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Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is especially hypoxic and composed of heterogeneous cell populations containing hypoxia-adapted cells. Hypoxia as a microenvironment of PDAC is known to cause epithelial-mesenchymal transition (EMT) and resistance to therapy. Therefore, cells adapted to hypoxia possess malignant traits that should be targeted for therapy. However, current 3D organoid culture systems are usually cultured under normoxia, losing hypoxia-adapted cells due to selectivity bias at the time of organoid establishment. To overcome any potential selection bias, we focused on oxygen concentration during the establishment of 3D organoids. We subjected identical PDAC surgical samples to normoxia (O2 20%) or hypoxia (O2 1%), yielding glandular and solid organoid morphology, respectively. Pancreatic cancer organoids established under hypoxia displayed higher expression of EMT-related proteins, a Moffitt basal-like subtype transcriptome, and higher 5-FU resistance in contrast to organoids established under normoxia. We suggest that hypoxia during organoid establishment efficiently selects for hypoxia-adapted cells possibly responsible for PDAC malignant traits, facilitating a fundamental source for elucidating and developing new treatment strategies against PDAC., 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 © 2024 Kumano, Nakahashi, Louphrasitthiphol, Kuroda, Miyazaki, Shimomura, Hashimoto, Akashi, Mathis, Kim, Owada, Goding and Oda.)

Fatty acid-binding protein 7 (FABP7) is vital for uptake and trafficking of fatty acids in the nervous system. To investigate the involvement of FABP7 in noise-induced hearing loss (NIHL) pathogenesis, we used Fabp7 knockout (KO) mice generated via CRISPR/Cas9 in the C57BL/6 background. Initial auditory brainstem response (ABR) measurements were conducted at 9 weeks, followed by noise exposure at 10 weeks. Subsequent ABRs were performed 24 h later, with final measurements at 12 weeks. Inner ears were harvested 24 h after noise exposure for RNA sequencing and metabolic analyses. We found no significant differences in initial ABR measurements, but Fabp7 KO mice showed significantly lower thresholds in the final ABR measurements. Hair cell survival was also enhanced in Fabp7 KO mice. RNA sequencing revealed that genes associated with the electron transport chain were upregulated or less impaired in Fabp7 KO mice. Metabolomic analysis revealed various alterations, including decreased glutamate and aspartate in Fabp7 KO mice. In conclusion, FABP7 deficiency mitigates cochlear damage following noise exposure. This protective effect was supported by the changes in gene expression of the electron transport chain, and in several metabolites, including excitotoxic neurotransmitters. Our study highlights the potential therapeutic significance of targeting FABP7 in NIHL., (© 2023. The Author(s).)

A 60s woman was diagnosed to transverse colon cancer and she underwent laparoscopic right hemicolectomy. Localized peritoneal dissemination surrounding tumor was detected during surgery. She was administrated to chemotherapy due to a hepatic metastasis in S2/3 postoperatively. Subsequently, PET-CT revealed a left ovarian metastasis in addition to a liver metastasis during chemotherapy. Laparoscopic hepatic left lateral segmentectomy and bilateral adnexectomy was performed at 1 year and 9 months after the first surgery and histopathological examination showed a metastasis of transverse colon cancer. The growth of liver and lung metastases and peritoneal disseminations was detected at 6 months later after the second surgery and the patient is currently receiving palliative treatment. Previous literatures described that ovarian metastasis of colon cancer showed bilateral metastasis and resistance to chemotherapy frequently and ruptured in some cases. We should consider to resect bilateral ovary even if unilateral metastasis alone was detected by imaging examination.

A 36-year-old woman was diagnosed with acute appendicitis after a close examination of her abdominal pain and nausea. Laparoscopic appendectomy was performed, and pathological examination revealed a NET G1. They were localized lesions on the tips and body of the appendix, with no additional resection because the tumor size was less than 2 cm and no risk factors for recurrence and metastasis(vascular invasion, NET G2 or higher, or invasion of the mesentery). The patient was followed up with contrast-enhanced CT every 6 months and has been recurrence-free for 2 years postoperatively.

A woman in her 70s underwent distal pancreatectomy(D2 dissection)for a pancreatic tail carcinoma after a close examination of the cause of her poorly controlled diabetes mellitus. Intraoperative rapid peritoneal washing cytology showed no malignant findings, but histopathological examination revealed Ptb, TS2, tub2, pT3, ly1, v3, ne3, mpd0, pS0, pRP1, pOO0, pPCM0, pDPM0, pN0, pM0, pCY1, pStage ⅡA, R0(Pancreatic Cancer Treatment Protocol 7th Edition). The patient was treated with S-1 therapy for 6 months postoperatively and is alive 1 year and 9 months without recurrence. The prognosis after resection of pancreatic cancer with positive peritoneal washing cytology is said to be worse than that of patients with negative, because of the high recurrence rate of peritoneal metastasis. We report a case of pancreatic tail carcinoma with positive peritoneal washing cytology with recurrence-free survival after surgery and chemotherapy.

Tumor metastasis is one of the worst prognostic features of cancer. Although metastasis is a major cause of cancer-related deaths, an effective treatment has not yet been established. Here, we explore the antitumor effects of GO-Y030, a curcumin analog, via various mechanisms using a mouse model. GO-Y030 treatment of B16-F10 melanoma cells inhibited TGF-β expression and glycolysis. The invasion assay results showed almost complete invasion inhibition following GO-Y030 treatment. Mouse experiments demonstrated that GO-Y030 administration inhibited lung tumor metastasis without affecting vascular endothelial cells. Consistent with this result, GO-Y030 treatment led to the downregulation of MMP2 and VEGFα, inhibiting tumor invasion and metastasis. The silencing of eIF4B, a downstream molecule of S6, attenuated MMP2 expression. Our study demonstrates the novel efficacy of GO-Y030 in inhibiting tumor metastasis by regulating metastasis-associated gene expression via inhibiting dual access, glycolytic and TGF-β pathways., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: Superior mesenteric artery (SMA) nerve plexus (PLsma) dissection has been performed to achieve R0 resection in pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) in high-volume centers. However, full-extent PLsma preservation in PD is employed in our institution. The feasibility of the PLsma preservation strategy was investigated., Methods: Between January 2010 and December 2020, 156 patients underwent PLsma preservation PD for PDAC at our institution. Of these, 118 patients had resectable PDAC (R group) and 38 patients had borderline resectable artery (BR-A group). Clinical and oncological outcomes focusing on local recurrence, patient prognoses, and morbidities (including postoperative refractory diarrhea) were retrospectively analyzed and our postoperative outcomes were compared with those of other institutions., Results: Pathological R0 resection by PLsma preservation PD was achieved in 96 R group patients (81.4%) and 27 BR-A group patients (71.1%). The median postoperative hospital stay was 15.0 days in both groups. Local site-only recurrence was observed in 10.2% (12/118) of R-group and 10.5% (4/38) of BR-A-group patients, whereas distant site-only recurrence occurred in 21.2% (25/118) of R-group and 28.9% (11/38) of BR-A-group patients. Median survival times were 64.3 months (R group) and 35.4 months (BR-A group, p = 0.07). Median disease-free survival (DFS) times were 31.0 months (R group) and 12.0 months (BR-A group). No diarrhea requiring opioids was observed in either group. These results were equal or superior to those of PLsma dissection PD in other institutions., Conclusions: PLsma preservation in PD was feasible compared to PLsma dissection in recurrence and overall survival., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) has a significant impact on the therapeutic efficacy of chemotherapy and patients' quality of life. The aim of this study was to assess the preventive effect of lafutidine on CIPN., Methods: Patients were randomly assigned (1:1) to carboplatin and paclitaxel chemotherapy with lafutidine 10 mg twice daily (lafutidine group) or without lafutidine (control group). Peripheral neuropathy in both groups was assessed with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and two patient-based questionnaires, the Patient Neurotoxicity Questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx). The primary outcome was the incidence of grade 2 or higher peripheral neuropathy in CTCAE version 5.0. The target number of cases was set at approximately 40., Results: In total, 18 patients were screened, and 16 patients were assigned to the lafutidine group (n=9) or control group (n=7) between January 2021 and January 2023. Due to poor recruitment, the target number of cases was not reached. Grade 2 or higher neuralgia was 22.2% in the lafutidine group and 14.3% in the control group. Grade 2 or higher peripheral sensory neuropathy was 100% in the lafutidine group and 71.4% in the control group (P=0.175). Grade 3 or higher peripheral neuropathy was not detected in either group. There was no significant difference in PNQ scores between the two groups. Median FACT/GOG-Ntx scores after the fourth cycle tended to be lower in the lafutidine group than in the control group. There was no statistically significant difference in progression free survival (PFS) between the two groups. There were no adverse events due to lafutidine administration., Conclusions: Although the preventive effect of lafutidine on CIPN could not be demonstrated statistically, lafutidine FACT/GOG-Ntx scores showed a trend toward decreased neurotoxicity as chemotherapy proceeded. More reliable studies using lafutidine on the prevention of CIPN should be conducted., Trial Registration: Japan Registry of Clinical Trials, identifier: jRCTs021200031.

Background: Kirsten rat sarcoma virus ( KRAS ) gene mutations are a type of driver mutation discovered in the 1980s, but for a long time no molecular targeted drugs were available for them. Recently, sotorasib was developed as a molecular targeted drug for KRAS mutations. It is therefore necessary to identify the characteristics of patients with KRAS mutations., Methods: This was the single-institution retrospective study. Surgically resected tumors from lung adenocarcinoma patients were collected at a single institution from June 2016 to September 2019. Peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp analysis of KRAS G12X mutations was compared with analysis by therascreen KRAS RGQ kit. The association between KRAS mutation status and patient characteristics and prognosis was assessed., Results: Among 499 lung adenocarcinomas, KRAS mutations were evaluated in 197 cases, excluding stage IV lung cancer and tumors with epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase (ALK ) mutations. KRAS G12X mutations were detected in 59 cases (29.9%). The highest frequency by gene mutation subtype was G12V in 23 cases (39.0%), followed by G12C in 16 cases (27.1%), G12D in 12 cases (20.3%), G12S in 4 cases (6.8%) and G12A in 2 cases. For the G12C mutation, the PNA-LNA PCR clamp and therascreen methods were consistent, but for the G12D and G12S mutations, the PNA-LNA PCR clamp method showed higher detection rates. In operable tumors, G12C mutations were more frequent in males, smokers, and patients with high expression of programmed death-ligand 1 (PD-L1), and had no correlation with prognosis., Conclusions: By the PNA-LNA PCR clamp method, G12C mutation of surgical specimens was detected successfully. The PNA-LNA PCR clamp method is expected to be applied to the detection of druggable G12C mutations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-15/coif). HT is a current employee of LSI Medience, Inc., which is a for-profit company that deals with clinical testing and research equipment and reagents. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Natural disasters, including earthquakes, floods, landslides, tsunamis, wildfires, and hurricanes, have become more common in recent years due to rapid climate change. For Post-Disaster Management (PDM), authorities deploy various types of user equipment (UE) for the search and rescue operation, for example, search and rescue robots, drones, medical robots, smartphones, etc., via the Internet of Robotic Things (IoRT) supported by cellular 4G/LTE/5G and beyond or other wireless technologies. For uninterrupted communication services, movable and deployable resource units (MDRUs) have been utilized where the base stations are damaged due to the disaster. In addition, power optimization of the networks by satisfying the quality of service (QoS) of each UE is a crucial challenge because of the electricity crisis after the disaster. In order to optimize the energy efficiency, UE throughput, and serving cell (SC) throughput by considering the stationary as well as movable UE without knowing the environmental priori knowledge in MDRUs aided two-tier heterogeneous networks (HetsNets) of IoRT, the optimization problem has been formulated based on emitting power allocation and user association combinedly in this article. This optimization problem is nonconvex and NP-hard where parameterized (discrete: user association and continuous: power allocation) action space is deployed. The new model-free hybrid action space-based algorithm called multi-pass deep Q network (MP-DQN) is developed to optimize this complex problem. Simulations results demonstrate that the proposed MP-DQN outperforms the parameterized deep Q network (P-DQN) approach, which is well known for solving parameterized action space, DQN, as well as traditional algorithms in terms of reward, average energy efficiency, UE throughput, and SC throughput for motionless as well as moveable UE.

Mitochondrial dysfunction can cause cochlear dysfunction and accelerate noise-induced hearing loss (NIHL). NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and has a role in the assembly and stabilization of complex I. However, the involvement of Ndufs4 in the pathogenesis of NIHL has not been reported. The aim of this study was to evaluate whether Ndufs4 deletion causes vulnerability to noise exposures. The wild-type (WT) and Ndufs4 knockout (KO) mice with C57BL/6J genetic background were used. Cochlear histology and hearing thresholds were assessed after noise exposure at 100 or 86 dB sound pressure level (SPL). Immunostaining showed the widespread expression of Ndufs4 in the cochlea. After noise exposure at 100 dB SPL, auditory brainstem response (ABR) threshold shifts at 4 kHz in Ndufs4 KO mice were significantly higher than that in WT mice. After noise exposure at 86 dB SPL, ABR threshold shifts, wave 1 amplitudes, and the number of synapses in the inner hair cells were not significantly different. RNA sequencing revealed the decreased expression of energy generation-related genes inNdufs4 KO mice. Ndufs4 deficiency accelerates permanent low-frequency threshold shifts after moderate noise exposure.

Introduction: In the Enhanced Recovery After Surgery program, abdominal wall blocks are strongly recommended as postoperative multimodal analgesia for laparoscopic abdominal surgery. The purpose of this study was to compare the efficacy of single-shot rectus sheath block (RSB) with that of thoracic epidural analgesia (TEA) as a method of multimodal analgesia in patients receiving conventional laparoscopic abdominal surgery., Methods: A noninferiority comparison was performed. Patients scheduled for laparoscopic gastric or colorectal surgery were enrolled in this study. Patients were divided randomly into two groups: TEA and RSB. The primary endpoint was the numerical rating scale (NRS) score upon coughing as of 24 hours after surgery., Results: In total, 80 patients were randomly assigned to receive TEA (n = 42) or RSB (n = 38). Three patients were excluded from the TEA group after randomization. The NRS score on coughing as of 24 hours after surgery was significantly lower in the TEA group than in the RSB group (least square mean: 3.59 vs 6.39; 95% confidence interval for the difference: 1.87 to 3.74, P < .001). The NRS scores upon coughing and at rest were significantly lower in the TEA group than in the RSB group as of 4, 24 and 48 hours after surgery. Patient satisfaction with postoperative analgesia was significantly higher in the TEA group. Postoperative adverse events were not significantly different between groups., Conclusion: This is the first report of comparing RSB with TEA in laparoscopic surgery. TEA may be recommended as a multimodal analgesia protocol for laparoscopic gastric and colorectal surgery., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background: Although the transmediastinal approach as a radical esophagectomy for esophageal carcinoma patients has attracted attention, its advantages over the transthoracic approach remain unclear. This study aimed to evaluate the efficacy of transmediastinal esophagectomy (TME) in terms of postoperative respiratory complications compared to that of open transthoracic esophagectomy (TTE)., Methods: We reviewed patients with thoracic and abdominal esophageal carcinoma who underwent TME or TTE between February 2014 and November 2021. We compared postoperative respiratory complications as the primary outcome. The secondary outcomes included perioperative operation time, blood loss, postoperative complications, and the number of harvested mediastinal lymph nodes., Results: Overall, 60 and 54 patients underwent TME and TTE, respectively. The baseline characteristics were similar between the two groups, except for age and histological type. There were no intraoperative lethal complications in either group. The incidence of respiratory complications was significantly lower in the TME group than in the TTE group (6.7 vs. 22.2%, p = 0.03). The TME group had a shorter operation time (403 vs. 451 min, p < 0.01), less blood loss (107 vs. 253 mL, p < 0.01), and slightly higher anastomotic leakage (11.7 vs. 5.6%, p = 0.33). The number of harvested lymph nodes was similar in both groups (24 vs. 26, p = 0.10). Multivariate analysis revealed that TME is an independent factor in reducing respiratory complications (odds ratio = 0.27, p = 0.04)., Conclusions: TME for esophageal carcinoma was performed safely. TME was superior to TTE in terms of postoperative respiratory complications; however, the relatively higher frequency of anastomotic leakage should be considered and requires further evaluation., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

We previously reported that septoclasts, which are uncalcified growth plate (GP) cartilage matrix-resorbing cells, are derived from pericytes surrounding capillary endothelial cells. Resorption of the GP is assumed to be regulated synchronously by septoclasts, pericytes, and endothelial cells. To reveal the contribution of the extracellular matrix (ECM) to the regulatory mechanisms of septoclastic cartilage resorption, we investigated the spatial correlation between the cells and the ECM in the GP matrix and basement membrane (BM) and investigated the expression of integrins-ECM receptors-in the cells. Septoclasts attached to the transverse septa containing collagen-II/-X at the tip of their processes and to the longitudinal septa containing collagen-II/-X at the spine-like processes extending from their bodies and processes. Collagen-IV and laminin α4 in the BM were sparsely detected between septoclasts and capillary endothelial cells at the chondro-osseous junction (COJ) and were absent in the outer surface of pericytes at the metaphysis. Integrin α1/α2, integrin α1, and integrin α2/α6 were detected in the cell membranes of septoclasts, pericytes, and endothelial cells, respectively. These results suggest that the adhesion between septoclasts and the cartilage ECM forming the scaffolds for cartilage resorption and migration is provided by integrin α2-collagen-II/-X interaction and that the adhesions between the BM and pericytes or endothelial cells are mediated by integrin α1-collagen-IV and integrin α2/α6-laminin interaction, respectively., (© 2022 Anatomical Society.)

Aim: To investigate the risk factors for postoperative delirium among elderly patients undergoing elective surgery for gastroenterological cancer., Methods: From May 2020 to March 2022, patients ≥75 years old with gastroenterological cancer who underwent radical surgery were enrolled. The geriatric assessment, including evaluations of frailty, physical function, nutrition status, and cognitive function, was conducted preoperatively. The confusion assessment method was used to diagnose postoperative delirium. A multivariate logistic regression analysis was used to determine risk factors for postoperative delirium., Results: A total of 158 patients were eligible for inclusion in this study. Of these 53 patients (34%) developed postoperative delirium. In the univariate analysis, the age, regular use of sleeping drugs and benzodiazepine, Charlson Comorbidity Index score, performance status, Fried's frailty score, Vulnerable Elders Survey-13 score, grip weakness, Short Physical Performance Battery (SPPB) score, Mini Nutritional Assessment Short-Form score, and Mini-Mental State Examination score were statistically associated with the incidence of postoperative delirium. In the multivariate analysis, a SPPB score ≤9, Mini Nutritional Assessment score ≤11, a Mini-Mental State Examination score ≤24, and regular use of benzodiazepine were found to be independent preoperative risk factors for postoperative delirium., Conclusion: Certain findings during the preoperative geriatric assessment, especially low SPPB, Mini Nutritional Assessment Short-Form and Mini-Mental State Examination scores, and regular use of benzodiazepine were risk factors for postoperative delirium in elderly patients undergoing gastroenterological surgery., Competing Interests: The authors declare no conflicts of interest for this article., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Purpose: Even though minor, stoma-related complications significantly impact quality of life, they are often excluded from clinical analyses that compare short-term postoperative outcomes of loop ileostomy and loop colostomy. This study compares stoma-related complications between loop ileostomy and loop colostomy after rectal resection, including minor complications, and discusses the characteristics of diverting stoma types., Methods: A retrospective review was conducted in patients who underwent diverting stoma construction after rectal resection. Data on patient background and postoperative short-term outcomes, including stoma-related complications and morbidity after stoma closure, were collected and compared between loop ileostomy and loop colostomy groups. Morbidities of all severity grades were targeted for analysis., Results: A total of 47 patients (27 loop ileostomy, 20 loop colostomy) underwent diverting stoma construction following rectal resection. Overall stoma-related complications, incidence of skin irritation, high-output stoma, and outlet obstruction were significantly higher in the loop ileostomy group but high-output stoma and outlet obstruction were absent in the loop colostomy group. Regarding morbidity after stoma closure, operation times and surgical site infections were significantly higher in the loop colostomy group while anastomotic leakage after diverting stoma closure occurred (2 cases; 15%) in the loop colostomy group but not the loop ileostomy group., Conclusion: Because stoma-related complications were significantly higher in the loop ileostomy group, and even these minor complications may impair QOL, early loop ileostomy closure is recommended. For loop colostomy, stoma-related morbidities are lower but post-closure leakage is a calculated risk., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation., (© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Bipolar disorder (BD) is a common mental disorder characterized by recurrent mood episodes, which causes major socioeconomic burdens globally. Though its disease pathogenesis is largely unknown, the high heritability of BD indicates strong contributions from genetic factors. In this review, we summarize the recent achievements in the genetics of BD, particularly those from genome-wide association study (GWAS) of common variants and next-generation sequencing analysis of rare variants. These include the identification of dozens of robust disease-associated loci, deepening of our understanding of the biology of BD, objective description of correlations with other psychiatric disorders and behavioral traits, formulation of methods for predicting disease risk and drug response, and the discovery of a single gene associated with bipolar disorder and schizophrenia spectrum with a large effect size. On the other hand, the findings to date have not yet made a clear contribution to the improvement of clinical psychiatry of BD. We overview the remaining challenges as well as possible paths to resolve them, referring to studies of other major neuropsychiatric disorders., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Frequency-modulated continuous wave radar techniques typically have inadequate angular resolutions due to the limited aperture sizes of antenna arrays in spite of employing multiple-input multiple-output (MIMO) techniques. Therefore, despite the existence of multiple objects, angularly close objects with similar distances and relative velocities are recognized as one single object. Autonomous driving requires the accurate recognition of road conditions. This requirement is one of the critical issues to be solved to distinguish significantly close objects. This paper proposes a technique referred to as an antenna element space pseudo-peak suppressing (APPS) method to resolve angularly close targets. The proposed APPS method aims to identify closely spaced objects on roads. These angularly close targets cause a single peak in a spatial spectrum obtained by a beamformer-based angle estimation. The APPS considers this single peak as pseudo. The APPS radar cancels this pseudo peak from the spatial spectrum. Then, the obtained residual received signal is analyzed. With these procedures, the APPS identifies the number of targets. The APPS also estimates the target angles. The proposed APPS is experimentally validated using a typical single-chip MIMO-based radar evaluation board with three transmit (TX) and four receive (RX) antennas. The experimental results confirm that the proposed APPS successfully resolves angularly close pseudo targets with an angle difference of approximately [Formula: see text]., (© 2023. The Author(s).)

Federated learning (FL) is a technique that allows multiple clients to collaboratively train a global model without sharing their sensitive and bandwidth-hungry data. This paper presents a joint early client termination and local epoch adjustment for FL. We consider the challenges of heterogeneous Internet of Things (IoT) environments including non-independent and identically distributed (non-IID) data as well as diverse computing and communication capabilities. The goal is to strike the best tradeoff among three conflicting objectives, namely global model accuracy, training latency and communication cost. We first leverage the balanced-MixUp technique to mitigate the influence of non-IID data on the FL convergence rate. A weighted sum optimization problem is then formulated and solved via our proposed FL double deep reinforcement learning (FedDdrl) framework, which outputs a dual action. The former indicates whether a participating FL client is dropped, whereas the latter specifies how long each remaining client needs to complete its local training task. Simulation results show that FedDdrl outperforms the existing FL scheme in terms of overall tradeoff. Specifically, FedDdrl achieves higher model accuracy by about 4% while incurring 30% less latency and communication costs.

Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-β). However, GO-Y022 showed less impact on Foxp3 + Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-β. Therefore, naïve CD4 + T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. GO-Y022-induced tumor cell death was further enhanced by 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Combination treatment of GO-Y022 and 2DG results in reduced L-lactate production and Treg generation in gastric tumor cells. Overall, GO-Y022-treatment with restricted glucose metabolism inhibits gastric tumor cell survival and promotes anti-tumor immunity., 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 © 2023 MaruYama, Miyazaki, Lim, Gu, Ishikawa, Yoshida, Chen, Owada and Shibata.)

A 56-year-old man with diarrhea and bloody stools was found to have a type 2 tumor in the rectosigmoid region. A biopsy revealed well-differentiated tubular adenocarcinoma(tub1), and laparoscopic high anterior resection was performed. The final diagnosis was MiNEN(NEC:adenocarcinoma=6:4), RS, type 2, Ly0, V0, pT3(SS), pN0, M0, and pStage Ⅱa. He has been followed up without postoperative adjuvant chemotherapy and has been alive without recurrence for 1 year and 4 months after surgery. MiNEN is a rare disease, and most of them are mixed with NEC components or high- grade NET G3 and have a poor prognosis. We present an important case of rectal MiNEN.

A woman in her 70s was diagnosed with cancer of pancreatic head. She underwent subtotal stomach-preserving pancreatoduodenectomy. Moderately differentiated adenocarcinoma, positive peripancreatic exfoliation surface, and R1 resection was diagnosed by histopathological examination. She underwent adjuvant chemotherapy(S-1), but 5 years and 6 months after the operation, a single nodule(16×9 mm)appeared on anterior segment of left lung. She underwent thoracoscopic left upper lobectomy on suspicion of primary lung cancer. Adenocarcinoma consistent with pancreatic cancer metastasis was diagnosed by histopathological examination. She didn't choose chemotherapy after second operation. 1 year and 1 month after the left pneumonectomy, a single nodule(11×10 mm)reappeared in lateral basal segment of right lung. Although it was difficult to diagnose whether it was primary or metastatic, she decided to undergo thoracoscopic partial lung resection. Histopathological examination revealed that the histology was similar to that of the previous lung lesion and was consistent with pancreatic cancer metastasis. After that, she also didn't choose chemotherapy. She has been alive for 7 years and 7 months after her first pancreatic cancer surgery without any new obvious recurrence.

Background: The treatment of duplicated thoracic ducts (TDs) injury after esophagectomy generally requires a bilateral transthoracic approach. We present the cases of two patients with postoperative chylothorax who underwent transhiatal bilateral TD ligation for duplicated TDs., Case Presentation: Two patients diagnosed with chylothorax after esophagectomy performed for thoracic esophageal cancer underwent transhiatal TD ligation. Although supradiaphragmatic mass ligation was performed on the fat tissue of the right side of the aorta containing the TD, chyle leakage persisted. To tackle this, the fat tissue of the left side of the aorta was ligated, after which the chyle leakage stopped., Conclusion: Compared to the conventional transthoracic approach, the transhiatal approach enables the ligation of both left- and right-sided TD in a single surgical operation, without the need to change the patient's posture. This approach may be appropriate for the treatment of chylothorax after esophagectomy, considering the possibility of duplicated TDs., (© 2022. The Author(s).)

A 67-year-old woman presented with abdominal distention. Computed tomography and magnetic resonance imaging revealed a huge tumor measuring >30 cm with solid and cystic regions. The serum level of CA125 was elevated. An exploratory laparotomy was performed by a gastroenterologist and a gynecologist for the purpose of diagnosis and tumor removal. During laparotomy, the ovary and uterus were found to be intact. The tumor was found to originate from the greater curvature of the stomach and invade the mesentery of the transverse colon. Histopathologically, tumor cells were positive on c-kit immunohistochemical staining. A high-risk gastrointestinal stromal tumor of the stomach was diagnosed according to the modified-Fletcher classification. Because cystic GIST is relatively rare and CA125 was elevated similar to that in Pseudo-Meigs syndrome, preoperative diagnosis was difficult in this case.

Objective: Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2)., Design: A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures., Results: JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (C max ) and the area under the plasma concentration-time curve from time 0 to τ (AUC 0-τ ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues., Conclusions: Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD., Ethics: This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice., Competing Interests: Declaration of Competing Interest This clinical study was fully sponsored by JCR Pharmaceuticals, Co., Ltd. Yasuko Owada was an investigator for the studies sponsored by JCR Pharmaceuticals, Co., Ltd. (formerly Japan Chemical Research, Co., Ltd. ) in 2012, 2018, and 2019. Mika Okazaki, Toshiaki Ikeda, Ryuji Yamamoto, Kohtaro Minami, Kenichi Takahashi, Tohru Hirato, Yoko Mita, Tatsuyoshi Yamamo, Kazunori Tanizawa, Hiroyuki Sonoda and Yuji Sato are employed by JCR Pharmaceuticals, Co., Ltd., of which Hiroyuki Sonoda is a board member., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: General surgeons are at high risk for work-related musculoskeletal disorders (WRMSDs), especially in their neck and back. The prevalence and risk factors for surgeons' WRMSDs in Japan have not been well surveyed., Methods: A cross-sectional questionnaire survey on WRMSDs was conducted among general surgeons in Japan. Surgeons were asked about the presence and degree of neck, shoulder, and back disability in relation to open and laparoscopic surgery., Results: The questionnaire was sent to 174 general surgeons in 21 hospitals and 106 (60.9%) responded. The prevalence of WRMSDs in the last month was 65.1%, and the prevalence at least once in a lifetime was 79.2%. The rate of WRMSDs of the neck and back was higher after open surgery (44.3%, 42.5%) than after laparoscopic surgery (28.2%, 31.1%), but there was no marked difference in shoulder pain. Age was the strongest risk factor for WRMSDs, and the pain scores, prevalence of chronic pain, and rate of WRMSD-related absence from work tended to increase with age., Conclusion: A questionnaire survey of surgeons in Japan showed that about 80% of surgeons suffer from WRMSDs. Countermeasures for WRMSDs among surgeons are urgently desired to ensure that limited numbers of surgeons work in the operating theatre throughout their career., Clinical Trial Registration: Registry name: a survey of surgeons' musculoskeletal pain associated with performing surgery. University of Tsukuba Institutional Review Board registration number: 1519., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Mediastinoscope and laparoscope-assisted esophagectomy for esophageal cancer occasionally causes postoperative accumulation of pleural effusion despite the preservation of the mediastinal pleura. Transhiatal chest drainage has been reported to be useful for thoracic esophagectomy; however, its use in mediastinoscope and laparoscope-assisted esophagectomy remains unelucidated. This study aimed to evaluate the effectiveness and safety of transhiatal chest drainage in mediastinoscope and laparoscope-assisted esophagectomy., Methods: This retrospective study included patients who underwent mediastinoscope and laparoscope-assisted esophagectomy for esophageal cancer from 2018 to 2021. Transhiatal chest drainage involved the insertion of a 19-Fr Blake® drain from the abdomen to the left thoracic cavity through the hiatus. We assessed its effectiveness and safety by the daily drainage output, accumulation of postoperative pleural effusion, frequency of postoperative thoracentesis, and other complications. The drainage group comprising 24 patients was compared with the non-drainage group comprising 13 patients, in whom a transhiatal chest drainage tube was not placed during mediastinoscope and laparoscope-assisted esophagectomy., Results: The median daily output of the transhiatal chest drainage was 230 mL on day 1, 385 mL on day 2, and 313 mL on day 3. The number of patients with postoperative pleural effusion was significantly reduced from 10/13 (76.9%) in the non-drainage group to 4/24 (16.7%) in the drainage group (p = 0.001). The frequency of thoracentesis in the drainage group was significantly lower than that in the non-drainage group (p = 0.002). There were no significant differences in the occurrence of other postoperative complications., Conclusions: Transhiatal chest drainage could evacuate pleural effusion effectively and safely after mediastinoscope and laparoscope-assisted esophagectomy., (© 2022. The Author(s).)

Background: Pancreatic fistula remains the biggest problem in pancreatic surgery. We have previously reported a new pancreatojejunostomy method using an inter-anastomosis drainage (IAD) suction tube with Blumgart anastomosis for drainage of the pancreatic juice leaking from the branched pancreatic ducts. This study aimed to evaluate the postoperative outcomes of our novel method, in pancreatojejunostomy and investigate the nature of the inter-anastomosis space between jejunal wall and pancreas parenchyma., Methods: This retrospectively study consist of 282 pancreatoduodenectomy cases, including 86 reconstructions via the Blumgart method plus IAD (B + IAD group) and 196 cases reconstructed using the Blumgart method alone (B group). Postoperative outcomes and the amylase value and the volume of the drainage fluids were compared between the two groups. The IAD tube was placed to collect amylase-rich fluid from the inter-anastomosis space during operative procedure between the jejunal wall and pancreatic stump., Results: The daily IAD drainage volume and the amylase level was significantly higher in patients with a soft pancreas (vs hard pancreas; 16.5 vs. 10.0 mL/day, p = 0.012; 90,900 vs. 1634 IU/L, p < 0.001, respectively). The mean amylase value of IAD collection in 86 cases of B + IAD group was 63,100 IU/L. The incidence of clinically relevant pancreatic fistula grade B and C (23.2% vs. 23.0%, p = 0.55) and the hospital stay was similar between the groups (median 17 vs. 18 days, p = 0.55). In 176 patients with soft pancreas, the incidence of pancreatic fistula grade B and C (33.3% vs. 35.3%, p = 0.67) and the hospital stay was also similar between the groups (median 22.5 vs. 21 days, p = 0.81)., Conclusions: Positive effect of the IAD method observed in the pilot cases was not reproduced in the current study. IAD tube objectively demonstrated the existence of amylase-rich discharge at the anastomosis site, and countermeasures to eliminate this liquid are highly desired for preventing pancreatic fistula, especially in patients with soft pancreatic texture. Trial registration Retrospectively registered., (© 2022. The Author(s).)

Fatty acid-binding proteins (FABPs) are intracellular chaperone proteins involved in the trafficking of n-3 polyunsaturated fatty acids and endocannabinoids. Inhibiting two of the main FABP subtypes found in the brain (FABP5 and FABP7) hinders endocannabinoid uptake and hydrolysis. Prior data indicates that cannabinoid receptor stimulation can ameliorate the consequences associated with chronic stress. To this end, FABP expression may play a similar role in response to stressful conditions. Male C57BL/6 J (WT) and FABP7 knockout (KO) mice were assigned to either a non-stress cohort or an unpredictable chronic mild stress (UCMS) cohort for a period of 4 weeks. Immediately after 4 weeks, mice were injected with [ 18 F]2-fluoro-2-deoxy-d-glucose (FDG) and scanned using micro positron emission tomography (mPET) to examine brain glucose metabolism (BGluM). WT mice exposed to UCMS showed reduced BGluM in striatal, cortical, and hypothalamic regions and showed increased BGluM in the hippocampus, thalamus, periaqueductal gray, superior colliculi, inferior colliculi, and cerebellum. In contrast, there were limited effects of UCMS on BGluM in FABP7 KO mice, with a reduction in the thalamus, periaqueductal gray, and superior colliculi. These findings provide novel insight into FABP7 expression and indicate this gene to play an important role in response to aversive stimuli., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Total or proximal gastrectomy of the upper-third early gastric cancer (u-EGC) often causes severe post-gastrectomy syndrome, suggesting that these procedures are extremely invasive for patients without pathologically positive lymph node (LN) metastasis. This study aimed to evaluate the clinical applicability of a stomach function-preserving surgery, local resection (LR), with prophylactic left gastric artery (LGA)-basin dissection (LGA-BD)., Materials and Methods: The data of patients with u-EGC (pathologically diagnosed as T1) were retrospectively analyzed. Total gastrectomy was performed in 30 patients, proximal gastrectomy in 45, and subtotal gastrectomy in 6; the LN status was evaluated assuming that the patients had already underwent LR + LGA-BD. This procedure was considered feasible in patients without LN metastases or in patients with cancer in the LGA basin. The reproducibility of the results was also evaluated using an external validation dataset., Results: Of the 82 eligible patients, 79 (96.3%) were cured after undergoing LR + LGA-BD, 74 (90.2%) were pathologically negative for LN metastases, and 5 (6.1%) had LN metastases, but these findings were only observed in the LGA basin. Similarly, of the 406 eligible tumors in the validation dataset, 396 (97.5%) were potentially curative. Tumors in the lesser curvature, post-endoscopic resection status, and small tumors (<20 mm) were considered to be stronger indicators of LR + LGA-BD as all subpopulation cases met our feasibility criteria., Conclusions: More than 95% of the patients with u-EGC might be eligible for LR + LGA-BD. This function-preserving procedure may contribute to the development of u-EGC without pathological LN metastases, especially for tumors located at the lesser curvature., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2022. Korean Gastric Cancer Association.)

Introduction: Rectal prolapse typically presents in elderly women with protruding full-thickness rectum from the anus. Rectopexy using mesh is known to be a highly curative treatment for rectal prolapse, however, this procedure carries the risk of severe complication as mesh erosion., Presentation of Case: A 78-year-old woman who had undergone laparoscopic posterior rectopexy 4 years earlier visited the outpatient clinic with a complaint of bloody stool. A colonoscopy and computed tomography revealed that part of the mesh had migrated into the rectal lumen at 8 cm from the anal verge. Based on the above findings, a diagnosis of mesh erosion into the rectum was made. Complete removal of the mesh and tacker with rectal resection was performed. Before rectopexy, the patient had severe fecal incontinence, and her anal sphincter function was decreased, therefore, Permanent colostomy was indicated instead of anastomosis. In the resected specimen, the mesh was folded and placed in the mesenteric fat of the posterior wall of the rectum, with the corner of the edge of the mesh protruding into the inside lumen., Discussion: Mesh erosion typically occurs when using mesh made of synthetic mesh and non-absorbable threads; it might induce chronic irritation and friction due to mesh shrinkage., Conclusion: To prevent mesh erosion, it is important to pay attention to the mesh materials used and ensure secure fixation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene ( Fabp7 ) influence changes in stress-dependent sleep disturbances and associated anxiety behavior., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Fatty acid-binding proteins (FABPs) are intracellular carriers of bioactive lipids and play a role in the trafficking of endocannabinoids as well as polyunsaturated fatty acids. Mice lacking the FABP5 gene have memory impairments. Environmental enrichment is a potent manipulation known to rescue or improve memory performance. The extent to which the memory impairments in FABP5 knockout (KO) mice can be rescued or improved through environmental conditions remains to be understood. To address this, we raised wild type (WT) and FABP5 KO mice in either socially isolated or environmental enrichment conditions during adolescence. Once in adulthood, mice were tested for Novel Object Recognition (NOR), T-maze, and Morris Water Maze (MWM) to evaluate memory performance. Mice were then euthanized to assess hippocampal brain-derived neurotrophic factor (BDNF) concentrations. MWM results showed that male FABP5 KO mice performed worse compared to WT counterparts. Male and female mice raised in an enriched environment improved performance regardless of genotype. Results on the NOR test showed that male FABP5 KO mice displayed lower object recognition compared to WT counterparts across both environments. No differences of genotype or environment were seen in female mice. T-maze findings revealed impaired performance in socially isolated FABP5 KO mice. Adolescent environmental enrichment rescued this deficit in male, but not female, FABP5 KO mice. Lastly, environmental enrichment increased hippocampal BDNF levels in male WT mice only. Our results corroborate the previously observed role of the FABP5 gene on memory performance and identify an important interaction with the environment during adolescence., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Meckel's cartilage (MC) in the first branchial arch of mammals is a transient structure that disappears before birth, except for the most anterior and posterior portions. Recent studies reported that some congenital abnormalities in craniofacial regions are linked with the persistence or dysplasia of MC. However, the mechanisms underlying the resorption of MC have not been elucidated. Cartilage resorption in endochondral ossification is performed by multinuclear osteoclasts/chondroclasts as well as mononuclear septoclasts, which were newly added to the list of cartilage phagocytes. Septoclasts located exclusively at the chondro-osseous junction of the growth plate resorb the uncalcified cartilage matrix. We hypothesized that septoclasts participate in the resorption of MC and attempted to clarify the localization and roles of septoclasts in MC of mouse using a specific immunohistochemistry marker, epidermal type-fatty acid-binding protein (E-FABP/FABP5). E-FABP-immunopositive septoclasts were detected for the first time at the beginning of MC resorption and localized along the resorption surface. Septoclasts of MC in embryonic mice possessed several processes that elongated toward the uncalcified cartilage matrix, expressed cathepsin B, and exhibited characteristic pericapillary localization. Additionally, they localized between hypertrophied cartilage and osteoclasts/chondroclasts in the resorption surface. Confocal laser-scanning microscopy revealed a decrease in the numbers of septoclasts and their processes with the progression of MC disappearance before birth. The present study showed that E-FABP-immunopositive septoclasts participated in the disappearance of MC through the resorption of the uncalcified cartilage matrix and that they have different roles from osteoclasts/chondroclasts., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This paper reports the 5-year operational status of the third phase of the"All Japan E-Learning Cloud of the Training Program for Oncology Professionals"by tabulating the viewing trends of available lecture contents. In this phase, the goal was to train cancer genome medical professionals in this new, advanced medical technology field as well as train personnel to treat rarely encountered pediatric, adolescent/young adult, and other life stage cancers. Additionally, new lecture items have been added to the e-learning cloud in collaboration with 7 oncology specialist centers, contributing to the development of human capital in cancer care(including graduate student education)and faculty development for local medical professionals.

Background: Various minimally invasive surgery (MIS) procedures are used for gastric submucosal tumors (SMTs), and their technical difficulties vary. Preoperative understanding of difficulties is crucial; however, objective indicators are lacking., Methods: Gastric SMTs requiring MIS (n = 36) were retrospectively analyzed. Preoperative factors were evaluated using a multivariate linear regression analysis. A scoring system was then constructed, and its feasibility was evaluated., Results: Three factors were identified and scored based on the weighted contribution for predicting surgical time: tumor location (cardia, score of "2"; posterior wall of fundus, "1"); tumor size (greater than 4 cm, "1"); and tumor growth appearance (intraluminal, "1"). The summed scores could stratify the surgical time stepwise in each score, and patients who scored higher than 3 had larger intraoperative blood loss and a longer hospital stay., Conclusion: Our scoring system predicted surgical difficulties and may, therefore, be useful in selecting appropriate surgical approaches for gastric SMTs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear., Aims: To investigate the role of IκB-ζ in gut homeostasis., Methods: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS., Results: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4 + T cells in LP), and antibiotic treatment canceled this inflammatory phenotype., Conclusion: IκB-ζ plays a crucial role in maintaining homeostasis in the gut., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas are reported to underlie lymphomagenesis. However, our understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here we constructed a single-cell transcriptome atlas of more than 100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, and it revealed 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was useful for comparative analyses with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs. This facilitates our understanding of stromal remodelling in lymphoma and highlights potential clinical biomarkers. Our study largely updates NHC taxonomy in human LNs and analysis of disease status, and provides a rich resource and deeper insights into LN and lymphoma biology to advance lymphoma management and therapy., (© 2022. The Author(s).)

Background: The number of brain-dead donors has been increasing; however, the opportunity for young surgeons to experience deceased donor surgeries is extremely limited, especially in many Asian countries including Japan. Deceased donor surgeries require unique surgical skills and knowledge; however, it is difficult to provide on-the-job guidance and education. Therefore, cadaver training is meaningful and suitable for the training of deceased donor surgeries. Thiel's embalming method (TEM) provides natural coloration, flexibility, and tissue plasticity, and is widely used for cadaver surgical training. In this study, we evaluated the usefulness of Thiel's embalmed cadaver training for organ procurement surgery., Material and Methods: Each trainee performed hepatectomy, pancreatectomy, and nephrectomy using conventional open techniques. Faculty experts of transplantation surgery and organ procurement took attendees through surgical steps. After the procedure, all participants were asked to complete a voluntary, anonymous survey, consisting of a 10-point satisfaction scale, to evaluate their perceptions of the training., Results: A total of 33 gastrointestinal surgeons participated in the training program for procuring the liver, pancreas, and kidneys. In the questionnaire administered to the participants, the evaluation was generally satisfactory, with an average of 9.1 points on the 10-point scales. Some participants expressed that Thiel-embalmed cadavers are more suitable for training on organ procurement compared with animals used in wet-lab training., Conclusion: We conclude that organ procurement training in human cadavers preserved by TEM is useful and suitable for practicing deceased donor organ procurement, especially in countries where deceased donors are not common, as in Japan., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Long-chain fatty acids (LCFAs) and retinoic acid (RA) are abundant in the growth plates (GPs) of long bones; however, their roles have not been elucidated. We observed that epidermal fatty acid-binding protein (E-FABP/FABP5) with a high affinity for both LCFAs and RA is exclusively expressed in the septoclasts located at the chondro-osseous junction (COJ) of the GP., Highlights: E-FABP expressed in septoclasts is involved in both LCFA metabolism and RA signaling as an intracellular transporter of both LCFAs and RA. Septoclasts with shortened cytoplasmic processes are associated with cartilage resorptive activity downregulation because of E-FABP deficiency or excess or deficiency of RA. In ontogeny, the septoclasts are differentiated from the pericytes and involved in the resorption of the uncalcified matrix of the cartilage templates in endochondral ossification., Conclusion: Septoclasts originate from pericytes and express E-FABP to play crucial roles in uncalcified matrix resorption by LCFA metabolism and RA signaling during endochondral ossification., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

The effect of the difference in the thickness ratio of the double-layered thickness-shear resonator on the temperature characteristics of the resonance frequency was investigated using a Ca 3 TaGa 3 Si 2 O 14 (CTGS) single crystal. Three specimens with thickness ratios of x = 0.25 , 0.33, and 0.50 were prepared using 122 ° Y - and 171 ° Y -cut CTGS substrates. For the specimens with x = 0.25 and 0.33, the temperature characteristics varied depending on the order of the resonance mode. For the specimen with x = 0.50 , on the other hand, almost the same temperature characteristics were observed regardless of the order of the resonance mode. To interpret this phenomenon, a new equation for predicting the temperature characteristics of the fundamental mode (first mode) for the double-layered resonator was created using the electric flux density ratio generated in the two substrates. The expected values using this equation were in good agreement with the result of the first mode temperature characteristics.

Plasmacytoid dendritic cells (pDCs) promote viral elimination by producing large amounts of Type I interferon. Recent studies have shown that pDCs regulate the pathogenesis of diverse inflammatory diseases, such as cancer. Fatty acid-binding protein 5 (FABP5) is a cellular chaperone of long-chain fatty acids that induce biological responses. Although the effects of FABP-mediated lipid metabolism are well studied in various immune cells, its role in pDCs remains unclear. This study, which compares wild-type and Fabp5 -/- mice, provides the first evidence that FABP5-mediated lipid metabolism regulates the commitment of pDCs to inflammatory vs tolerogenic gene expression patterns in the tumor microenvironment and in response to toll-like receptor stimulation. Additionally, we demonstrated that FABP5 deficiency in pDCs affects the surrounding cellular environment, and that FABP5 expression in pDCs supports the appropriate generation of regulatory T cells (Tregs). Collectively, our findings reveal that pDC FABP5 acts as an important regulator of tumor immunity by controlling lipid metabolism., (© 2021 UICC.)

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild-type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular-targeted therapies is of paramount importance. Fatty acid-binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild-type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin-1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin-1 promoter through controlling the nuclear acetyl-CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin-1 expression, increased levels of histone acetylation, and increased levels of acetyl-CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin-1, and this mechanism is critically important for IDH1wt tumor biology., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: The treatment for the locally advanced esophageal cancer invading adjacent organs is controversial. We performed a radical surgery for a patient suffering from lower esophageal cancer with pancreatic invasion, and led to long-term survival., Case Presentation: A 62-year-old man with dysphagia, was endoscopically diagnosed lower esophageal cancer. Abdominal computed tomography shows that the tumor formed a mass with the solitary metastatic abdominal lymph node, which invaded pancreas body and gastric body. He was diagnosed locally advanced esophageal cancer cStage IIIC. As chemoradiotherapy was difficult because of the high risk of gastric mucosal damage, radical esophagectomy with distal pancreatectomy and reconstruction of gastric conduit were performed. The postoperative course was uneventful and the patient was discharged 16 days after operation. At present, 7 years after surgery, he is still alive with disease-free condition., Conclusion: Esophagectomy with distal pancreatectomy may be feasible for locally advanced esophageal cancer with pancreatic invasion in terms of curability and long-term survival., (© 2021. The Author(s).)

Case 1 was a 78-year-old woman with a tumor in the stomach on preoperative CT of an inguinal hernia. The patient was diagnosed with advanced gastric cancer at posterior wall of fornix and underwent total gastrectomy and splenectomy. Postoperative pathological diagnosis was gastric mixed adenoneuroendocrine carcinoma(MANEC), T1b2, N1, M0, StageⅠB. She has been alive without recurrence for 3 years without postoperative adjuvant chemotherapy. Case 2 was a 78-year-old man who was admitted to the hospital with acute pancreatitis and had a thickened wall of the lesser curvature of the gastric antrum on CT. He was diagnosed with advanced gastric cancer and underwent distal gastrectomy and D2 dissection. Postoperative pathological diagnosis was gastric MANEC, T1b2, N1, M0, Stage ⅠB. Oral administration of S-1 was started as postoperative adjuvant chemotherapy, but he was very tired and ended in 1 course at his request. Computed tomography 6 months after the operation revealed multiple liver metastases, and he was transferred to best supportive care at his request. He died 1 year after surgery. We experienced 2 valuable cases of gastric MANEC.