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Abstract Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate; therefore, the development of effective treatments is a priority. The stimulator of interferon genes (STING) pathway enhances tumor immunity by inducing the production of type 1 interferon (IFN) and proinflammatory cytokines and chemokines and promoting the infiltration of cytotoxic T cells. To assess the function of STING on pancreatic tumorigenesis, Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP mice (KPC mice) and Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP/STING−/− mice (KPCS mice) were generated. However, STING deletion did not affect pancreatic tumorigenesis in mice. Because STING is expressed not only in immune cells but also in cancer-associated fibroblasts (CAFs), we evaluated the STING function in PDAC CAFs. A mouse STING agonist 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) was administered to KPC mice and CAFs from KPC mice and the resulting immune response was evaluated. DMXAA activated STING in PDAC CAFs in KPC mice, promoting cytotoxic T cell infiltration by secreting proinflammatory cytokines and enhancing tumor immunity. We next generated STING-deficient PDAC cells and subcutaneous tumors in which STING was expressed only in CAFs by performing bone marrow transplantation and assessed the antitumor effect of STING-activated CAFs. The administration of DMXAA to subcutaneous tumors expressing STING only in CAFs sustained the antitumor effect of DMXAA. About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors with high than in those with low STING expression in the stroma.

Abstract Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Abstract Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

The literature on city branding has two main shortcomings. First, each related factor is evaluated individually, resulting in an insufficiently comprehensive evaluation. Second, the differences between brand image and loyalty factors have not been investigated sufficiently. Addressing these gaps, this study aimed to answer the following research question: ‘From the perspective of city residents, do brand image and loyalty factors differ?’ Structural equation modeling was performed, based on data from an online survey of 800 residents in 21 major Japanese cities. Results demonstrated that educational facilities and tourism resources had the most positive impact on brand image, while urban greenery and local governments had the most positive impact on loyalty. Brand image negatively affected loyalty. City branding needs differ between elite residents (e.g. those who own multiple homes/land in the city center and are keen on improving their brand image to increase land prices), tourists, and local residents (e.g. those who are worried about their mortgages). This is supported by numerous cases worldwide of famous tourist destinations – subject to overtourism – being the reason for conflict between local residents and tourists. The results underscore that practitioners need to clarify whether their objective is to strengthen external brand image or internal loyalty.

Abstract In clinical cases of pancreas divisum, endoscopic retrograde cholangiopancreatography often necessitates cannulation of the pancreatic duct through the minor papilla. Nevertheless, this procedure can be challenging because of the small size of the minor papilla and the difficulty in visualizing the ductal orifice. A new image‐enhanced endoscopy technique called texture and color enhancement imaging (TXI) has been developed, which enhances texture, brightness, and color compared with white‐light imaging, resulting in subtle differences in the surface mucosa. Herein, we describe the case of a 73‐year‐old man with pancreas divisum in whom TXI was useful in identifying the orifice of the minor papilla. He was referred to our hospital with repetitive acute exacerbation of chronic pancreatitis. Since contrast‐enhanced computed tomography revealed a pancreatic stone in the main pancreatic duct, endoscopic retrograde cholangoepancreatography was performed as a therapeutic intervention. Despite the initial difficulty in identifying the orifice of the minor papilla on white‐light imaging, TXI enhanced its visibility successfully, enabling dorsal pancreatic duct cannulation via the minor papilla. Subsequently, endoscopic pancreatic sphincterotomy was performed and a 6Fr plastic stent was placed. Post‐endoscopic therapy, the patient's abdominal pain was relieved. TXI was useful in identifying the minor papilla orifice and led to successful cannulation.

Abstract Background and Aim The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC. Methods This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low‐score group and a high‐score group, and compared the cumulative incidence of MGC. Results In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5‐year cumulative incidence of MGC was significantly higher in the high‐score group than in the low‐score group (29.8% vs 10.0%, P = 0.004). Conclusion The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow‐up.

Abstract Two main issues in ethical consumption attract attention: environmental and labor issues. However, few studies have compared the conditions and effects that contribute to ethical purchasing behavior. To fill this gap, we conducted two studies targeting the Japanese food industry. In Study 1, we examined consumers who are accustomed to ethical consumption and clarified the product characteristics valued by consumers with high awareness of ethical issues. In Study 2, we conducted a randomized controlled trial to examine the effects of product concepts of environmental and labor issues on coffee purchase intentions. Study 1 confirmed that environmental and labor issues are emphasized for coffee, whereas recycling is emphasized for tea. This difference is due to the difference in production countries (coffee: developing countries, tea: Japan) and packaging materials (coffee: paper cups, tea: PET bottles). Study 2 showed that labor issues had a greater impact on purchase intention and willingness to pay than that of environmental issues owing to the adoption of producers’ photographs. This study complemented existing literature by comparing the conditions and effects of environmental and labor issues on ethical purchasing behavior. Considering the limited resources of companies and limited ability of consumers to process information, understanding predictive factors is extremely crucial.

The electron beam current of high-power, long-pulse gyrotrons for fusion devices is typically controlled to remain constant by adjusting the power to the cathode heater by using a pre-programmed waveform. However, this pre-programmed waveform is usually developed through a time-consuming trial and error process and its precision is low. Therefore, a system to automatically control electron beam current was developed and its performance was tested with one of the JADA/QST-manufactured gyrotrons for ITER. The control system automatically adjusted beam current to a target value of 47 A within ±0.5% for 900 s. This high-precision beam current control can maintain an output power of 1 MW and, being automated, it is useful for power on/off modulation operations. If the operation is switched from continuous to modulated, the beam current can be changed to compensate for the decrease in emission cooling of the cathode. This automatic control system demonstrates the quick recovery of a stable beam current in modulation operations.

Abstract A 45‐year‐old man underwent esophagogastroduodenoscopy because of symptoms of laryngopharyngeal discomfort. We found a protruded reddish lesion adjacent to the ectopic gastric mucosa (EGM) in the cervical esophagus, and a biopsy revealed that it was a tubular adenocarcinoma. We diagnosed the patient with intramucosal cancer and performed endoscopic submucosal dissection. Esophageal endoscopic submucosal dissection was performed under general anesthesia using a conventional procedure. The resected tumor measured 23 × 14 mm and was adjacent to the EGM. Histologically, the tumor cells showed moderately well‐differentiated adenocarcinoma confined to the muscularis mucosa with no lymphovascular infiltration. Immunohistochemically, the tumor cells were positive for intestinal markers, namely MUC2 and CD10, and negative for gastric markers, namely MUC5AC and MUC6. The patient had no post‐endoscopy submucosal dissection stenosis and remained disease‐free without local recurrence. EGM of the cervical esophagus develops from the columnar epithelium during embryonic development. There are few reports on endoscopic submucosal dissection for mucosal cancer. Of these, immunostaining was performed in three cases. All were positive for MUC5AC and MUC6 and negative for MUC2 and CD10. Usually, EGM shows gastric type epithelium, but occasional cases with intestinal metaplasia, which show positivity for MUC2 and CD10, have been reported. Therefore, we consider this to be an extremely rare case of esophageal adenocarcinoma arising from intestinal metaplasia within the EGM.

High-power (1 MW), long-pulse operations up to 300 s were demonstrated by multi-frequency oscillations at 170 GHz, 137 GHz, and 104 GHz. A multi-frequency gyrotron based on the design of the ITER gyrotron has been developed and studied. By redesigning the built-in mode convertor and internal mirrors of the ITER gyrotron, the internal scattered power of the gyrotron was reduced while maintaining the same output beam size and beam direction for the three frequencies. In addition, the mirrors of a matching optics unit were designed to efficiently couple the RF beam at 170 GHz, 137 GHz, and 104 GHz oscillations to a waveguide 50 mm in diameter, the same size that will be used in ITER. An HE _11 mode content of ∼94% was achieved for the three frequencies. Output powers of 1 MW at 170 GHz and 137 GHz, and 0.9 MW at 104 GHz were demonstrated up to 300 s. These oscillation frequencies can facilitate in a wide range of toroidal magnetic field operations at ITER, including plasma start-up and electron heating and current drive.

Background. Vonoprazan affords more clinical benefits than proton pump inhibitors (PPIs) during the healing of gastroduodenal ulcers. However, it remains controversial whether vonoprazan is more effective than PPIs when used to heal artificial ulcers arising after endoscopic submucosal dissection (ESD). Aim. This study investigated the effects of vonoprazan compared with esomeprazole on the healing of post-ESD artificial ulcers. Methods. Sixty patients who underwent gastric ESD between May 2015 and May 2017 were randomized to treatment with vonoprazan (V group) or esomeprazole (E group) for 8 weeks. Upper endoscopy was performed at 4 and 8 weeks after ESD, and drug effects were estimated based on the ulcer healing rates and shrinkage rates. Results. Fifty-three patients were analyzed. The respective 4- and 8-week ulcer healing rates did not differ significantly between V and E groups (8.0 versus 11.5%, P=0.669; 88.9 versus 84.6%, P=0.420). Similarly, the respective 4- and 8-week ulcer shrinkage rates did not differ significantly between V and E groups (96.8 versus 97.5%, P=0.656; 100 versus 100%, P=0.257). Conclusion. The healing of artificial ulcers after ESD did not differ using vonoprazan or esomeprazole. Both vonoprazan and esomeprazole were effective when used to promote artificial ulcer healing after ESD.

Background and study aims Endoscopic submucosal dissection (ESD) is used to treat superficial colorectal tumors. Previous studies have reported the efficacy of ESD for treating residual or local recurrent colorectal tumors. This study sought to evaluate the efficacy of ESD in treating these lesions and to assess factors that prevent successful ESD. Methods This retrospective study assessed 25 cases of residual or local recurrent lesions that were previously treated using EMR (18 lesions), TEM (5 lesions), ESD (1 lesion) or surgery (1 lesion), and 459 primary lesions treated using ESD between April 2008 and September 2015. Clinicopathological characteristics, treatment outcome and adverse events were compared between groups with or without scar tissue. Factors related to perforation and a prolonged treatment time, which indicate the likelihood of technical difficulties, were identified using multiple logistic regression analysis. Results In residual or local recurrent lesions groups, patients experienced more perforations (32 % vs 4 %, P

Background Endoscopic resection is recommended for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in diameter and confined to the submucosal layer, without lymph node or distant metastasis. However, the efficacy and safety of endoscopic submucosal dissection (ESD) for NAD-NET remains unclear. The aim of this study was to assess the short-term efficacy and safety and the long-term outcomes of ESD for NAD-NET. Methods Eight patients with 8 NAD-NETs who underwent ESD between 2015 and 2018 were included. The indications for ESD were: i) tumor ≤10 mm in diameter; ii) NET G1; iii) confined to the submucosal layer; and iv) without lymph node or distant metastasis. We retrospectively assessed the short- and long-term outcomes and safety. Results The median patient age was 69 (48-76) years. All tumors were located in the duodenal bulb and showed 0-Is morphology. The median size was 6.4 (3-9.3) mm. The rates of en bloc resection, histologically free horizontal and vertical margins, and curative resection were 100%, 88%, and 88%, respectively. Intraoperative and postoperative perforation each occurred in 13% of patients, all of whom were treated conservatively and avoided emergent surgery. Delayed bleeding was not observed. No local, lymph node or distant recurrence was observed during a median follow-up period of 34 (18.5-62.5) months. Conclusions The rates of en bloc and curative resection, and histologically free margins were sufficiently high. Although intraoperative and postoperative perforations occurred, emergency surgery was not needed. The results show that ESD is an efficacious and safe treatment for NAD-NET. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although magnifying endoscopy with narrow-band imaging (ME-NBI) can help identify the horizontal margin (HM) of early gastric cancer (EGC), little is known about the factors that can clarify the HM by using ME-NBI. We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI. METHODS: The HMs of 639 differentiated-type EGCs treated with endoscopic submucosal dissection or surgery were analyzed using conventional endoscopy and ME-NBI. The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured. RESULTS: In 13 lesions (2.0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas. CONCLUSIONS: Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM. [ABSTRACT FROM AUTHOR]

This paper presents a summary of recent progress pertaining to the manufacturing and inspection of ITER gyrotrons and the operation system in QST. Major achievements are as follows. (i) The final design of the ITER gyrotron was accomplished and manufacturing of two ITER gyrotrons was completed. Then operation test in QST prior the shipment to ITER has started with ITER relevant high voltage power supply configuration. The 1st ITER gyrotron has achieved 1.05 MW operation for 300 s with 51% efficiency. Measured cooling channel waveform of 300 s pulse demonstrated thermally stable condition representing sufficient cooling performance for 1 MW CW operation; (ii) 5 kHz modulation operation was demonstrated up to 200 s at with  >0.8 MW at flat top of pulses; (iii) 300 s/1 MW operation was repeated for 20 shots with successful 19 shots which demonstrating  >95% of reliability requirement. These results lead to success of ITER EC H&CD system construction and commissioning toward first plasma. [ABSTRACT FROM AUTHOR]

To study the performance of multi frequency operation of transmission lines for electron cyclotron heating and current drive (EC H&CD) systems, the performance of a transmission line (TL) with 104 GHz/137 GHz/170 GHz operation was evaluated using a multi frequency gyrotron. The TL test stand for multi frequency high-power operation was composed from corrugated waveguides with 63.5 mm inner diameter and TL components, such as miter bends. The coupling efficiency of gyrotron power into the TL inlet, mode purity at the TL end, and power transmission efficiency were measured for three frequency operations. The transmission efficiency of the 40 m length TL remained at 94%–95% for three frequencies and that of the MOU varied because of the quasi-optical design in the MOU. The mode conversion in TL was found to be less than 2% for three frequencies. These results indicate that the TL using corrugated waveguide can deliver radio frequency power from the gyrotron to the launcher with similar performance expected in single frequency operation in ITER. [ABSTRACT FROM AUTHOR]

Background: Endoscopic resection is recommended for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in diameter and confined to the submucosal layer, without lymph node or distant metastasis. However, the efficacy and safety of endoscopic submucosal dissection (ESD) for NAD-NET remains unclear. The aim of this study was to assess the short-term efficacy and safety and the long-term outcomes of ESD for NAD-NET., Methods: Eight patients with 8 NAD-NETs who underwent ESD between 2015 and 2018 were included. The indications for ESD were: i) tumor ≤10 mm in diameter; ii) NET G1; iii) confined to the submucosal layer; and iv) without lymph node or distant metastasis. We retrospectively assessed the short- and long-term outcomes and safety., Results: The median patient age was 69 (48-76) years. All tumors were located in the duodenal bulb and showed 0-Is morphology. The median size was 6.4 (3-9.3) mm. The rates of en bloc resection, histologically free horizontal and vertical margins, and curative resection were 100%, 88%, and 88%, respectively. Intraoperative and postoperative perforation each occurred in 13% of patients, all of whom were treated conservatively and avoided emergent surgery. Delayed bleeding was not observed. No local, lymph node or distant recurrence was observed during a median follow-up period of 34 (18.5-62.5) months., Conclusions: The rates of en bloc and curative resection, and histologically free margins were sufficiently high. Although intraoperative and postoperative perforations occurred, emergency surgery was not needed. The results show that ESD is an efficacious and safe treatment for NAD-NET., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Aim: To investigated the relationship between postoperative bleeding following gastric endoscopic submucosal dissection (ESD) and individual antithrombotic agents., Methods: A total of 2488 gastric neoplasms in 2148 consecutive patients treated between May 2001 and June 2016 were studied. The antithrombotic agents were categorized into antiplatelet agents, anticoagulants, and other antithrombotic agents, and we included combination therapies [ e.g ., dual antiplatelet therapy (DAPT)]. The risk factors associated with post-ESD bleeding, namely, antithrombotic agents overall, individual antithrombotic agents, withdrawal or continuation of antithrombotic agents, and bleeding onset period (during the first six days or thereafter), were analyzed using univariate and multivariate analyses., Results: The en bloc resection and complete curative resection rates were 99.2% and 91.9%, respectively. Postoperative bleeding occurred in 5.1% cases. Bleeding occurred in 10.3% of the patients administered antithrombotic agents. Being male ( P = 0.007), specimen size ( P < 0.001), and antithrombotic agent used ( P < 0.001) were independent risk factors for postoperative bleeding. Heparin bridging therapy (HBT) ( P = 0.002) and DAPT/multidrug combinations ( P < 0.001) were independent risk factors associated with postoperative bleeding. The bleeding rate of the antithrombotic agent continuation group was significantly higher than that of the withdrawal group ( P < 0.01). Bleeding within postoperative day (POD) 6 was significantly higher in warfarin ( P = 0.015), and bleeding after POD 7 was significantly higher in DAPT/multidrug combinations ( P = 0.007). No thromboembolic events were reported., Conclusion: We must closely monitor patients administered HBT and DAPT/multidrug combinations after gastric ESD, particularly those administered multidrug combinations after discharge., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.