior of the electron-atom Compton profile.

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.

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 Conclusion patients with NVAF aged ≥80 years and using DOACs had a lower mortality than those using warfarin.

TAR DNA-binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates, namely, stress granules (SGs) first and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that ubiquitin-specific protease 10 (USP10) promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding-dependent manner; however, impaired RNA binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35 aggregates in the neurons of ALS patients were USP10 negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

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, The wound closure rate was compared between groups with or without cancer‐derived exosome exposure. There was a significant difference between 10 μg/mL exosome concentration and control at 12 and 24 h in both TE2 and T.Tn (P

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.

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.

Background/Aim: Several articles have assessed the prognostic significance of the expression of sirtuin 1 (SIRT1) in esophageal squamous cell carcinoma (ESCC). However, evidence in this field is insufficient. Thus, we conducted a meta-analysis to investigate the prognostic and clinical impact of SIRT1 expression in ESCC. Materials and Methods: We searched the PubMed, Cochrane Library, and Web of Science databases for articles on the expression of SIRT1 and clinicopathological features in patients with ESCC. A meta-analysis was conducted. Results: Four studies with 429 patients were included. The meta-analysis revealed a significant relationship between the high expression of SIRT1 and higher T-stage (odds ratio=2.39. 95% confidence interval=1.12-5.13, p=0.02), more advanced TNM stage (odds ratio=2.35. 95% confidence interval=1.20-4.60, p=0.01), and a poor overall survival (hazard ratio=1.90, 95% confidence interval=1.45-2.47, p

This chapter aims to provide novel support for a phrasal complementation approach to restructuring phenomena on the basis of an analysis of some novel observations concerning the scope properties of nominative objects in Japanese. It is first shown that nominative objects must take scope under the potential suffix when subjects receive an instrumental case. It is then argued that the obligatory narrow scope of nominative objects under consideration follows from the phrasal complementation approach, which dictates that the nominative object is base-generated below the potential suffix. The observation is difficult to capture with an alternative complex head approach, in which the nominative object is always base-generated above the potential suffix.

The authors report experimental measurements on electron-impact ionization of CO${}_{2}$ using the angle- and energy-resolved electron-ion-coincidence technique. The results provide experimental evidence of symmetry breaking in electron-impact dissociative ionization of symmetric molecules.

Summary Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin (OPTN) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43., Graphical abstract, Highlights • ALS-linked mutations of optineurin (OPTN) delay clearance of stress granules (SGs). • Depletion of OPTN increases ubiquitinated TDP-43 levels by increasing TIA1 • ALS-linked OPTN mutants increase ubiquitinated TDP-43 levels by increasing TIA1 • High TIA1 induces aberrant SGs with ubiquitinated TDP-43 and delays SG clearance, Biological sciences; Molecular neuroscience; Cellular neuroscience

The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

Background The optimal strategy for catheter ablation of persistent atrial fibrillation (PeAF) remains unknown. A preprocedural additive treatment for patients undergoing pulmonary vein isolation (PVI) alone to optimize catheter ablation should be investigated. Objective The purpose of this study was to determine whether pharmacologic cardioversion with a fixed low-dose antiarrhythmic drug (AAD) before ablation could stratify the long-term outcome of a PVI-alone strategy. Methods We conducted a prospective cohort study of PeAF patients who underwent PVI using contact force-sensing catheters. No substrate modification was performed. Fixed low-dose bepridil was administered before ablation for cardioversion and patients were classified into 2 groups based on obtaining sinus rhythm (SR). The rate of recurrence of atrial fibrillation (AF) and/or atrial tachycardia (AT) within 36 months was compared between the 2 groups. Results Among the 303 PeAF patients who received the AAD, 102 returned to SR (SR group), and the other 201 had persistence of AF (non-SR group). AF persistence duration at baseline and during bepridil administration was similar between the 2 groups. The SR group had a significantly lower 36-month AF/AT recurrence rate than the non-SR group (17 [22.2%] vs 55 [34.0%], log-rank P = .022). AT-type recurrence was observed in 16 patients (2 [3.3%] in the SR group vs 14 [8.9%] in the non-SR group; log-rank P = .051). Nonresponse to AAD was an independent predictor of AF/AT recurrence after adjusting for other risk factors (hazard ratio 1.34; 95% confidence interval 1.01–1.77; P = .040). Conclusion Preprocedural pharmacologic cardioversion could be a useful determinant for patients with treatable PeAF by PVI alone.

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.

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.