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The case is a female, 50s. She presented to our hospital because of her intestinal obstruction. A CT scan at her visit showed wall thickening of her ascending colon. Colonoscopy revealed type 2 advanced cancer in the ascending colon. The pathological examination was a diagnosis of adenocarcinoma. Laparoscopic right hemicolectomy was performed for cT3N1M0, cStage Ⅲb ascending colon cancer. The pathological result was pT3N1M0, Stage Ⅲb. Contrast-enhanced CT was performed 10 months after the operation. As a result, she was found to have recurrent multiple liver metastases. A laparoscopic partial hepatectomy was performed at the site of recurrence. The pathological result was adenocarcinoma. It was a diagnosis of metastasis recurrence from colorectal cancer. A CT scan 16 months after primary surgery revealed enlarged cardiodiaphragmatic lymph nodes. A PET-CT scan revealed an accumulation of SUVmax 3.0 in the same area. She was diagnosed with lymph node recurrence of colorectal cancer and underwent resection. Histopathological result was adenocarcinoma. It was diagnosed as metastasis from ascending colon cancer.

An 82-year-old man presented with right cervical swelling. Cervical ultrasonography revealed several swollen lymph nodes which were diagnosed with adenocarcinoma by fine needle aspiration cytology. Computed tomography showed right axillary lymph nodes were also swelling. Upper and lower gastrointestinal endoscopy found type 0-Ⅱa gastric cancer located at the posterior wall of the middle region. Pathology was HER2-positive moderately differentiated tubular adenocarcinoma. Doublet chemotherapy with S-1 and cisplatin was administered for unresectable gastric cancer(cT1bN0M1, cStage Ⅳb). One month later, doublet chemotherapy was changed to triplet chemotherapy with trastuzumab, capecitabine, and cisplatin. A month later, complete response(CR)was achieved. After 8 courses of triplet chemotherapy, we changed to doublet chemotherapy with trastuzumab and capecitabine due to impaired kidney function 8 months. Two months later from that, endoscopic mucosal dissection was performed for gastric cancer as local therapy(pathology: well differentiated tubular adenocarcinoma, pT1a, ly0, v0). Two years and 2 months after the beginning of chemotherapy, the right axillary lymph nodes were enlarged again and surgically resected(pathology: HER2-positive poorly differentiated adenocarcinoma). He had CR for 8 years and 2 months, and chemotherapy was canceled due to his decision. During 1 year and 7 months, disease progression was not observed. We present a long-term survival case of HER2-positive gastric cancer with distant lymph node metastasis receiving multidisciplinary therapy.

Precision walking (PW) incorporates precise step adjustments into regular walking patterns to navigate challenging surroundings. However, the brain processes involved in PW control, which encompass cortical regions and interregional interactions, are not fully understood. This study aimed to investigate the changes in regional activity and effective connectivity within the frontoparietal network associated with PW. Functional near-infrared spectroscopy data were recorded from adult subjects during treadmill walking tasks, including normal walking (NOR) and PW with visual cues, wherein the intercue distance was either fixed (FIX) or randomly varied (VAR) across steps. The superior parietal lobule (SPL), dorsal premotor area (PMd), supplementary motor area (SMA), and dorsolateral prefrontal cortex (dlPFC) were specifically targeted. The results revealed higher activities in SMA and left PMd, as well as left-to-right SPL connectivity, in VAR than in FIX. Activities in SMA and right dlPFC, along with dlPFC-to-SPL connectivity, were higher in VAR than in NOR. Overall, these findings provide insights into the roles of different brain regions and connectivity patterns within the frontoparietal network in facilitating gait control during PW, providing a useful baseline for further investigations into brain networks involved in locomotion., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/aim: The enhanced recovery after surgery (ERAS) program is expected to improve perioperative outcomes in patients with esophageal cancer. However, how ERAS impacts the postoperative body composition and factors related to compliance rate of ERAS have not been fully investigated., Patients and Methods: The study included 252 consecutive patients with thoracic esophageal cancer who underwent minimally invasive esophagectomy. We compared the postoperative outcomes including body composition between the old perioperative program and the new one that aimed to shorten postoperative length of stay (LOS). Compliance-related clinical factors were also examined., Results: From 252 patients, 129 underwent the old program and 123 the new program. Postoperative LOS, postoperative complications, and hospital costs were reduced with the new program. Body weight loss was significantly improved with the new program at discharge and 3-months after esophagectomy (94.9% vs. 96.6%, p=0.013, 89.5% vs. 91.1%, p=0.028, respectively). Patients in the new program had better body composition at discharge than those in the old program [body fat mass (91.6% vs. 94.1%), lean body mass (95.2% vs. 97.2), and skeletal muscle mass (95.3% vs. 97.0%)]. Major reasons for incompliance were dysphagia, pneumonia, and anastomotic leakage. Multivariate analysis revealed that age ≥70 years at surgery and sex (male) were independent risk factors for incompliance with the postoperative program., Conclusion: The new ERAS program aimed to shorten postoperative LOS had clinical benefits in body composition early after esophagectomy. Personalized ERAS programs based on age might lead to better postoperative outcomes because of low compliance rates for older patients., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To avoid the need for extensive adhesiolysis in patients with small bowel obstruction (SBO). We evaluated the feasibility of using advanced imaging, percutaneous access, and endoscopy as alternative therapies for SBO., Design: Retrospective case series (IDEAL [Idea, Development, Exploration, Assessment, and Long-term Study Collaborative] stages 1 and 2a)., Setting: Single tertiary referral center., Participants: Twelve adults with chronic SBO resulting from inflammatory bowel disease, disseminated cancer, radiation, and/or adhesive disease. Participants were included if they underwent one of three novel access procedures. There were no exclusion criteria. The median age of participants was 67.5 years (range 42-81); two-thirds were women; and median American Society of Anesthesiology class was 3., Interventions: All participants underwent one of three novel access methods, followed by wire-guided balloon dilation of a narrowed area of small bowel. These methods combined endoscopic, fluoroscopic, and surgical techniques. The techniques were (1) a purely endoscopic approach aided by an over-the-scope double-balloon device, (2) a combined endoscopic and percutaneous approach, and (3) a cut-down approach., Main Outcome Measures: Procedural success (defined as successful access to the small bowel and successful balloon dilation of the stenotic area). Secondary outcomes included major complications, recurrence, length of stay, and procedure time., Results: Procedural success was achieved in 10 of 12 patients (83%). At the time of median follow-up of 10 months, recurrence of SBO was observed in two patients. In only one patient, the novel method did not change the treatment plan. No major complications occurred. Conventional operative intervention was avoided in all patients who achieved technical success with one of the novel approaches. The median postprocedure length of hospital stay was 4 days. Median procedure time was 135 min., Conclusions: Novel minimally invasive approaches to SBO represent feasible alternatives to surgical procedures in select patients. Further study should compare these approaches to standard ones as new methods are refined., Competing Interests: Competing interests: Art Sedrakyan is an Editor-in-Chief of this journal., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An accurate evaluation method for preoperative diagnosis has not yet been established in patients with gastric cancer (GC), though it is essential for optimal treatment. Current standard modalities are endoscopy and contrast computed tomography (CT). In this study, we investigated the efficacy and limitations of transabdominal ultrasonography (TUS) for the assessment of tumor invasion., Methods: We enrolled 178 consecutive patients with GC evaluated by TUS, endoscopy, and contrast CT before gastrectomy. For the TUS examination, patients ingested water to fill their stomachs. The clinical staging determined using these modalities was compared to the pathological staging., Results: The overall accuracy of clinical T staging using TUS was 47.8% (pT1a: 5.8% (2/35); pT1b: 58.8% (20/35); pT2: 69.6% (16/23); pT3: 66.7% (22/33); pT4a: 46% (23/50); pT4b: 100% (2/2)). Using endoscopy, contrast CT, and TUS, the overall accuracy was 60.7%. The accuracy of TUS was associated with the tumor region (U region: 50% (14/28); M: 31.8% (14/44); L: 53.7% (57/106); P = 0.048), but not with the cross-sectional parts (P = 0.49). Multivariate analysis identified inaccurate TUS as independently correlating with tumor region (M vs. U/L, odds ratio (OR) = 3.11, 95% confidence interval (CI) 1.41-6.87; P = 0.005) and pT (pT1 vs. pT2-4, OR = 3.00, 95%CI 1.31-6.87; P = 0.009)., Conclusions: The present study demonstrated the importance of TUS in evaluating GC. Thus, TUS may be useful for clinical T staging in certain circumstances, leading to treatment optimization., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To assess the potential clinical utility of cell-free DNA (cfDNA)-based biomarkers for identifying gastric cancer (GC) patients who benefit from nivolumab. From 31 GC patients treated with nivolumab monotherapy (240 mg/body, Bi-weekly) in 3rd or later line setting, we prospectively collected blood samples at baseline and before the 3rd dose. We compared cfDNA-based molecular findings, including microsatellite instability (MSI) status, to tissue-based biomarkers. We assessed the clinical value of blood tumor mutation burden (bTMB) and copy number alterations (CNA) as well as the cfDNA dynamics. The concordance between deficient-MMR and cfDNA-based MSI-high was 100% (3/3). Patients with bTMB ≥ 6 mut/Mb had significantly better progression-free survival (PFS) and overall survival (OS); however, such significance disappeared when excluding MSI-High cases. The combination of bTMB and CNA positivity identified patients with survival benefit regardless of MSI status (both PFS and OS, P < 0.001), with the best survival in those with bTMB ≥6mut/Mb and CNA negative . Moreover, patients with decreased bTMB during treatment had a better disease control rate (P = 0.04) and longer PFS (P = 0.04). Our results suggest that a combination of bTMB and CNA may predict nivolumab efficacy for GC patients regardless of MSI status. bTMB dynamics have a potential utility as an on-treatment biomarker., (© 2023. The Author(s).)

Background: Endoscopic tumor resection and intestinal defect repair are technically challenging leading to invasive surgery and colectomy performed for resection of benign polyps. In this study, we evaluated the use of an endoscopic overtube with bilateral tool channels for these procedures., Methods: Using a fresh porcine colorectum in a 3D ex vivo model, 3 cm lesions at the posterior wall of the transverse colon were removed by two different techniques: standard endoscopic submucosal dissection (ESD) technique (STD, n = 12) and ESD using the overtube with an endoscopic snare and grasper through the bilateral channels (OT, n = 12). Procedure times and the number of muscular injuries were evaluated. Using the same model, 5-10 mm full-thickness perforations within a 3 cm mucosal defect at the posterior wall of the transverse colon were closed by two different techniques: standard endoscopic closure technique (STD, n = 12) and endoscopic closure using the overtube with two graspers (OT, n = 12). The outcomes measured included bursting pressure and the number of endoscopic clips used for closure., Results: Endoscopic resection of lesions was performed by the OT group in a significantly shorter total procedure time (STD vs. OT = median 38.9 min vs. 17.3, p < 0.001) and with fewer muscular injuries (median 0 vs. 2, p = 0.002), compared with the STD group. After repair of intestinal defects, the OT group showed higher median bursting pressures (STD vs. OT = 11.2 mmHg vs. 57.1, p = 0.008) despite using fewer clips (median 13 vs. 10, p < 0.001)., Conclusion: This study demonstrates a novel traction technique with an endoscopic overtube using multiple instruments to remove lesions and repair intestinal defects in the colon more effectively. This endoscopic platform could provide a safe alternative to invasive surgical treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The effect of early initiation of gait training using hybrid assistive limb (HAL) remains unclear. This observational study aimed to investigate whether early initiation of gait training using HAL improves functional outcomes in patients with stroke., Methods: We retrospectively analyzed patients with acute stroke admitted to our facility. HAL was used for exoskeletal robotic gait training. Study participants were median split into an early group and a late group based on the days from stroke onset to initiation of gait training using HAL. The functional outcomes, defined by the Brunnstrom recovery stage (BRS), modified Rankin Scale (mRS), and Functional Independence Measure (FIM) at discharge, were compared using propensity score-matched analysis., Results: We performed a propensity score-matched analysis in 63 patients with stroke (31 from the early group and 32 from the late group), and 17 pairs were matched. There were no significant differences in discharge in the BRS of the upper limb and finger in the post-matched cohort. On the other hand, the BRS of the lower limb in the early group was significantly higher than that in the late group. In addition, the mRS, but not FIM scores, was significantly better in the early group than that in the late group., Conclusions: In conclusion, early initiation of gait training using HAL might improve the motor function of the paralyzed lower limb and disability in patients with stroke., (© 2022 S. Karger AG, Basel.)

An 83-year-old man presented with melena and weight loss. Upper gastrointestinal endoscopy showed type 3 advanced gastric cancer with pyloric stenosis. Surgical findings revealed numerous peritoneal dissemination, then gastro-jejunum anastomosis was performed. The oral diet was resumed on POD4, however severe dysphagia occurred immediately on POD6. There were no specific findings on MRI/MRA and nasal endoscopy. Serum antibodies related to neuromuscular diseases and connective tissue diseases were also negative. Despite the rehabilitation, the dysphagia remained. Before total parenteral nutrition on POD16, hypophosphatemia was discovered(1.4 mg/dL). His dysphagia disappeared with the improvement in the serum phosphate level. Hypophosphatemia might be caused by an inadequate intake as urine phosphate, serum calcium and serum PTH levels were normal. We present a recent case of severe dysphagia due to hypophosphatemia in a patient with peritoneal dissemination of gastric cancer.

We report a case of recurrent descending colon cancer in which QOL was maintained for a long period by performing resection with intestinal reconstruction, chemotherapy, and radiotherapy for local recurrence with hydronephrosis. A man in his 60s with good ADL underwent laparoscopic left hemicolectomy for descending colon cancer. After 4.5 years postoperatively, computed tomography and positron emission tomography showed a local recurrence of 32 mm contacting with the left external iliac artery and sigmoid colon, and CAPOX plus BEV was started. When cholecystitis developed after 5 chemotherapy courses, the recurrent lesion was resected simultaneously. After 8 months, repeated recurrent lesion with a major axis of 13 mm with left hydronephrosis was observed at the same site. After 3 years of chemotherapy after placing the left ureteral stent, CEA level gradually increased, and tumor growth was observed. Because of the aggressive chemotherapy limitation due to high proteinuria, 66 Gy/22 Fr radiotherapy was performed. After 1 month of radiotherapy, the CEA level decreased and proteinuria improved in that period. Radiotherapy for local recurrence can be a useful interval for chemotherapy and effective local control.

Introduction: Interacting with the environment requires the planning and execution of reach-to-target movements along given reach trajectory paths. Human neural mechanisms for the motor planning of linear, or point-to-point, reaching movements are relatively well studied. However, the corresponding representations for curved and more complex reaching movements require further investigation. Additionally, the visual and proprioceptive feedback of hand positioning can be spatially and sequentially coupled in alignment (e.g., directly reaching for an object), termed coupled visuomotor feedback, or spatially decoupled (e.g., dragging the computer mouse forward to move the cursor upward), termed decoupled visuomotor feedback. During reach planning, visuomotor processing routes may differ across feedback types., Methods: We investigated the involvement of the frontoparietal regions, including the superior parietal lobule (SPL), dorsal premotor cortex (PMd), and dorsolateral prefrontal cortex (dlPFC), in curved reach planning under different feedback conditions. Participants engaged in two delayed-response reaching tasks with identical starting and target position sets but different reach trajectory paths (linear or curved) under two feedback conditions (coupled or decoupled). Neural responses in frontoparietal regions were analyzed using a combination of functional near-infrared spectroscopy and electroencephalography., Results: The results revealed that, regarding the cue period, curved reach planning had a higher hemodynamic response in the left SPL and bilateral PMd and a smaller high-beta power in the left parietal regions than linear reach planning. Regarding the delay period, higher hemodynamic responses during curved reach planning were observed in the right dlPFC for decoupled feedback than those for coupled feedback., Conclusion: These findings suggest the crucial involvement of both SPL and PMd activities in trajectory-path processing for curved reach planning. Moreover, the dlPFC may be especially involved in the planning of curved reaching movements under decoupled feedback conditions. Thus, this study provides insight into the neural mechanisms underlying reaching function via different feedback conditions., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Diabetes mellitus induces neuropsychiatric comorbidities at an early stage, which can be ameliorated by exercise. However, the neurobiological mechanisms underlying this ameliorative effect remain unclear. The present study was conducted in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which develop diabetes with age, and aimed to investigate whether social and anxiety-like behaviors and neurobiological changes associated with these behavioral phenotypes were reversed by voluntary exercise and whether those were maintained in the later stage. We investigated the effects of exercise at different diabetic stages in OLETF rats by comparing with control rats. Three groups of OLETF rats were used: sedentary rats, rats exercising on a wheel for two weeks at 4-5 weeks of age (early voluntary exercise), and those exercising at 10-11 weeks of age (late voluntary exercise). In the elevated plus-maze test, both early and late voluntary exercises did not affect anxiety-like behavior. In the social interaction tests, both early and late voluntary exercises ameliorated impaired sociability, novel exploration deficits, and hypoactivity in OLETF rats. Both early and late voluntary exercises reversed the increases in cholecystokinin-positive neuron densities in the infralimbic cortex and hippocampal cornu ammonis area 3 in the OLETF rats, although they did not affect the area-reduction in the medial prefrontal cortex and the increase in cholecystokinin-positive neuron densities in the basolateral amygdala. These suggest that voluntary exercise has therapeutic effects on impaired sociability and novel exploration deficits associated with cholecystokinin-positive neurons in specific corticolimbic regions in OLETF rats, and those are maintained after early exercise., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The preventive effects of regular exercise on obesity-related health problems are carried over to the non-exercise detraining period, even when physical activity decreases with aging. However, it remains unknown whether regular childhood exercises can be carried over to adulthood. Therefore, this study aimed to investigate the effects of long-term childhood exercise and detraining on lipid accumulation in organs to prevent obesity in adulthood. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as obese animals. OLETF rats were allocated into sedentary and exercise groups: exercise from 4- to 12-week-old and detraining from 12- to 20-week-old. At 12-week-old immediately after the exercise period, regular exercise completely inhibited hyperphagia, obesity, enlarged pancreatic islets, lipid accumulation and lobular inflammation in the liver, hypertrophied adipocytes in the white adipose tissue (WAT), and brown adipose tissue (BAT) whitening in OLETF rats. Additionally, exercise attenuated the decrease in the ratio of muscle wet weight to body weight associated with obesity. Decreased food consumption was maintained during the detraining period, which inhibited obesity and diabetes at 20-week-old after the detraining period. Histologically, childhood exercise inhibited the enlargement of pancreatic islets after the detraining period. In addition, inhibition of lipid accumulation was completely maintained in the WAT and BAT after the detraining period. However, the effectiveness was only partially successful in lipid accumulation and inflammation in the liver. The ratio of muscle wet weight to body weight was maintained after detraining. In conclusion, early long-term regular exercise effectively prevents obesity and diabetes in childhood, and its effectiveness can be tracked later in life. The present study suggests the importance of exercise during childhood and adolescence to inhibit hyperphagia-induced lipid accumulation in metabolic-related organs in adulthood despite exercise cessation., Competing Interests: The authors have declared that no competing interests exist.

Background: The optimal number of neoadjuvant chemotherapy (NAC) cycles remains to be established for treating oesophageal squamous cell carcinoma (ESCC). We compared two versus three courses of NAC for treating locally advanced ESCC in a multi-institutional, randomised, Phase II trial., Methods: We randomly assigned 180 patients with locally advanced ESCC at 6 institutions to either two (N = 91) or three (N = 89) courses of DCF (docetaxel 70 mg/m 2 , cisplatin 70 mg/m 2 i.v. on day 1, fluorouracil 700 mg/m 2 continuous infusion for 5 days) every 3 weeks, prior to surgery. The primary endpoint was 2-year progression-free survival (PFS) with an intention-to-treat analysis., Results: Patient background parameters were well-balanced. The R0 resection rates were 98.9 and 96.5% in the two- and three-course groups, respectively (P = 0.830). In resected cases, the two- and three-course groups had comparable pN0 rates (P = 0.225) and histological responses (P = 0.898). The 2-year PFS rate was also comparable between the two groups (71.4 vs. 71.1%, P = 0.669). Among subgroups based on baseline characteristics, only patients aged under 65 years old showed a tendency for better survival with the three-course treatment (hazard ratio = 2.612, 95% confidence interval: 1.012-7.517)., Conclusions: Two courses of a DCF regimen showed potential as an optional NAC treatment for locally advanced ESCC., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN 000015788)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Assistive exoskeleton robots are being widely applied in neurorehabilitation to improve upper-limb motor and somatosensory functions. During robot-assisted exercises, the central nervous system appears to highly attend to external information-processing (IP) to efficiently interact with robotic assistance. However, the neural mechanisms underlying this process remain unclear. The rostromedial prefrontal cortex (rmPFC) may be the core of the executive resource allocation that generates biases in the allocation of processing resources toward an external IP according to current behavioral demands. Here, we used functional near-infrared spectroscopy to investigate the cortical activation associated with executive resource allocation during a robot-assisted motor task. During data acquisition, participants performed a right-arm motor task using elbow flexion-extension movements in three different loading conditions: robotic assistive loading (ROB), resistive loading (RES), and non-loading (NON). Participants were asked to strive for kinematic consistency in their movements. A one-way repeated measures analysis of variance and general linear model-based methods were employed to examine task-related activity. We demonstrated that hemodynamic responses in the ventral and dorsal rmPFC were higher during ROB than during NON. Moreover, greater hemodynamic responses in the ventral rmPFC were observed during ROB than during RES. Increased activation in ventral and dorsal rmPFC subregions may be involved in the executive resource allocation that prioritizes external IP during human-robot interactions. In conclusion, these findings provide novel insights regarding the involvement of executive control during a robot-assisted motor task., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Le, Watanabe, Ogawa, Matsushita, Imada, Taki, Iwamoto, Imura, Araki, Araki, Ono, Nishijo, Fujita and Urakawa.)

Background: Endoscopic submucosal dissection (ESD) is a challenging procedure for the removal of colorectal tumors, especially tumors located in the right colon. The use of traction could make this procedure technically easier and reduce procedure times and complication rates. In this study, we demonstrated the feasibility and utility of a traction technique utilizing an endoscopic snare through an overtube, a double-balloon endolumenal interventional platform (DEIP) in a porcine colorectal model., Methods: A total of 120 procedures were performed using three different techniques: standard ESD technique (STD), ESD with DEIP (DEIP alone), and ESD with DEIP and a snare (DEIP + Snare). The snare was passed inside the overtube and used as a grasper on the tissue to provide traction. Lesions 3 or 4 cm in diameter were removed with a 5 mm margin from the anterior and posterior walls of the proximal Transverse Colon, the Hepatic Flexure, and the posterior wall of the Cecum. The outcomes measured included procedure times and the number of muscularis propria injuries., Results: The DEIP + Snare group showed significantly shorter total procedure and submucosal dissection times for lesions in all locations (median 28.1 min (DEIP + Snare, n = 32) vs 39.8 (STD, n = 32) vs 39.7 (DEIP alone, n = 32); 7.5 min vs 25.3 vs 25.1) and had fewer muscularis propria injuries (median 0 [range 0-2] vs 2 [0-7] vs 1 [0-6]) than the two other groups. Larger lesions (4 cm) were successfully removed by regrasping the tissue in DEIP + Snare group, which showed significantly shorter total procedure time [31.4 min (DEIP + Snare, n = 8) vs 40.1 (STD, n = 8) vs 45.6 (DEIP alone, n = 8)] and submucosal dissection time (12.3 min vs 27.6 vs 29.1) than the two other groups., Conclusions: ESD traction technique with an endolumenal platform and snare enables faster removal of large polyps in the right colon with fewer injuries than standard methods of ESD., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to investigate the influence of childhood exercise and detraining on brown adipose tissue (BAT) whitening in obesity. Four-week-old male Long-Evans Tokushima Otsuka (LETO) rats ( n = 9) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats ( n = 24) were used as non-obese and obese animals, respectively. OLETF rats were divided into non-exercise sedentary ( n = 9) and exercise groups. OLETF rats in the exercise group were further divided into subgroups according to the exercise period-exercise from 10- to 12-weeks-old ( n = 6); and exercise from 4- to 6-weeks-old, and detraining from 6- to 12-weeks-old ( n = 9). At 12-weeks-old, immediately after exercise period, BAT whitening in OLETF rats was inhibited by exercise despite the fact that hypertrophy was not caused in the plantaris muscle. However, the effectiveness was attenuated during the detraining period. Histological BAT whitening and downregulation of uncoupling protein-1 (UCP-1) were found in non-exercise sedentary OLETF rats at 12-weeks-old. The downregulation was not inhibited, even though exercise histologically inhibited BAT whitening in OLETF rats. Childhood exercise decreased BAT whitening in obesity. Detraining attenuated the inhibition of BAT whitening. These results suggest that regular exercise is needed to improve BAT whitening and downregulation of UCP-1 in obesity.

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP + Ig), and ESD using IgE (DESP + IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig's reach. Compared with the STD, both DESP + Ig and DESP + IgE showed significantly shorter procedure time (STD vs. DESP + Ig vs. DESP + IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP + IgE had a shorter procedure time than the DESP + Ig (p = 0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon., (© 2021. The Author(s).)

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats., Competing Interests: No authors have competing interests.

Objective: The aim of this study was to evaluate primary tumor (PT) and lymph node (LN) responses to neoadjuvant chemotherapy (NACT) for predicting long-term survival in patients with metastatic esophageal cancer (EC)., Background: In evaluating NACT responses in patients with EC, imaging modalities typically target the PT in the esophagus, which is unmeasurable. Targeting measurable organs, like positive LNs, might provide more accurate assessments., Methods: We enrolled 251 patients with EC and clinically positive LNs that underwent curative resections, after triplet NACT. The percent reduction of PT area was measured with bidimensional computed tomography. The LN response was defined as the percent reduction of the sum of the short diameters in all positive LNs., Results: NACT reduced PTs and LNs by (median, range) 58.0% (38.1-94.9) and 34.5% (46.2-68.2), respectively. Based on the receiver-operating characteristic analyses for predicting a histological response and a 10% stepwise cutoff analyses of recurrence-free survival (RFS), responder/nonresponder cutoff values were ≥60% for PT area reductions and ≥30% for LN size reductions. 39.6% of patients showed discordant PT and LN responses. Compared with PT-responders, LN-responders had significantly less advanced pN (P < 0.0001) and pM (P = 0.015) in addition to less advanced pT (P < 0.0001) and better histological responses (P < 0.0001), and closer correlations to lymphatic, distant metastases and dissemination. A multivariate analysis of RFS identified 2 independent prognostic factors: the LN response [hazard ratio (HR) = 2.51, 95% confidence interval (CI) = 1.63-3.95, P < 0.0001] and the pN (HR = 2.72, 95% CI = 1.44-5.64, P = 0.0016), but not the PT response., Conclusions: The LN response to NACT predicted long-term survival more precisely than the PT response in patients with metastatic EC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background and study aims  The risk of aerosolization of body fluids during endoscopic procedures should be evaluated during the COVID-19 era, as this may contribute to serious disease transmission. Here, we aimed to investigate if use of endoscopic tools during flexible endoscopy may permit gas leakage from the scope or tools. Material and methods  Using a fresh 35-cm porcine rectal segment, a colonoscope tip, and manometer were placed intraluminally at opposite ends of the segment. The colonoscope handle, including the biopsy valve, was submerged in a water bath. Sequentially, various endoscopic devices (forceps, clips, snares, endoscopic submucosal dissection (ESD) knives) were inserted into the biopsy valve, simultaneously submerging the device handle in a water bath. The bowel was slowly inflated up to 74.7 mmHg (40 inH 2 O) and presence of gas leakage, leak pressure, and gas leakage volume were measured. Results  Gas leakage was observed from the biopsy valve upon insertion and removal of all endoscopic device tips with jaws, even at 0 mmHg (60/60 trials). The insertion angle of the tool affected extent of gas leakage. In addition, gas leakage was observed from the device handles (8 of 10 devices) with continuous gas leakage at low pressures, especially two snares at 0 mmHg, and an injectable ESD knife at 0.7 ± 0.8 mmHg). Conclusions  Gas leakage from the biopsy valve and device handles commonly occur during endoscopic procedures. We recommend protective measures be considered during use of any tools during endoscopy., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

It remains unclear whether Helicobacter pylori (H. pylori), a major cause of gastric cancer (GC), is involved in other intestinal cancers. In our previous study, ICOS + Foxp3 + CD4 + T cells (ICOS + Tregs) in GC tumors were identified as effector Tregs and associated with H. pylori. In the present study, the impact of ICOS + Tregs on not only GC, but also colorectal cancer (CRC) and their prognosis was investigated in association with H. pylori. Tissue-infiltrating lymphocytes (TILs) purified from fresh tumor and sera were obtained from GC and CRC patients prospectively. % ICOS + Tregs were analyzed by flow cytometry and their production of anti-H. pylori antibody (Hp-Ab) in sera was detected by ELISA. % ICOS + Tregs were higher in GC and CRC patients with Hp-Ab than in those without Hp-Ab, including eradicated patients. ICOS + Tregs purified had higher potential to produce IL-10 than ICOS - Tregs. For prognostic analysis, immunohistochemical analysis and ELISA were performed using archival fixed specimens and frozen sera, respectively, obtained from GC and CRC patients. Overall survival was longer in patients with low % ICOS + Tregs than in those with high % ICOS + Tregs, and patients with Hp-Ab showed shorter recurrence-free survival than those without Hp-Ab. These results suggested that ICOS + Tregs in GC and CRC patients were closely associated with H. pylori in gastric epithelium and their prognosis, and that pre-operative H. pylori eradication has potential as a novel immunotherapy for GC and CRC patients.

Competing Interests: Financial Disclosures: Dr Milsom is on the clinical advisory board of Lumendi. Dr Nishimura is consultant of Lumendi and Boston Scientifics. Drs Urakawa, Momose, Kono, and Hirashita have no conflicts of interest or financial ties to disclose.

We previously identified a new Bacillus sporothermodurans strain, TM-I-3, which produces volatile compounds that show potent inhibitory activity against certain types of fungi, including Aspergillus fumigatus and Cladosporium cladosporioides. Non-contact antifungals derived from this bacterium may provide multidirectional inhibition and may be useful in disease prevention. This study is aimed at identifying the stage of fungal growth that is inhibited by TM-I-3 to elucidate the mechanism of its contact-independent antifungal activity. We evaluated mycelial growth and the gross fungal colony areas after 7 days in each experimental group varying the time in the proximity of TM-I-3 for 24 hours each. The fungal growth inhibition assay showed that TM-I-3 inhibited spore germination: the lag phase in the sigmoid growth curve. The present study demonstrated that TM-I-3 might be an effective fungistatic agent against pathogenic and allergenic fungi.

Individuals with autism spectrum disorder (ASD) show impairments in processing social cues such as facial expressions and gaze direction. Several researchers have proposed that autistic traits form a continuum that may be distributed within the general, typically developed, population. Accordingly, several studies have indicated that typically developed individuals with high levels of self-reported autistic traits have autistic-like performance in a variety of paradigms. Here, we designed a gaze-cueing task to examine whether gaze-triggered orienting is related to the extent of typically developed (TD) individuals' autistic traits (determined by their AQ test scores) and whether it is modulated by previous eye contact and different facial expressions. At each trial, TD subjects observed faces with or without eye contact. This facial stimulus then gazed toward the left or right side. Finally, a target appeared on the left or right side of the display and reaction time (RT) to the target was measured. RTs were modulated by congruency between gazing directions and target locations, and by prior eye contact in the congruent trials. In addition, individuals with higher AQ scores were slower at detecting the target when the cue was a happy face. Furthermore, faster RTs in congruent trials were associated with one specific autistic trait (attention switching deficits). Together, these results indicate that autistic traits may influence performance in a gaze cueing task., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© 2021 the Author(s), licensee AIMS Press.)

Background/aim: We previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial-mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17-producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation., Methods: In total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC-GR cells to undergo T cell differentiation was investigated in vitro., Results: Tregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs., Conclusion: Cytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.

Metabolic disorders can induce psychiatric comorbidities. Both brain and neuronal composition imbalances reportedly induce an anxiety-like phenotype. We hypothesized that alterations of localized brain areas and cholecystokinin (CCK) and parvalbumin (PV) expression could induce anxiety-like behavior in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Twenty-week-old OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used. The areas of corticolimbic regions were smaller in OLETF rats. The densities of CCK positive neurons in the lateral and basolateral amygdala, hippocampal cornu ammonis area 2, and prelimbic cortex were higher in OLETF rats. The densities of PV positive neurons were comparable between OLETF and LETO rats. Locomotion in the center zone in the open field test was lower in OLETF rats. These results suggest that imbalances of specific brain region areas and neuronal compositions in emotion-related areas increase the prevalence of anxiety-like behaviors in OLETF rats.

The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre-therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4 + lymphocytes (with/without Foxp3 expression), CD8 + lymphocytes (with/without PD-1 expression), monocytes (CD14 + ) and macrophages (CD86 + , CD163 + and CD206 + ) by multiplex immunohistochemistry (IHC). The number of tumor-infiltrating CD206 + macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD-1) was not associated with clinico-pathological features. The high infiltration of CD163 + or CD206 + macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase-1 in CD163 + macrophages tended to be higher in non-responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5-year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long-term survival in EC patients., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Delayed-onset muscle soreness (DOMS) is a common but displeasing event induced by excessive muscle use or unaccustomed exercise and characterized by tenderness and movement-related pain in the exercised muscle. Thermal therapies, either icing or heating applied to muscles immediately after exercise, have been used as therapeutic interventions for DOMS. However, the mechanisms of their analgesic effects, and physiological and metabolic changes in the muscle during thermal therapy, remain unclear. In the present study, we investigated the effects of both thermal treatments on mechanical hyperalgesia of DOMS and physiological and muscle metabolite changes using the rat DOMS model induced by lengthening contraction (LC) to the gastrocnemius muscle. Heating treatment just after LC induced analgesic effects, while rats with icing treatment showed mechanical hyperalgesia similar to that of the LC group. Furthermore, increased physiological responses (e.g., muscle temperature and blood flow) following the LC were significantly kept high only in the rats with heating treatment. In addition, heating treatment increased metabolites involved in the improvement of blood flow and oxidative metabolisms in the exercised muscle. The results indicated that heating treatment just after LC has analgesic effects on DOMS, which might be mediated partly through the improvement of muscle oxidative metabolisms by changes in metabolites and elevated physiological responses. NEW & NOTEWORTHY Physiological effects of thermal therapy in the muscle and its mechanisms of analgesic effects remain unclear. The results indicated that heating, but not icing, treatment just after lengthening contractions induced analgesic effects in the rat muscle. Increases in hemodynamics, muscle temperature, and metabolites such as nicotinamide were more prominent in heating treatment, consistent with improvement of muscle oxidative metabolisms, which might reduce chemical factors to induce mechanical hyperalgesia.

CXCL9, an IFN-γ inducible chemokine, has been reported to play versatile roles in tumor-host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor-infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor-infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor-related apoptosis-inducing ligand-expressing NK cells into tumors, CXCL9-sufficient cells were less tumorigenic in the liver than CXCL9-deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9-expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9-expressing iCCA by augmenting anti-tumor immune surveillance., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

To develop a real-time neurofeedback system from the anterior prefrontal cortex (aPFC) using functional near-infrared spectroscopy (fNIRS) for motor rehabilitation, we investigated the effects of motor imagery training with neurofeedback from the aPFC on hand dexterity and cerebral hemodynamic activity during a motor rehabilitation task. Thirty-one right-handed healthy subjects participated in this study. They received motor imagery training six times for 2 weeks under fNIRS neurofeedback from the aPFC, in which they were instructed to increase aPFC activity. The real group subjects ( n = 16) were shown real fNIRS neurofeedback signals from the aPFC, whereas the sham group subjects ( n = 15) were shown irrelevant randomized signals during neurofeedback training. Before and after the training, hand dexterity was assessed by a motor rehabilitation task, during which cerebral hemodynamic activity was also measured. The results indicated that aPFC activity was increased during the training, and performance improvement rates in the rehabilitation task after the training was increased in the real group when compared with the sham group. Improvement rates of mean aPFC activity across the training were positively correlated with performance improvement rates in the motor rehabilitation task. During the motor rehabilitation task after the training, the hemodynamic activity in the left somatosensory motor-related areas [premotor area (PM), primary motor area (M1), and primary somatosensory area (S1)] was increased in the real group, whereas the hemodynamic activity was increased in the supplementary motor area in the sham group. This hemodynamic activity increases in the somatosensory motor-related areas after the training correlated with aPFC activity during the last 2 days of motor imagery training. Furthermore, improvement rates of M1 hemodynamic activity after the training was positively correlated with performance improvement rates in the motor rehabilitation task. The results suggest that the aPFC might shape activity in the somatosensory motor-related areas to improve hand dexterity. These findings further suggest that the motor imagery training using neurofeedback signals from the aPFC might be useful to patients with motor disability., (Copyright © 2020 Ota, Takamoto, Urakawa, Nishimaru, Matsumoto, Takamura, Mihara, Ono and Nishijo.)

Mild hyperbaric treatment prevents type 2 diabetes progression due to increased oxygen concentration and blood flow in skeletal muscle. However, it remains unknown whether this treatment is effective during all stages of type 2 diabetes. This study aimed to investigate the influences of hyperbaric treatment at 1.3 atmospheres absolute (ATA) on hemodynamic response in various stages of type 2 diabetes. Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as models of type 2 diabetes and healthy controls, respectively. Glucose levels were significantly higher in OLETF rats than in LETO rats at all ages. Glucose intolerance gradually increased with age in OLETF rats. Insulin levels in OLETF rats were significantly higher at 20-week-old, however, were significantly lower at 60-week-old than in LETO rats. Oxy-Hb, total Hb, and StO 2 in skeletal muscle were increased during hyperbaric treatment in both rats. The hemodynamic changes were significantly higher in OLETF rats than LETO rats, and those changes were also pronounced at 8-week-old compared with other age in OLETF rats. These results suggest that hyperbaric treatment at 1.3 ATA acts on pathophysiological factors and the efficacy could be found only in the early stage of type 2 diabetes.

Tomato plants (Solanum lycopersicum) contain steroidal glycoalkaloid α-tomatine, which functions as a chemical barrier to pathogens and predators. α-Tomatine accumulates in all tissues and at particularly high levels in leaves and immature green fruits. The compound is toxic and causes a bitter taste, but its presence decreases through metabolic conversion to nontoxic esculeoside A during fruit ripening. This study identifies the gene encoding a 23-hydroxylase of α-tomatine, which is a key to this process. Some 2-oxoglutarate-dependent dioxygenases were selected as candidates for the metabolic enzyme, and Solyc02g062460, designated Sl23DOX, was found to encode α-tomatine 23-hydroxylase. Biochemical analysis of the recombinant Sl23DOX protein demonstrated that it catalyzes the 23-hydroxylation of α-tomatine and the product spontaneously isomerizes to neorickiioside B, which is an intermediate in α-tomatine metabolism that appears during ripening. Leaves of transgenic tomato plants overexpressing Sl23DOX accumulated not only neorickiioside B but also another intermediate, lycoperoside C (23-O-acetylated neorickiioside B). Furthermore, the ripe fruits of Sl23DOX-silenced transgenic tomato plants contained lower levels of esculeoside A but substantially accumulated α-tomatine. Thus, Sl23DOX functions as α-tomatine 23-hydroxylase during the metabolic processing of toxic α-tomatine in tomato fruit ripening and is a key enzyme in the domestication of cultivated tomatoes., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Hyperbaric treatment improves hyperglycemia and hyperinsulinemia in type 2 diabetes associated with obesity. However, its mode of action is unknown. The purpose of the present study was to investigate the influences of regular hyperbaric treatment with normal air at 1.3 atmospheres absolute (ATA) on glucose tolerance in type 2 diabetes with obesity. The focus was directed on inflammatory cytokines in the adipose tissue and skeletal muscle. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as models of type 2 diabetes with obesity and Long-Evans Tokushima Otsuka (LETO) rats served as healthy controls. The rats were randomly assigned to untreated or hyperbaric treatment groups exposed to 1.3 ATA for 8 h d -1 and 5 d wk -1 for 16 wks. Glucose levels were significantly higher in the diabetic than in the healthy control rats. Nevertheless, glucose levels at 30 and 60 min after glucose administration were significantly lower in the diabetic rats treated with 1.3 ATA than in the untreated diabetic rats. Insulin levels at fasting and 120 min after glucose administration were significantly lower in the diabetic rats treated with 1.3 ATA than in the untreated diabetic rats. Hyperbaric treatment also increased interleukin-10 (IL-10) expression in the skeletal muscle and decreased tumor necrosis factor α (TNF α ) expression in adipose tissue. These results suggested that TNF α downregulation and IL-10 upregulation in diabetic rats subjected to hyperbaric treatment participate in the crosstalk between the adipose and skeletal muscle tissues and improve glucose intolerance., Competing Interests: There are no conflicts of interest to declare., (Copyright © 2019 Naoto Fujita et al.)

Gastric cancer (GC) is the most common malignant tumor in digestive organs, and the prognosis of GC patients who have undergone surgery remains poor because of frequent recurrence. Therefore, the identification of new markers to predict the outcome of these patients is needed. Monocyte count is a negative prognostic factor associated with inflammation. We investigated the relationship between peripheral monocytes in the peri-operative period and prognosis in GC patients. A high pre-operative monocyte count was identified as a prognostic factor in a retrospective analysis of 278 stage II and III GC patients who underwent curative gastrectomy. In contrast, an increased post-operative monocyte count compared to the pre-operative monocyte count was a marker of poor prognosis, particularly for early relapse. In a prospective analysis of 75 GC patients, a subset of the increased post-operative monocytes was similar to CD14 + HLA-DR - CD11b + CD33 + cells by flow cytometry, and these monocytes produced IDO and arginase and suppressed T cell functions; therefore, we classified these cells as monocytic myeloid-derived suppressive cells (M-MDSCs). Peri-operative neutrophils and C-reactive protein (CRP), which are also related to inflammation, did not affect the prognosis of GC patients, and a neutrophil immunosuppressive function was not observed. These results suggest that peripheral monocytes in the peri-operative period in GC patients are a useful marker for the prognosis of GC patients, and a subset of increased post-operative monocytes may be characterized as M-MDSCs.

Previously, we isolated and examined a bacterial strain designated as TM-I-3, belonging to the genus Bacillus, from soil in Nagasaki, Japan. This bacterium was able to inhibit the growth of molds, without coming into direct contact with them. Non-contact antifungals are capable of providing multidirectional inhibition and may contribute to disease prevention. In this study, we revealed the bacteriological properties of TM-I-3 and evaluated the antifungal activity of the compounds emitted from this bacterium. In addition, we analyzed the antimicrobial substances released from TM-I-3 using GC/MS to elucidate the mechanism of its action. Antimicrobial compounds from strain TM-I-3 were identified as acetic acid, propanoic acid, isovaleric acid, 2-methylbutanoic acid, and benzaldehyde, which are all reported to have antimicrobial activity. TM-I-3 demonstrated possible efficacy in inhibiting the growth of Aspergillus fumigatus, Cladosporium cladosporioides and Penicillium expansum, which may lead to inhibition of common fungal contaminants of household products and prevention of some pulmonary diseases.

The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA - CD27 - , and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3 + CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.

Anti-tumor responses induced by immunotherapy such as cancer vaccine are presumed to be mediated by induction of cancer-specific immune responses. Therefore, the immune-related response criteria(irRC)have been applied for cancer immunotherapies instead of the Response Evaluation Criteria in Solid Tumors(RECIST). Clinical responses of 91 patients enrolled in our cancer vaccine clinical studies were evaluated using RECIST. In this study, we re-analyzed their clinical responses using irRC. We identified 2 patients whose responses were evaluated as PD by RECIST, but as PR and SD by irRC, respectively. As these 2 patients showed relatively long survival rate, we concluded that irRC was suitable for the assessment of clinical outcomes in cancer immunotherapy.

Previous research suggests that aging-related deterioration of oral functions causes not only eating/swallowing disorders but also various conditions such as sleep disorders and higher-order brain dysfunction. The aim of the present study was to examine the effects of lip closure training on eating behavior, sleep, and brain function in elderly persons residing in an elder care facility. The 20 elderly subjects (mean age, 86.3 ± 1.0 years) were assigned to a control group or a lip closure training (LCT) group, in which an oral rehabilitation device was used for daily LCT sessions over a 4-week period. Before and after the 4-week intervention period, maximal lip closure force was measured, and prefrontal cortical hemodynamic activity (changes in oxygenated hemoglobin concentration) during lip closure movements was measured with (LCT group) or without (control group) use of the oral rehabilitation device. We also analyzed eating behavior and daytime sleep before and after the intervention period. Compared with the control group, the LCT group showed improved maximal lip closure force, shortened eating time, decreased food spill rates, and decreased daytime sleeping. Furthermore, compared with the control group, the LCT group showed a significant increase in prefrontal cortical activity during lip closure. In addition, the increase rate in the right dorsolateral prefrontal cortical activity after the intervention period was significantly correlated with the increase rate in the maximal lip closure force after the intervention period. These findings suggest that LCT is useful in elderly individuals with decreased eating/oral and cognitive functions without the risk of pulmonary aspiration during training., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long-Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight.

Background: Ramucirumab is a monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Ramucirumab either alone or in combination with paclitaxel (PTX) has been found to be safe and effective for patients with previously treated advanced gastric cancer. One of the serious adverse events associated with ramucirumab is gastrointestinal (GI) perforation., Case Presentation: We report the case of a 67-year-old man who developed a ramucirumab-related GI perforation while undergoing treatment for gastric cancer with small bowel metastasis. He underwent laparoscopic total gastrectomy following neoadjuvant chemotherapy in January 2015 and was diagnosed with hepatic and bone recurrence in October 2015. Ramucirumab in combination with PTX was administered for one and half months after first-line chemotherapy failure. He presented with abdominal pain 7 days after the last ramucirumab dose, and emergency exploratory surgery revealed a small intestinal perforation. Pathological findings indicated that it occurred in a zone containing a small intestinal tumor, which was found to be metastasis of the gastric cancer. He had no postoperative complications, but chemotherapy was not reintroduced and he died 3 months later., Conclusion: We present a recent case of ramucirumab-related gastrointestinal perforation in gastric cancer with small bowel metastasis. This case is rare, but important to consider.

Compression at myofascial trigger points (MTrPs), known as "ischemic compression," has been reported to provide immediate relief of musculoskeletal pain and reduce the sympathetic activity that exacerbates chronic pain. We conducted a pilot study to investigate the possible involvement of the prefrontal cortex in pain relief obtained by MTrP compression in the present study, and analyzed the relationships among prefrontal hemodynamic activity, activity of the autonomic nervous system, and subjective pain in patients with chronic neck pain, with and without MTrP compression. Twenty-one female subjects with chronic neck pain were randomly assigned to two groups: MTrP compression ( n = 11) or Non-MTrP compression ( n = 10). Compression for 30 s was conducted 4 times. During the experiment, prefrontal hemodynamic activity [changes in Oxy-hemoglobin (Hb), Deoxy-Hb, and Total-Hb concentrations] and autonomic activity based on heart rate variability (HRV) were monitored by using near infrared spectroscopy (NIRS) and electrocardiography (ECG), respectively. The results indicated that MTrP compression significantly reduced subjective pain compared with Non-MTrP compression. The spectral frequency-domain analyses of HRV indicated that a low frequency (LF) component of HRV was decreased, and a high frequency (HF) component of HRV was increased during MTrP compression, while LF/HF ratio was decreased during MTrP compression. In addition, prefrontal hemodynamic activity was significantly decreased during MTrP compression compared with Non-MTrP compression. Furthermore, changes in autonomic activity were significantly correlated with changes in subjective pain and prefrontal hemodynamic activity. Along with previous studies indicating a role for sympathetic activity in the exacerbation of chronic pain, the present results suggest that MTrP compression in the neck region alters the activity of the autonomic nervous system via the prefrontal cortex to reduce subjective pain.

Regulatory T cells (Tregs) have an immunosuppressive role in the tumor microenvironment. Since effector Tregs (eTregs), which have highly suppressive functions, are located in a subpopulation of Foxp3 + CD4 + Tregs, the TCR-inducible costimulatory receptor (ICOS) was applied as a marker of eTregs that infiltrated gastric cancer tissue and the induction pathway of ICOS + Foxp3 + cells was analyzed by flow cytometry and immunohistochemistry. In tumor-infiltrating lymphocytes (TILs), ICOS + Foxp3 + CD4 + T cells were abundantly observed in the late stages of gastric cancer. ICOS + CD4 + TILs exhibited the ability to produce IL-10, but not IFN-γ, TNF, or IL-17 and also to suppress the proliferation of CFSE-labeled responder CD8 + T cells. With the agonistic ICOS-L protein (rICOS-L Ig), ICOS + Foxp3 + cells were efficiently induced from naive CD4 + T cells under a stimulation with TGF-β and CD3/CD28 mAbs. Furthermore, when A*0201 PBMCs were cultured with the CMV or Melan-A antigenic peptide and rICOS-L Ig, the induction of CMV or Melan-A tetramer-binding CD8 + T cells, respectively, was inhibited. The expression of ICOS in Foxp3 + cells was closely related to plasmacytoid dendritic cells (pDCs) and their expression of ICOS-L and TLR9 as well as Helicobacter pylori infection. Collectively, our results demonstrate the potential of ICOS as a promising target for direct Treg-targeting therapeutic agents for gastric cancer, and that of eradicating therapy for H. pylori as an indirect immune therapy for gastric cancer., (© 2016 UICC.)

Although, clinical studies reported hyperactivation of the auditory system and amygdala in patients with auditory hallucinations (hearing others' but not one's own voice, independent of any external stimulus), neural mechanisms of self/other attribution is not well understood. We recorded neuronal responses in the dorsal amygdala including the lateral amygdaloid nucleus to ultrasonic vocalization (USVs) emitted by subjects and conspecifics during free social interaction in 16 adult male rats. The animals emitting the USVs were identified by EMG recordings. One-quarter of the amygdalar neurons (15/60) responded to 50 kHz calls by the subject and/or conspecifics. Among the responsive neurons, most neurons (Type-Other neurons; 73%, 11/15) responded only to calls by conspecifics but not subjects. Two Type-Self neurons (13%, 2/15) responded to calls by the subject but not those by conspecifics, although their response selectivity to subjects vs. conspecifics was lower than that of Type-Other neurons. The remaining two neurons (13%) responded to calls by both the subject and conspecifics. Furthermore, population coding of the amygdalar neurons represented distinction of subject vs. conspecific calls. The present results provide the first neurophysiological evidence that the amygdala discriminately represents affective social calls by subject and conspecifics. These findings suggest that the amygdala is an important brain region for self/other attribution. Furthermore, pathological activation of the amygdala, where Type-Other neurons predominate, could induce external misattribution of percepts of vocalization.

To investigate the role of the prefrontal cortex (PFC) in processing multimodal communicative ostensive signals in infants, we measured cerebral hemodynamic responses by using near-infrared spectroscopy (NIRS) during the social interactive play "peek-a-boo", in which both visual (direct gaze) and auditory (infant-directed speech) stimuli were presented. The infants (mean age, around 7 months) sat on their mother's lap, equipped with an NIRS head cap, and looked at a partner's face during "peek-a-boo". An eye-tracking system simultaneously monitored the infants' visual fixation patterns. The results indicate that, when the partner presented a direct gaze, rather than an averted gaze, toward an infant during social play, the infant fixated on the partner's eye region for a longer duration. Furthermore, hemodynamic activity increased more prominently dorsomedial prefrontal cortex (mPFC) in response to social play with a partner's direct gaze compared to an averted gaze. In contrast, hemodynamic activity increased in the right dorsolateral prefrontal cortex (R-lPFC) regardless of a partner's eye gaze direction. These results indicate that a partner's direct gaze shifts an infant's attention to the partner's eyes for interactive communication, and specifically activates the mPFC. The differences in hemodynamic responses between the mPFC and R-lPFC suggest functional differentiation within the PFC, and a specific role of the mPFC in the perception of face-to-face communication, especially in mutual gaze, which is essential for social interaction.

Delayed-onset muscle soreness (DOMS) can be induced by lengthening contraction (LC); it can be characterized by tenderness and movement-related pain in the exercised muscle. Manual therapy (MT), including compression of exercised muscles, is widely used as physical rehabilitation to reduce pain and promote functional recovery. Although MT is beneficial for reducing musculoskeletal pain (i.e. DOMS), the physiological mechanisms of MT remain unclear. In the present study, we first developed an animal model of MT in DOMS; LC was applied to the rat gastrocnemius muscle under anesthesia, which induced mechanical hyperalgesia 2-4 days after LC. MT (manual compression) ameliorated mechanical hyperalgesia. Then, we used capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS) to investigate early effects of MT on the metabolite profiles of the muscle experiencing DOMS. The rats were divided into the following three groups; (1) normal controls, (2) rats with LC application (LC group), and (3) rats undergoing MT after LC (LC + MT group). According to the CE-TOFMS analysis, a total of 171 metabolites were detected among the three groups, and 19 of these metabolites were significant among the groups. Furthermore, the concentrations of eight metabolites, including branched-chain amino acids, carnitine, and malic acid, were significantly different between the LC + MT and LC groups. The results suggest that MT significantly altered metabolite profiles in DOMS. According to our findings and previous data regarding metabolites in mitochondrial metabolism, the ameliorative effects of MT might be mediated partly through alterations in metabolites associated with mitochondrial respiration., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

The novel object recognition (NOR) test has been widely used to test memory function. We developed a 3D computerized video analysis system that estimates nose contact with an object in Long Evans rats to analyze object exploration during NOR tests. The results indicate that the 3D system reproducibly and accurately scores the NOR test. Furthermore, the 3D system captures a 3D trajectory of the nose during object exploration, enabling detailed analyses of spatiotemporal patterns of object exploration. The 3D trajectory analysis revealed a specific pattern of object exploration in the sample phase of the NOR test: normal rats first explored the lower parts of objects and then gradually explored the upper parts. A systematic injection of MK-801 suppressed changes in these exploration patterns. The results, along with those of previous studies, suggest that the changes in the exploration patterns reflect neophobia to a novel object and/or changes from spatial learning to object learning. These results demonstrate that the 3D tracking system is useful not only for detailed scoring of animal behaviors but also for investigation of characteristic spatiotemporal patterns of object exploration. The system has the potential to facilitate future investigation of neural mechanisms underlying object exploration that result from dynamic and complex brain activity., (Copyright © 2014 Elsevier B.V. All rights reserved.)