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Abstract We discuss the effects of electric fields along compact directions within (supersymmetric) gauge theory in ℝ 1 , 3 × T 2 × T 2 × T 2 $$ {\mathbb{R}}^{1,3}\times {\mathbbm{T}}^2\left(\times {\mathbbm{T}}^2\times {\mathbbm{T}}^2\right) $$ . The electric field along compact directions is equivalent to time-dependent homogeneous configuration of Wilson line moduli, which would be relevant to physics in the early universe. In particular, we consider models with and without background magnetic fluxes, which lead to completely different effects of the electric field due to the difference in the Kaluza-Klein (KK) level structure. We show that, in the case without magnetic fluxes, the deceleration of KK momenta may cause non-perturbative KK particle production dubbed as the KK Schwinger effect, whereas in the case with magnetic flux such KK particle production does not take place but flavor structure of low energy effective theory may be affected.

Abstract Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life‐threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well‐controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid‐resistant LM with fulminant relapse.

Abstract The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

Chronic liver injury leads to decreased liver function and increased fibrosis. Fibrosis is not only associated with the development of portal hypertension and carcinogenesis, but with the occurrence of events and a poor prognosis, highlighting the importance of non‐invasive fibrosis assessment in patients. In the present study, we searched for markers related to liver fibrosis via proteomic analysis of small extracellular vesicles (sEVs). In the discovery cohort, proteomic analysis was carried out in the sEVs extracted from the sera of 5 patients with decompensated cirrhosis, 5 patients with compensated cirrhosis, and 5 controls without liver disease. Interestingly, in this cohort, fibulin‐4 was significantly associated with cirrhosis while in the validation cohort [formed by 191 patients: 7 patients without disease, 16 patients without liver disease (other diseases), 38 patients with chronic liver disease (CLD), 75 patients with cirrhosis of Child–Pugh class A (36 without hepatocellular carcinoma [HCC], 29 with HCC), and 65 patients with cirrhosis of Child–Pugh class B–C (39 without HCC, 26 with HCC)], fibulin‐4/CD9 levels increased with cirrhosis progression. Furthermore, the fibulin‐4/CD9 ratio was significantly higher in patients with varices. Immunostaining also revealed strong fibulin‐4 expression in cholangiocytes within the fibrous areas and mesothelial cells in liver tissue blood vessels. Taken together, our results suggest that fibulin‐4, essential for lysyl oxidase activation, might be a new liver fibrosis marker found in the sEVs of patients with cirrhosis.

Abstract Background The progression of liver fibrosis leads to portal hypertension and liver dysfunction. However, no antifibrotic agents have been approved for cirrhosis to date, making them an unmet medical need. Small extracellular vesicles (sEVs) of mesenchymal stem cells (MSCs) are among these candidate agents. In this study, we investigated the effects of sEVs of MSCs, analyzed their distribution in the liver post-administration, whether their effect was dose-dependent, and whether it was possible to collect a large number of sEVs. Methods sEVs expressing tdTomato were generated, and their uptake into constituent liver cells was observed in vitro, as well as their sites of uptake and cells in the liver using a mouse model of liver cirrhosis. The efficiency of sEV collection using tangential flow filtration (TFF) and changes in the therapeutic effects of sEVs in a volume-dependent manner were examined. Results The sEVs of MSCs accumulated mostly in macrophages in damaged areas of the liver. In addition, the therapeutic effect of sEVs was not necessarily dose-dependent, and it reached a plateau when the dosage exceeded a certain level. Furthermore, although ultracentrifugation was commonly used to collect sEVs for research purposes, we verified that TFF could be used for efficient sEV collection and that their effectiveness is not reduced. Conclusion In this study, we identified some unknown aspects regarding the dynamics, collection, and capacity dependence of sEVs. Our results provide important fundamentals for the development of therapies using sEVs and hold potential implications for the therapeutic applications of sEV-based therapies for liver cirrhosis.

Abstract Introduction B‐cell lymphoma/leukemia 11B (BCL11B) is a subunit of SWI/SNF chromatin remodeling complexes and functions in cell cycle regulation and apoptosis upon DNA replication stress and damages via transcription. Many malignancies were reported to exhibit changes in BCL11B gene expression; however, no study has focused on the relationship between BCL11B and hepatocellular carcinoma, which potentially exhibits DNA replication stress and damages upon its oncogenesis. Thus, in this study, we examined the molecular characterization of BCL11B expression in hepatocellular carcinoma. Methods and Results The cumulative progression‐free survival and overall survival were significantly longer in the clinical cases of BCL11B‐negative hepatocellular carcinoma than BCL11B‐positve cases. Microarray and real‐time PCR analyses in hepatocellular carcinoma cell lines indicated a correlation between BCL11B and GATA6, a gene reported to be correlated with oncogenic activities and resistance to anthracycline, which is often used for hepatocellular carcinoma chemotherapy. Consequently, BCL11B‐overexpressing cell lines exhibited resistance to anthracycline in cell growth assays and the resistance has been evidenced by the increased expression of BCL‐xL in cell lines. The results were supported by the analyses of human HCC samples showing the correlation between BCL11B and GATA6 expressions. Discussions and Conclusion Our results indicated that overexpression of BCL11B amplifies GATA6 expression in hepatocellular carcinoma in vitro and in vivo that leads to anti‐apoptotic signal activation, and induces resistance to chemotherapy, which influenced the postoperative prognosis.

Abstract Background and Aim Treatment response to ursodeoxycholic acid may predict the prognosis of patients with primary biliary cholangitis (PBC). Recent studies have suggested the benefits of using machine learning (ML) to forecast complex medical predictions. We aimed to predict treatment response in patients with PBC using ML and pretreatment data. Methods We conducted a single‐center retrospective study and collected data from 194 patients with PBC who were followed up for at least 12 months after treatment initiation. Patient data were analyzed with five ML models, namely random forest, extreme gradient boosting (XGB), decision tree, naïve Bayes, or logistic regression, to predict treatment response using the Paris II criteria. The established models were assessed using an out‐of‐sample validation. The area under the curve (AUC) was used to evaluate the efficacy of each algorithm. Overall survival and liver‐related deaths were analyzed using Kaplan–Meier analysis. Results Compared to logistic regression (AUC = 0.595, P = 0.0219, 0.031 models), ML analyses showed significantly high AUC in the random forest (AUC = 0.84) and XGB (AUC = 0.83) models; however, the AUC was not significantly high for decision tree (AUC = 0.633) or naïve Bayes (AUC = 0.584) models. Kaplan–Meier analysis showed significantly improved prognoses in patients predicted to achieve the Paris II criteria by XGB (log‐rank = 0.005 and 0.007). Conclusion ML algorithms could improve treatment response prediction using pretreatment data, which could lead to better prognoses. In addition, the ML model using XGB could predict the prognosis of patients before treatment initiation.

Abstract This paper introduces the development of test methods for capability evaluation of Unmanned Aircraft Systems (UASs) in Global Navigation Satellite System (GNSS)-denied environments. The purpose of this development is to facilitate growth in the UAS industry. We discuss the test method’s approach and what UAS’s capability evaluation is essential for UAS use in GNSS-denied environments. As a result, we decided to adopt an approach that a test method evaluates a capability to perform a single simple task. In addition, these test methods should be along with the requirement of UAS manufacturers and users. Thus, first, we develop test methods to assess mobility in narrow spaces with obstacles shielding GNSS radio. We repeatedly have demonstrations and discussions of our test method with UAS manufacturers and users from the early stage of this development and collect their opinions for improvement to proceed with the development while building consensus with them. In addition, we evaluate several UASs by the test methods and examine whether our test method makes it possible to show the difference in UAS capability. This paper describes the approach of the test methods, the test methods for mobility in a GNSS-denied environment, the demonstrations and discussions with UAS manufacturers and users, and the results of the UAS’s performance evaluation by the test methods.

Objectives: The prolonged presence of infectious SARS-CoV-2 in deceased patients with COVID-19 has been reported. However, infectious virus titers have not been determined. Such information is important for public health, death investigation, and handling corpses. The aim of this study was to assess the level of SARS-CoV-2 infectivity in the corpses of patients with COVID-19. Methods: We collected 11 nasopharyngeal swabs and 19 lung tissue specimens from 11 autopsy cases with COVID-19 in 2021. We then investigated the viral genomic copy number by real-time reverse transcription-polymerase chain reaction and infectious titers by cell culture and virus isolation. Results: Infectious virus was present in six of 11 (55%) cases, four of 11 (36%) nasopharyngeal swabs, and nine of 19 (47%) lung specimens. The virus titers ranged from 6.00E + 01 plaque-forming units/ml to 2.09E + 06 plaque-forming units/g. In all cases in which an infectious virus was found, the time from death to discovery was within 1 day and the longest postmortem interval was 13 days. Conclusion: The corpses of patients with COVID-19 may have high titers of infectious virus after a long postmortem interval (up to 13 days). Therefore, appropriate infection control measures must be taken when handling corpses.

Summary: The stomach is an important digestive organ with various biological functions. However, because of the complexity of its cellular and glandular composition, its precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequencing (scRNA-seq) and subcellular-level spatial transcriptomics analysis of the human stomach and constructed the largest dataset to date: a stomach encyclopedia. This dataset consists of approximately 380,000 cells from scRNA-seq and the spatial transcriptome, enabling integrated analyses of transcriptional and spatial information of gastric and metaplastic cells. This analysis identified LEFTY1 as an uncharacterized stem cell marker, which was confirmed through lineage tracing analysis. A wide variety of cell-cell interactions between epithelial and stromal cells, including PDGFRA+BMP4+WNT5A+ fibroblasts, was highlighted in the developmental switch of intestinal metaplasia. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies of development, aging, and carcinogenesis.

Background & Aims: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. Methods: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2−/−). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. Results: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. Conclusions: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

Abstract Infection with certain viruses is an important cause of cancer. The Pan‐Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole‐genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein–Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV‐positive cancer cases detected by WGS‐based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV‐High, EBV‐Low, and EBV‐Negative. The EBV‐High subgroup was found to be EBV‐positive in the cancer cells themselves, whereas the EBV‐Low subgroup was EBV‐positive in the surrounding lymphocytes. Further, the EBV‐Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV‐positive in the surrounding lymphocytes, which was associated with a poor prognosis.

Abstract Background Thresholding apparent diffusion coefficient (ADC) maps obtained from Diffusion-Weighted-Imaging (DWI) has been proposed for identifying benign lesions that can safely avoid biopsy. The presence of malignancies with high ADC values leads to high thresholds, limiting numbers of avoidable biopsies. Purpose We evaluate two previously reported methods for identifying avoidable biopsies: using case-set dependent ADC thresholds that assure 100% sensitivity and using negative likelihood ratio (LR-) with a fixed ADC threshold of 1.50 × 10–3 mm2/s. We evaluated improvements in efficacy obtained by excluding non-mass lesions and lesions with anisotropic intra-lesion morphologic characteristics. Study type Prospective. Population 55 adult females with dense breasts with 69 BI-RADS 4 or 5 lesions (38 malignant, 31 benign) identified on ultrasound and mammography and imaged with MRI prior to biopsy. Field strength/sequence 1.5 T and 3.0 T. DWI. Assessment Analysis of DWI, including directional images was done on an ROI basis. ROIs were drawn on DWI images acquired prior to biopsy, referencing all available images including DCE, and mean ADC was measured. Anisotropy was quantified via variation in ADC values in the lesion core across directional DWI images. Statistical tests Improvement in specificity at 100% sensitivity was evaluated with exact McNemar test with 1-sided p-value

Abstract Background and Aim Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan–Meier analysis with propensity score matching and logistic progression analysis. Results The cumulative risk of developing a new symptom after 10 and 20 years of follow‐up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033–1.165; P = 0.002), the serum D‐Bil level (HR, 6.262; 95% CI, 2.522–15.553, P

Abstract Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.

Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRASG12D-induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRASG12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRASG12D + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRASG12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis.

Abstract Understanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8+ T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer.

Abstract This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or

This study investigated the behavior of a non-corroded reinforced concrete (RC) beam and two RC beams with non-uniform corrosion (whole span and side span) in a four-point bending test. The corrosion distributions of the tensile steel rebars were measured by two methods: diameter loss and mass loss. The peak values of corrosion distribution in the diameter-loss measurements were much greater than those in the mass-loss measurements. However, the average corrosion according to the diameter measurements was smaller than that in the mass-loss measurements. The corrosion distribution trends were the same in the two methods, indicating good measurement accuracy. From the bending test results, it appears that increasing corrosion area and corrosion ratios reduce the beams’ stiffness, yielding capacity, and ultimate capacity. All three specimens had similar failure patterns: steel yielding followed by compression failure of the concrete. A nonlinear three-dimensional (3D) analysis model that considered the non-uniform corrosion of the rebars was established and verified by experimental data. The model’s predictions for stiffness, ultimate capacity, and failure patterns were consistent with experimental results. The spatial variability factor (R'), which is the ratio of the maximum corrosion ratio (γmax) to the average corrosion ratio (γave), was adopted to quantify the non-uniformity of the corrosion distribution in this study.

Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for 10%–20% of the total HCC numbers. Its clinical features include the occurrence in the younger generation, large tumors, and poor prognosis. The contribution of hepatitis B virus X (HBx) protein in hepatocytes during activation of various oncogenic pathways has been reported. We aimed to assess the possible association between HBx and Yes-associated protein (YAP) expression in the liver tissue and the clinical features of HBV-related HCC. Methods: The relationship between HBx and YAP expression was examined in vivo using HCC tumor and peritumor tissues (n = 55). The clinical information including tumor size, marker, and the prognosis was assessed with protein expressions. The in vitro gene expression analyses were conducted using HBx- and YAP-overexpressing HCC cell lines. Results: Among 19 cases of HBV-related, 17 cases of hepatitis C virus (HCV)-related, and 19 cases of nonviral-related HCC, the HBV-related tumor showed the largest size. The HBx-stained area in the tumor and peritumor tissue showed a significant correlation with tumor size and serum α-fetoprotein level. YAP expression was higher in HBV-related tumor tissue than in the peritumor tissue and HCV-related tumor. Additionally, HBx and YAP protein expressions are correlated and both expressions in the tumor contributed to the poor prognosis. An in vitro study demonstrated that HBx and YAP overexpression in the hepatocytes activate the various oncogenic signaling pathways. Conclusions: Our study demonstrated that YAP expression in the liver of HBV-infected patients might be the key factor in HBV-related HCC development and control of tumor-related features.

The effects of cross flow and fluctuating cross flow on the aerodynamic performance of multirotor drone propellers were investigated by using wind tunnel testing and numerical simulations. Three hovering propellers were examined and were designed based on Adkins and Liebeck theory with modifications. Thrust coefficient CT and power coefficient CP of each propeller were experimentally measured and Figure of Merit FM was evaluated. From the cross flow experiments and numerical simulations, CT, CP and FM calculated were in reasonable agreement with the experimental results at high cross flow velocity. The results implicated that a stall might occur at near the root of the propeller as well as demonstrated that the starting point of the propeller design played a role in aerodynamic performance under the cross flow conditions. Moreover, from the fluctuating cross flow experiments, CT, CP and FM fluctuated in time and the propellers are more susceptible to cross flow and fluctuating cross flow at lower rotational speed in terms of the amount of change of aerodynamic forces.

Endometrial stromal sarcoma is a rare uterine mesenchymal neoplasm, and extrauterine endometrial stromal sarcoma is even rarer, with a limited number of case reports. In the present report, we present a case of low-grade extrauterine endometrial stromal sarcoma originating from the mesentery in a 49-year-old woman, without endometrial stromal sarcoma in the uterus or evidence of endometriosis. The tumor was diagnosed using recombination of the JAZF1 gene by fluorescence in situ hybridization. Computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed a 13 cm, primarily polycystic, mass containing a contrast-enhancing solid component with restricted diffusion and mild 18F-fluorodeoxyglucose uptake. A large cystic component may be a characteristic feature of extrauterine endometrial stromal sarcoma, given the low pressure from the surrounding tissues.

Postmortem computed tomography (CT) is currently a well-known procedure and helps in postmortem investigations. In this case report, we report a unique postmortem CT finding: delayed cerebral enhancement associated with the antemortem infusion of contrast medium. A 72-year-old female lost consciousness at a restaurant and was taken to a hospital in an ambulance. Despite resuscitation efforts, she died of hypoxic–ischemic encephalopathy caused by cardiac arrest. About 6 h before her death, she underwent enhanced antemortem CT of the head. No abnormal enhancement was observed in the cerebral parenchyma. Then, 11 h after her death, she underwent unenhanced postmortem CT, which showed bilateral hyperdense caudate nucleus and putamina, due to residual iodinated contrast medium, in addition to other characteristic findings of hypoxic–ischemic encephalopathy. The mechanism underlying this phenomenon could be the destruction of the blood–brain barrier, and/or selective vulnerability, due to hypoxic–ischemic changes in the gray matter. Enhancement of basal ganglia on postmortem CT due to antemortem infusion of iodinated contrast medium might suggest hypoxic–ischemic encephalopathy, which should be noted in postmortem CT interpretations.

Abstract Background Schwannomas are neoplasms that typically arise from the myelin sheath of peripheral nerves and rarely originate within the brain parenchyma. Some case reports present schwannomas arising from the brainstem, but regrowth of the tumor and the efficacy of postoperative irradiation have not been examined. In addition, the genetic background of schwannomas arising from the brainstem has not been investigated. Case presentation A 21-year-old male presented with diplopia, dysphagia, and left-sided hemiparesis, dysesthesia, and ataxia. Intracranial imaging showed a heterogeneous mass with a cystic lesion in the pontomedullary junction. Since the tumor caused obstructive hydrocephalus, the patient underwent subtotal tumor resection. A histopathologic evaluation aided a diagnosis of brainstem intraparenchymal schwannoma. Gradual postoperative mass regrowth was recognized. Three-dimensional conformal radiotherapy was performed on the residual mass and surgical cavity. No tumor regrowth was observed 4 years after surgery. To investigate the genetic background of the tumor, target sequences for 36 genes, including NF2, SMARCB1, and LZTR1, and microsatellite analysis for loss of 22q did not show any somatic variants or 22q loss. Conclusions We suggest that brainstem schwannomas might differ from conventional schwannomas in their genetic background.

Abstract We pursue the time evolution of the domain walls in 5D gravitational theory with a compact extra dimension by numerical calculation. In order to avoid a kink-antikink pair that decays into the vacuum, we introduce a topological winding in the field space. In contrast to the case of non-gravitational theories, there is no static domain-wall solution in the setup. In the case that the minimal value of the potential is non-negative, we find that both the 3D space and the extra dimension will expand at late times if the initial value of the Hubble parameter is chosen as positive. The wall width almost remains constant during the evolution. In other cases, the extra dimension diverges and the 3D space shrinks to zero at a finite time.

Abstract Objectives Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double‐ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2–3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α‐diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

Abstract Background There is an increasing interest in non-contrast-enhanced magnetic resonance imaging (MRI) for detecting and evaluating breast lesions. We present a methodology utilizing lesion core and periphery region of interest (ROI) features derived from directional diffusion-weighted imaging (DWI) data to evaluate performance in discriminating benign from malignant lesions in dense breasts. Methods We accrued 55 dense-breast cases with 69 lesions (31 benign; 38 cancer) at a single institution in a prospective study; cases with ROIs exceeding 7.50 cm2 were excluded, resulting in analysis of 50 cases with 63 lesions (29 benign, 34 cancers). Spin-echo echo-planar imaging DWI was acquired at 1.5 T and 3 T. Data from three diffusion encoding gradient directions were exported and processed independently. Lesion ROIs were hand-drawn on DWI images by two radiologists. A region growing algorithm generated 3D lesion models on augmented apparent-diffusion coefficient (ADC) maps and defined lesion core and lesion periphery sub-ROIs. A lesion-core and a lesion-periphery feature were defined and combined into an overall classifier whose performance was compared to that of mean ADC using receiver operating characteristic (ROC) analysis. Inter-observer variability in ROI definition was measured using Dice Similarity Coefficient (DSC). Results The region-growing algorithm for 3D lesion model generation improved inter-observer variability over hand drawn ROIs (DSC: 0.66 vs 0.56 (p 0.8) in 46% vs 13% of cases, respectively (p

Abstract Purpose Our aim is to make an ideal embryo culture medium close to human oviduct fluid (HOF) components, and to evaluate the quality of this medium with embryo quality and clinical outcomes in assisted reproductive technology (ART) by a prospective randomized controlled trial (RCT). Methods Study I: HOF was collected laparoscopically from patients (n = 28) with normal pelvic findings. According to HOF analysis results, the new medium “HiGROW OVIT®” (OVIT) was designed. Study II: Embryos (2 pronuclei (2PN) = 9633) were assigned from 1435 patients. The blastulation rate (BR), good BR (gBR), utilized (transferred/cryo‐preserved) BR (uBR), pregnancy rate (PR), and miscarriage rate (MR) were compared between the OVIT and control groups by RCT. Results The novel medium ‘OVIT’ was produced according to 31 HOF components. The concentrations of essential amino acids (e‐AAs) were lower in OVIT than in current media, yet the opposite was true for ne‐AA concentrations. gBR and uBR were higher in the OVIT group than in the control group. In the older female group, gBT and uBR were significantly higher in the OVIT group. Conclusions The novel medium ‘OVIT’ was produced according to HOF data. The OVIT had significantly better embryo quality and clinical outcomes than the current media.

Serum amyloid A (SAA) is an acute phase protein, which undergoes structural changes and deposits in the extracellular matrix, causing organ damage. Systemic AA amyloidosis is a relatively common amyloid subtype among the more than 30 amyloid subtypes, but the mechanism of amyloid fibril formation remains unclear. In this study, we investigated the tissue distribution of SAA derived peptides in formalin-fixed paraffin embedded (FFPE) specimens of human myocardium with amyloidosis using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). In the whole SAA protein, four trypsin-digested peptides in the range of SAA2-67 were visualized and the N-terminal peptide; SAA2-15, was selectively localized in the Congo red-positive region. The C-terminal peptides; SAA47-62, SAA48-62, and SAA63-67 were detected not only in the Congo red-positive region but also in the surrounding negative region. Our results demonstrate that the N-terminal SAA2-15 plays a critical role in the formation of AA amyloid fibril, as previously reported. Roles of the C-terminal peptides require further investigation.

Serum amyloid A (SAA) is an acute phase protein, which undergoes structural changes and deposits in the extracellular matrix, causing organ damage. Systemic AA amyloidosis is a relatively common amyloid subtype among the more than 30 amyloid subtypes, but the mechanism of amyloid fibril formation remains unclear. In this study, we investigated the tissue distribution of SAA derived peptides in formalin-fixed paraffin embedded (FFPE) specimens of human myocardium with amyloidosis using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). In the whole SAA protein, four trypsin-digested peptides in the range of SAA2-67 were visualized and the N-terminal peptide; SAA2-15, was selectively localized in the Congo red-positive region. The C-terminal peptides; SAA47-62, SAA48-62, and SAA63-67 were detected not only in the Congo red-positive region but also in the surrounding negative region. Our results demonstrate that the N-terminal SAA2-15 plays a critical role in the formation of AA amyloid fibril, as previously reported. Roles of the C-terminal peptides require further investigation.

Overt hepatic encephalopathy (HE) is one of the complications of liver cirrhosis (LC), which negatively affects the prognosis and quality of life of patients. Small intestinal bacterial overgrowth (SIBO) is significantly associated with LC and its complications, including HE. We investigated the relationship between SIBO and LC, and the difference between hydrogen-producing and methane-producing SIBO (H-SIBO and M-SIBO, respectively). This is a prospective cohort study of 107 cases. Breath measurements of hydrogen and methane concentrations were performed for the diagnosis of SIBO. The study cohort included 81 males with a median age of 70 (40-86) years, and SIBO was detected in 31 cases (29.0%). There were no significant differences between the SIBO positive and SIBO negative groups. Reclassification into H-SIBO (16 cases) and others (91 cases) was performed, and the Child-Pugh score was only derived in the multivariate logistic analysis (P = 0.028, odds ratio 1.39, 95% confidence interval 1.04-1.85). Furthermore, H-SIBO was significantly associated with covert HE in chi-square test (50.0% vs. 24.2%, P = 0.034). In addition, we evaluated the therapeutic response on SIBO of rifaximin in eight covert HE patients. 20% patients with M-SIBO and 67% patients with H-SIBO showed an improvement of the breath test. In conclusion, H-SIBO, but not M-SIBO, is significantly associated with liver function, and rifaximin might be more effective for covert HE with H-SIBO. Therefore, the diagnosis of SIBO, including the classification as H-SIBO and M-SIBO, might help to determine the choice of treatment for HE.

Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

Abstract We study the supersymmetry breaking patterns in four-dimensional N $$ \mathcal{N} $$ = 2 gauged supergravity. The model contains multiple (Abelian) vector multiplets and a single hypermultiplet which parametrizes SO(4, 1)/SO(4) coset. We derive the expressions of two gravitino masses under general gaugings and prepotential based on the embedding tensor formalism, and discuss their behaviors in some concrete models. Then we confirm that in a single vector multiplet case, the partial breaking always occurs when the third derivative of the prepotential exists at the vacuum, which is consistent with the result of ref. [1], but we can have several breaking patterns otherwise. The discussion is also generalized to the case of multiple vector multiplets, and we found that the full ( N $$ \mathcal{N} $$ = 0) breaking occurs even if the third derivative of the prepotential is nontrivial.

Abstract Background Imaging techniques can provide information about the tumor non-invasively and have been shown to provide information about the underlying genetic makeup. Correlating image-based phenotypes (radiomics) with genomic analyses is an emerging area of research commonly referred to as “radiogenomics” or “imaging-genomics”. The purpose of this study was to assess the potential for using an automated, quantitative radiomics platform on magnetic resonance (MR) breast imaging for inferring underlying activity of clinically relevant gene pathways derived from RNA sequencing of invasive breast cancers prior to therapy. Methods We performed quantitative radiomic analysis on 47 invasive breast cancers based on dynamic contrast enhanced 3 Tesla MR images acquired before surgery and obtained gene expression data by performing total RNA sequencing on corresponding fresh frozen tissue samples. We used gene set enrichment analysis to identify significant associations between the 186 gene pathways and the 38 image-based features that have previously been validated. Results All radiomic size features were positively associated with multiple replication and proliferation pathways and were negatively associated with the apoptosis pathway. Gene pathways related to immune system regulation and extracellular signaling had the highest number of significant radiomic feature associations, with an average of 18.9 and 16 features per pathway, respectively. Tumors with upregulation of immune signaling pathways such as T-cell receptor signaling and chemokine signaling as well as extracellular signaling pathways such as cell adhesion molecule and cytokine-cytokine interactions were smaller, more spherical, and had a more heterogeneous texture upon contrast enhancement. Tumors with higher expression levels of JAK/STAT and VEGF pathways had more intratumor heterogeneity in image enhancement texture. Other pathways with robust associations to image-based features include metabolic and catabolic pathways. Conclusions We provide further evidence that MR imaging of breast tumors can infer underlying gene expression by using RNA sequencing. Size and shape features were appropriately correlated with proliferative and apoptotic pathways. Given the high number of radiomic feature associations with immune pathways, our results raise the possibility of using MR imaging to distinguish tumors that are more immunologically active, although further studies are necessary to confirm this observation.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct molecular subtype of gastric cancer characterized by viral infection and cellular abnormalities, including loss of AT-rich interaction domain 1A (ARID1A) expression (lost ARID1A). To evaluate the significance of lost ARID1A in the development of EBVaGC, we performed in situ hybridization of EBV-encoded RNA (EBER) and immunohistochemistry of ARID1A in the non-neoplastic gastric mucosa and intramucosal cancer tissue of EBVaGC with in vitro infection analysis of ARID1A-knockdown and -knockout gastric cells. Screening of EBER by in situ hybridization revealed a frequency of approximately 0.2% EBER-positive epithelial cells in non-neoplastic gastric mucosa tissue samples. Six small foci of EBV-infected epithelial cells showed two types of histology: degenerated (n = 3) and metaplastic (n = 3) epithelial cells. ARID1A was lost in the former type. In intramucosal EBVaGC, there were ARID1A-lost (n = 5) and -preserved tumors (n = 7), suggesting that ARID1A-lost carcinomas are derived from ARID1A-lost precursor cells in the non-neoplastic mucosa. Lost ARID1A was also observed in non-neoplastic mucosa adjacent to an ARID1A-lost EBVaGC. In vitro experiments using siRNA knockdown and the CRISPR/Cas9-knockout system demonstrated that transient reduction or permanent loss of ARID1A expression markedly increased the efficiency of EBV infection to stomach epithelial cells. Taken together, lost ARID1A plays a role in initiating EBV-driven carcinogenesis in stomach epithelial cells, which develop to a distinct subtype of EBVaGC within the proper mucosal layer. Lost ARID1A is one of the constituents of virus-host interactions in the carcinogenesis of EBVaGC.

In alcoholic liver cirrhosis (LC) patients, obesity has become a problem that progresses into liver dysfunction. Herein, we investigated the relationship between the prognosis of steatohepatitis and body weight, along with fat accumulation in patients with alcoholic LC. We conducted a single-center retrospective study, enrolled 104 alcoholic LC patients without hepatocellular carcinoma (HCC) based on histological and clinical evidence, and investigated factors related to poor prognosis using multivariate Cox regression and cluster analyses. Cox regression analysis revealed three independent relevant factors: subcutaneous adipose tissue (SAT) index (median 34.8 cm2/m2, P = 0.009, hazard ratio [HR] 1.017, 95% confidence interval [CI] 1.004-1.030), total bilirubin level (median 1.7 mg/dL, P = 0.003, HR 1.129, 95% CI 1.042-1.223), and prothrombin time value (median 64%, P = 0.007, HR 0.967, 95% CI 0.943-0.991). In the cluster analysis, we categorized the patients into three groups: no adipose tissue accumulation (NAT group), SAT prior accumulation (SAT group), and visceral adipose tissue prior accumulation (VAT group). The results of the three groups revealed that the SAT group displayed a significantly poor prognosis of the Kaplan-Meier curve (67.1 vs 21.2 vs 65.3, P

Abstract We provide N=1 $$ \mathcal{N}=1 $$ superfield description of BPS backgrounds in six-dimensional supergravity (6D SUGRA) with 3-branes, which is compactified on a two-dimensional space. The brane terms induce the localized fluxes. We find a useful gauge in which the background equations become significantly simple. This is not the Wess-Zumino gauge, and the relation to the usual component-field expression of 6D SUGRA is not straightforward. One of the equations reduces to the Liouville equation. By moving to the Wess-Zumino gauge, we check that our expressions reproduce the known results of the previous works, which are expressed in the component fields. Our results help us develop the systematic derivation of four-dimensional effective theories that keeps the N=1 $$ \mathcal{N}=1 $$ SUSY structure.

Abstract We propose a four-dimensional N = 1 supergravity-based Starobinsky-type inflationary model in terms of a single massive vector multiplet, whose action includes the Dirac-Born-Infeld-type kinetic terms and a generalized (new) Fayet-Iliopoulos-type term, without gauging the R-symmetry. The bosonic action and the scalar potential are computed. The inflaton is the superpartner of the Goldstino in our model, and supersymmetry is spontaneously broken after inflation by the D-type mechanism, whose scale is related to the value of the cosmological constant.

Development of an effective, safe, and convenient method for gene delivery to the pancreas is a critical step toward gene therapy for pancreatic diseases. Therefore, we tested the possibility of applying the principle of hydrodynamic gene delivery for successful gene transfer to pancreas using rats as a model. The established procedure involves the insertion of a catheter into the superior mesenteric vein with temporary blood flow occlusion at the portal vein and hydrodynamic injection of DNA solution. We demonstrated that our procedure achieved efficient pancreas-specific gene expression that was 2,000-fold higher than that seen in the pancreas after the systemic hydrodynamic gene delivery. In addition, the level of gene expression achieved in the pancreas by the pancreas-specific gene delivery was comparable to the level in the liver achieved by a liver-specific hydrodynamic gene delivery. The optimal level of reporter gene expression in the pancreas requires an injection volume equivalent to 2.0% body weight with flow rate of 1 mL/s and plasmid DNA concentration at 5 μg/mL. With the exception of transient expansion of intercellular spaces and elevation of serum amylase levels, which recovered within 3 days, no permanent tissue damage was observed. These results suggest that pancreas-targeted hydrodynamic gene delivery is an effective and safe method for gene delivery to the pancreas and clinically applicable.

Abstract We complete the four-dimensional N=1 $$ \mathcal{N}=1 $$ superfield description of six-dimensional supergravity. The missing ingredients in the previous works are the superfields that contain the sechsbein e4ν¯,e5ν¯,eμ4¯,eμ5¯ $$ {e}_4^{\underline{\nu}},{e}_5^{\underline{\nu}},{e}_{\mu}^{\underline{4}},{e}_{\mu}^{\underline{5}} $$ and the second gravitino. They are necessary to make the action invariant under the diffeomorphisms and the Lorentz transformations involving the extra dimensions. We find the corresponding superfield transformation laws, and show the invariance of the action under them. We also check that the resultant action reproduces the known superfield description of five-dimensional supergravity through the dimensional reduction.

Metastatic peritoneal tumors of gastric origin usually appear as multiple small nodules on the peritoneal surface or as scirrhous-type infiltrating lesions. A mass-forming cystic appearance is highly unusual and is unique to peritoneal metastasis. Herein, we report a 79-year-old man who presented with a rapidly growing pelvic tumor after total gastrectomy for advanced gastric cancer. Fine needle aspiration yielded a diagnosis of recurrent gastric cancer. Chemotherapy failed to slow the disease progression, and an exophytic tumor in the pelvic cavity caused secondary urethral as well as large bowel obstruction. The tumor, resected by Hartmann’s procedure, consisted of a large quantity of old blood, necrotic tumor tissues and a thick wall surrounding the capsule. A pathological evaluation revealed syncytiotrophoblast cell-like multinucleated giant cells that were positive for the beta subunit of human chorionic gonadotropin, suggesting trophoblastic differentiation of the recurrent tumor. Repeated internal hemorrhage associated with a trophoblastic histological phenotype may have been the cause of the unusually rapid cystic expansion. Keywords: Gastric cancer, Peritoneal recurrence, Trophoblastic differentiation

Acute upper gastrointestinal bleeding (UGIB) is a common disorder and a gastroenterological emergency. With the development of new techniques and devices, the survivability after gastrointestinal bleeding is improving. However, at the same time, we are facing the difficulty of severely complicated cases with various diseases. For example, while endoscopic examination with a normal diameter endoscope is essential for the diagnosis and treatment of UGIB, there are several cases in which it cannot be used. In these cases, transnasal endoscopy (TNE) may be a viable treatment option. This report reviews current hemostatic devices for endoscopic treatment and the safety and efficiency of using TNE in complicated cases. The latter will be demonstrated in a case report where TNE was employed in a patient with severe esophageal stenosis. This review summarizes the advances made in the devices used and will provide further ideas for the physician in terms of combining these devices and TNE.

Abstract Background Adenocarcinoma with lepidic growth pattern presents as a ground glass nodule (GGN) on high resolution computed tomography (CT), whereas peripheral pulmonary squamous cell carcinoma (SCC) usually presents as a solid nodule. We herein report a rare case of pulmonary SCC extending along the alveolar lumen representing as a GGN on a CT scan in a patient with pneumoconiosis. Case presentation A 77-year-old man with pneumoconiosis was found to have a gradually enlarging GGN in the right lower lobe of the lung on CT. An adenocarcinoma of the lung was suspected. The GGN was successfully resected by thoracoscopic segmentectomy. Pathological examination of the resected specimen was pathologically diagnosed as a stage IA SCC extending along the alveolar lumen. The patient had no evidence of recurrence 19 months after surgery. Conclusions SCC should be included in the differential diagnosis of peripherally located GGNs, especially in patients at high risk of SCC of the lung such as those with pneumoconiosis.

We consider magnetized orbifolds, where the supersymmetric mass term for a pair of up- and down-type Higgs (super)fields, called μ-term, is localized at the orbifold fixed points, and study the effects on the zero-mode spectra. The zero-mode degeneracy to be identified as the generation in four-dimensional (4D) effective theories is determined by the magnetic fluxes. It is known that multiple Higgs zero-modes appear in general in magnetized orbifold models. We derive the analytic form of the μ-term matrix in the 4D effective theory generated by the localized sources on T2/Z2 orbifold fixed points, and find that this matrix can lead to a distinctive pattern of the eigenvalues that yields hierarchical μ-terms for the multiple Higgs fields. The lightest ones can be exponentially suppressed due to the localized wavefunctions of zero-modes determined by the fluxes, while the others are of the order of the compactification scale, which can provide a dynamical origin of the electroweak scale as well as a simultaneous decoupling of extra Higgs fields. We also show that a certain linear combination of the lightest Higgs fields could generate the observed mass ratios of down-type quarks through their Yukawa couplings determined by the wavefunctions.

We discuss an N=2 supergravity model that interpolates the full and the partial supersymmetry breakings. In particular, we find the conditions for an N=0 Minkowski vacuum, which is continuously connected to the partial-breaking (N=1 preserving) one. The model contains multiple (Abelian) vector multiplets and a single hypermultiplet, and is constructed by employing the embedding tensor technique. We compute the mass spectrum on the Minkowski vacuum, and find some non-trivial mass relations among the massive fields. Our model allows us to choose the two supersymmetry-breaking scales independently, and to discuss the cascade supersymmetry breaking for the applications to particle phenomenology and cosmology.

Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor and is widely used for relapsing-remitting multiple sclerosis (MS). Here we report the first case of non-traumatic acute epidural hematoma in a relapsing-remitting MS patient treated with fingolimod. Fingolimod might increase the risk of hemorrhage by enhancing vasospasm and causing vascular disruption. Switching fingolimod to other disease-modifying drugs, including dimethyl fumarate, should be considered when non-traumatic hemorrhage is observed in MS patients.

BACKGROUND:Factors associated with efficacy and safety of cold snare polypectomy (CSP) are not well established. The aim is to elucidate the predictors of R0 resection and immediate bleeding of CSP. METHODS:We retrospectively reviewed a database of patients who underwent CSP for subcentimetric polyps at the University of Tokyo Hospital in Japan. Using the data regarding the characteristics of patients and polyps, such as location, size, and macroscopic appearance; use of narrow band imaging with magnification (NBI-M); and endoscopists' experience, we revealed the predictive factors associated with R0 resection and immediate post-CSP bleeding by univariate and multivariate analyses. RESULTS:In total, 399 polyps, in 200 patients without antithrombotics, were removed. Failure of tissue retrieval was noted in 4% of resected lesions. There was no intramucosal carcinoma observed. The overall rate of R0 resection was 46%. Multivariate analysis elucidated that the observation of the polyp with NBI-M was an independent predictor associated with R0 resection (odds ratio [OR] 1.90; p = 0.024). Although immediate post-CSP bleeding occurred in 19 polyps (4.8%), no delayed bleeding or perforation was observed. Multivariate analysis revealed protruded lesion as an independent risk factor for immediate bleeding (OR 3.54; p = 0.018). CONCLUSIONS:A higher rate of R0 resection with CSP can be achieved by performing colonoscopy with NBI-M, than with white-light imaging. Macroscopic protruding appearance of a polyp is a risk factor for immediate bleeding.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), one of four major gastric cancer types, consists of clonal growth of EBV-infected epithelial cells. However, the significance of viral loads in each tumor cell has not been evaluated. EBV-DNA is stably maintained in episomal form in the nucleus of each cancer cell. To estimate EBV copy number per genome (EBV-CN), qPCR of viral EBNA1 and host GAPDH, standardized by Namalwa DNA (one copy/genome), was applied to the formalin-fixed paraffin embedded (FFPE) surgically resected EBVaGC specimens (n = 43) and EBVaGC cell lines (SNU-719 and NCC-24). In surgical specimens, the cancer cell ratio (CCR) was determined with image analysis, and EBV-CN was obtained by adjusting qPCR value with CCR. Fluorescent in situ hybridization (FISH) was also applied to the FFPE sections using the whole EBV-genome as a probe. In surgical specimens, EBV-CN obtained by qPCR/CCR was between 1.2 and 185 copies with a median of 9.9. EBV-CN of SNU-719 and NCC-24 was 42.0 and 1.1, respectively. A linear correlation was observed with qPCR/CCR data up to 20 copies/genome (40 signals/nucleus), the limit of FISH analysis. In addition, substantial variation in the number of EBV foci was observed. Based on qPCR/CCR, high EBV-CN (>10 copies) correlated with PD-L1 expression in cancer cells (P = 0.015), but not with other pathological indicators. Furthermore, EBVaGC with high EBV-CN showed worse disease-specific survival (P = 0.041). Our findings suggest that cancer cell viral loads may contribute to expression of the immune checkpoint molecule and promotion of cancer progression in EBVaGC.