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Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (-)] GC. The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS-STING was highly expressed in dMMR GC compared to pMMR/EBV (-) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8 + tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (-). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment., (© 2024. The Author(s).)

Background: The preservation period afforded by cold storage of cells is short. However, the use of rare gases for cold storage as a means of extending the period of preservation would be highly beneficial., Objective: To examine the effect of temperature on the protective effect of cold storage of cells using pressurized dissolution of xenon gas, with particular focus on the inhibition of substance transport by viscosity., Methods: Human dermal fibroblast monolayers incubated in a culture dish for 48 h were used as a test sample, with culture medium used as a preservation solution. Samples were placed into a pressure-resistant vessel, which was pressurized with xenon gas at 0 or 0.5 MPa, and cells were stored at 0 to 5 °C for 18 h. Cell activity was evaluated by tetrazolium salt assay. The viscosity of the medium under pressurization at each storage temperature was estimated., Results: The maximum protective effect against cell damage of cold storage with pressurized dissolution of xenon gas was observed at 4 °C. An increase in estimated viscosity by pressurization was correlated with increased cell activity at 4 °C., Conclusion: Analysis of the temperature dependence of the protective effect against cell damage of cold storage with pressurized dissolution of xenon gas revealed that the most effective temperature is 4 °C. The data also suggest that increased viscosity due to pressurization plays a role in the protective effect.

Nonhuman primates (NHPs) exhibit complex and diverse behavior that typifies advanced cognitive function and social communication, but quantitative and systematical measure of this natural nonverbal processing has been a technical challenge. Specifically, a method is required to automatically segment time series of behavior into elemental motion motifs, much like finding meaningful words in character strings. Here, we propose a solution called SyntacticMotionParser (SMP), a general-purpose unsupervised behavior parsing algorithm using a nonparametric Bayesian model. Using three-dimensional posture-tracking data from NHPs, SMP automatically outputs an optimized sequence of latent motion motifs classified into the most likely number of states. When applied to behavioral datasets from common marmosets and rhesus monkeys, SMP outperformed conventional posture-clustering models and detected a set of behavioral ethograms from publicly available data. SMP also quantified and visualized the behavioral effects of chemogenetic neural manipulations. SMP thus has the potential to dramatically improve our understanding of natural NHP behavior in a variety of contexts., (© 2024. The Author(s).)

Purpose: To evaluate short-term outcomes of intravitreal injection of aflibercept 8 mg for neovascular age-related macular degeneration (nAMD)., Study Design: Retrospective, interventional case series., Methods: We retrospectively studied 35 eyes of 34 consecutive patients with nAMD, assessing best-corrected visual acuity (BCVA), foveal thickness (FT), and central choroidal thickness (CCT) before and 4 weeks after the initial intravitreal dose of aflibercept 8 mg. The rate of achieving a dry macula and the incidence of intraocular inflammation (IOI) at week 4 were also determined., Results: BCVA showed significant improvement, with significant reductions in FT and CCT 4 weeks after the initial injection of aflibercept 8 mg (all P < 0.01), with a dry macula being achieved in 20 eyes (57.1%). However, 3 eyes (8.6%) developed non-infectious IOI associated with retinal vasculitis, an adverse event not reported previously. The IOI in these eyes was relatively mild and treated with a posterior subtenon injection of triamcinolone acetonide with or without betamethasone eye drops, resulting in amelioration of IOI without any visual loss., Conclusions: Intravitreal aflibercept 8 mg appears to be effective for improving visual acuity and ameliorating exudative changes in eyes with nAMD. However, special attention should be given to the potential development of IOI associated with retinal vasculitis., (© 2024. The Author(s).)

The fungus Wickerhamiella pararugosa (Candida pararugosa) has been detected in various human organs but has rarely caused bloodstream infections. This report presents a case of central venous catheter-related bloodstream infection (CRBSI) of W. pararugosa in an adult. A female patient in her 80s was admitted to our facility for intestinal obstruction caused by colorectal cancer. The patient's ability to consume food was hindered, necessitating the insertion of a central venous catheter (CVC) into the internal jugular vein. On day 3 after admission, the patient developed a fever, prompting blood and CVC tip cultures to be performed. On day 5, yeast-like fungi were discovered in the blood cultures, and fosfluconazole (fluconazole [FLCZ] pro-drug) treatment was initiated. On day 8, yeast-like fungi were identified in both the blood and CVC tip cultures, leading to a diagnosis of CRBSI. The fungus was identified as W. pararugosa through biochemical and genetic characterization. This finding justified the use of micafungin (MCFG) for combination therapy. On day 17, the minimum inhibitory concentrations (MIC) for FLCZ and MCFG were 4-8 and 0.06 μg/mL, respectively. Accordingly, the treatment was changed to monotherapy with MCFG. After a 21-day treatment regimen, the patient was discharged on day 31. We present a case of CRBSI caused by W. pararugosa in an adult with intestinal obstruction. The notable increase in the MIC of FLCZ necessitated monotherapy with MCFG, which resulted in successful recovery of the patient., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates., (© 2024. The Author(s).)

While N -heterocyclic carbenes (NHCs) have recently been shown to be effective ligands for gold nanoclusters, very few examples of heterometallic clusters incorporating nongroup 11 metals are known. We present herein an Au-Pt NHC cluster featuring a crown-shaped [Au 8 Pt(NHC) 8 ] 2+ core, produced in high yield without the need for chromatographic purification. The method was largely independent of the substitution pattern of the NHC backbone; however, bulky wingtip groups were needed for clean conversion to the Au 8 Pt cluster. Clusters were characterized using single crystal X-ray diffraction, multinuclear nuclear magnetic resonance, electrospray ionization mass spectroscopy, and ultraviolet-visible spectroscopy, and electrochemical features of the cluster are also presented. A detailed analysis of the in-progress reaction mixture by ESI-MS supports the direct involvement of Au-H species as intermediates in cluster formation. These studies further demonstrate that NHC wingtip sterics play a key part in determining the nature of the initial cluster species, providing critical information for the generation of new NHC-stabilized nanoclusters.

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT 4 receptor (5-HT 4 R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT 4 R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT 4 R in the dCDh. We then examined the effects of a specific 5-HT 4 R antagonist infused into the dCDh. Blockade of 5-HT 4 R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT 4 R blockade because saline controls showed no such effect. The results demonstrate that 5-HT 4 Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT 4 R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms., (© 2024. The Author(s).)

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18 F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18 F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development., Competing Interests: Declaration of interests M.O., M.-R.Z., and M. Higuchi filed a patent on compounds related to the present report (2019-034997, PCT/JP2020/002607)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages-crucial effector cells of ADCC-in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein-Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC., (© 2024. The Author(s).)

Background: We previously showed that total tumor resection enhances metastatic growth in a syngeneic metastatic mouse model of neuroblastoma. In this study, we further investigated which surgical factors contributed most to metastatic growth., Methods: Tumor cells derived from MYCN transgenic mice were subcutaneously injected into wild-type mice. Mice were randomly assigned to receive partial resection (PR group), subcutaneous implantation of a sponge (Sp group), or observation (Obs group). The lymph node metastasis volume and the frequency of lung metastasis were compared 14 days after assignment by measuring C-reactive protein (CRP) and interleukin-6 (IL-6) levels., Results: The lymph node metastasis volume in the Sp group was larger than in the Obs group (148.4 [standard deviation {SD}: 209.5] vs. 10.2 [SD 12.8] mm 3 ). The frequency of lung metastasis was greater in the Sp group than in the PR group (11.9 [SD 12.2] vs. 6.6 [SD 4.0] counts/slide). The CRP level in the Sp group was higher than in the PR group (2.3 [SD 0.5] vs. 1.5 [SD 0.4] μg/mL), and the IL-6 level in the Sp group was higher than in the PR or Obs groups (28.4 [SD 34.5] vs. 12.4 [SD 19.0] vs. 5.4 [SD 8.1] pg/mL)., Conclusion: Metastatic growth may be enhanced by systemic inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates., (© 2024. The Author(s).)

Severe cases of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome requiring plasma exchange or dialysis should be differentiated from other thrombotic microangiopathy (TMA) and treated appropriately. To evaluate the prevalence and clinical characteristics of such cases in Japan, a questionnaire-based survey was conducted among obstetricians who are members of the Perinatal Research Network Group in Japan. There were a total of 335 cases of HELLP syndrome over a 3-year period in the 48 facilities that responded to the survey. Four patients required plasma exchange or dialysis, of which two were diagnosed with atypical hemolytic uremic syndrome and two with TMA secondary to systemic lupus erythematosus. Although such severe HELLP syndrome is rare, identifying the clinical features and making accurate differential diagnosis are critical for optimal clinical outcomes for mothers and neonates., (© 2024 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

The biomarker-oriented chemo-immunotherapy is useful and promising in the development of new anticancer agents, since the responders can be enriched by selecting patients with biomarkers. Compared to colorectal and lung cancers, the development of biomarker-driven molecular-targeted therapeutics for gastric cancers has been straggled. However, several new biomarkers in gastric cancers have been discovered and clinical trials in enrichment design with certain biomarkers have been conducted. Therefore, there are currently several treatment options to treat gastric cancer patients based on individual biomarker-oriented strategies. In the present review, we describe the useful biomarkers in gastric cancer, with focusing on HER2, PD-L1, and Claudin18.2, in relation to their clinical significance and associated targeted agents., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background/aim: Regulatory T cells (Tregs) suppress various anti-tumor immune responses in the tumor microenvironment (TME) and their control is considered essential to enhancing efficacy of cancer immunotherapy. The purpose of the study was to evaluate the strategy to regulate Tregs through the vascular endothelial growth factor (VEGF) pathway., Materials and Methods: We evaluated VEGF receptor (VEGFR) expression in subtypes of Tregs by analysis of public databases and through flow cytometry by investigating surgically resected specimens and peripheral blood mononuclear cells (PBMCs) from 26 patients with advanced colorectal cancer (CRC)., Results: Analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n=592) showed that mRNA expression of both FLT1 (VEGFR1) and KDR (VEGFR2) was positively correlated with mRNA expression of FOXP3 as well as Treg signature. Clinical specimens revealed abundant VEGFR2 expression on Tregs, but very marginal VEGFR1 expression. The frequency of effector Tregs, the most immunosuppressive fraction of Tregs, was significantly higher in the tumor than in the PBMC and normal mucosa, and the majority of effector Tregs expressed VEGFR2. Furthermore, by using in vitro generated Tregs, the proportion of Tregs expressing IL-10 or TGF-β1 was significantly inhibited by a VEGFR2 inhibitor., Conclusion: A therapeutic strategy targeting the VEGFR2 axis may have a potential to control effector Tregs in the CRC-TME., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity, and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 h, n = 4) and LPS (12-24 h, n = 20), respectively. The local VZ values (15 and 10 h after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models, respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 h post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical epithelium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

TIM-3 was originally identified as a negative regulator of helper T cells and is expressed on dendritic cells (DCs). Since the inhibition of TIM-3 on DCs has been suggested to enhance T cell-mediated anti-tumor immunity, we examined its expression on DCs within the tumor microenvironment (TME) in colorectal cancer (CRC) using transcriptomic data from a public database ( n = 592) and immunohistochemical evaluations from our cohorts of CRC ( n = 115). The expression of TIM-3 on DCs in vitro was examined by flow cytometry, while the expression of its related molecules, cGAS and STING, on immature and mature DCs was assessed by Western blotting. The expression of HAVCR2 (TIM-3) was strongly associated with the infiltration of DCs within the TME of CRC. Immunohistochemical staining of clinical tissue samples revealed that tumor-infiltrating DCs expressed TIM-3; however, their number at the tumor-invasive front significantly decreased with stage progression. TIM-3 expression was higher on immature DCs than on mature DCs from several different donors ( n = 6). Western blot analyses showed that the expression of STING was higher on mature DCs than on immature DCs, which was opposite to that of TIM-3. We demonstrated that TIM-3 was highly expressed on tumor-infiltrating DCs of CRC and that its expression was higher on immature DCs than on mature DCs.

Objective: Although fetal growth restriction (FGR) is associated with an increased risk of cesarean delivery during induced labor, there is limited evidence to guide labor management. This study aimed to investigate the prognosis of induced labor in pregnancies with suspected FGR and whether oxytocin discontinuation during the active phase of labor affects maternal and neonatal outcomes., Study Design: This retrospective cohort study investigated singleton pregnancies with vertex presentation and indications for labor induction owing to FGR after 34.0 weeks of gestation at Osaka University Hospital. From January 2010 to December 2013, women were conventionally managed, and oxytocin was continued until delivery unless there was an indication for discontinuation (conventional management group). From January 2013 to December 2020, oxytocin was routinely discontinued, or the dose was reduced at the beginning of the active phase of labor (oxytocin discontinuation group)., Results: A total of 161 women (conventional management group, n  = 74; oxytocin discontinuation group, n  = 87) were included. After the active phase of induced labor, the total incidence of cesarean delivery was very low (3.1%), and the duration was short (173 ± 145 minutes). Oxytocin discontinuation was associated with lower cesarean delivery (1.1 vs. 5.4%; p  = 0.12) and uterine tachysystole (9.8 vs. 23.0%; p  = 0.08) rates and longer duration of the second stage of labor (mean: 56.5 ± 90 vs. 34.2 ± 45 minutes; p  = 0.08) than conventional management; however, the difference was not significant. The other maternal and neonatal outcomes, including postpartum hemorrhage, did not also significantly differ between them., Conclusion: After the active phase of induced labor for suspected FGR, the risk of cesarean delivery is low, and the high incidence of uterine tachysystole and rapid labor progression should be considered cautiously. Oxytocin can be safely discontinued during the active phase of labor in women undergoing labor induction for FGR without an increased risk of cesarean delivery or other unfavorable outcomes., Key Points: · The cesarean delivery rate was low after the active phase.. · The labor progress after the active phase was rapid.. · Oxytocin can be safely discontinued during the active phase.., Competing Interests: None declared., (Thieme. All rights reserved.)

Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Photoemission orbital tomography (POT) from photoelectron momentum maps (PMMs) is a powerful technique that visualizes the shape of the molecular orbitals (MOs) of molecular films. For further utilization of POT, a simple and low-cost method of POT is highly required. Here, we propose a new POT method based on the PhaseLift algorithm (PhaseLift POT). This method utilizes a lifting procedure to convert the PMM, which is a second-order polynomial of MO coefficients, into a first-order polynomial of the lifted MO coefficients and further relaxes the equality constraint for a given PMM. We also established a method to improve the accuracy of phase retrieval from the noisy PMM data by using sparsity for MO coefficients (sparse PhaseLift POT). These methods make it possible to reconstruct the three-dimensional MOs, including phases of the wave function, directly from a single experimental PMM. This method can also precisely determine the adsorption-induced molecular deformations with an accuracy of 0.05 [Å]. Furthermore, the robust sparse PhaseLift POT is robust against unavoidable noise in the experimental PMMs due to the relaxation of the matching condition for a given PMM. Therefore, this will be an innovative tool for POT, especially for analyzing the dynamics of the molecules during the chemical reaction and excitation processes.

Background: Chemotherapy has the potential to induce CD8 + T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated., Methods: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8 + T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC)., Results: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8 + T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC., Conclusion: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown., Methods: Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor β-chain (TCRβ), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB)., Results: Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRβ clonality (inverted Pielou's evenness) increased and TCRβ diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023)., Conclusion: Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer., Competing Interests: Competing interests: PHDN (former), HK (former), MF, and AN are shareholders or employees of ImmunoScape Pte Ltd. or ImmunoScape Inc. AN is on the board of directors of ImmunoScape Pte Ltd. KK reports speaker fee from ONO Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. The remaining authors have declared no conflict of interest exists., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Serotonin (5-HT) deficiency is a core biological pathology underlying depression and other psychiatric disorders whose key symptoms include decreased motivation. However, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system in macaque monkeys and quantified the effects on motivation for goal-directed actions in terms of incentives and costs. Reversible inhibition of 5-HT synthesis increased errors and reaction times on goal-directed tasks, indicating reduced motivation. Analysis found incentive-dependent and cost-dependent components of this reduction. To identify the receptor subtypes that mediate cost and incentive, we systemically administered antagonists specific to 4 major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography (PET) visualized the unique distribution of each subtype in limbic brain regions and determined the systemic dosage for antagonists that would achieve approximately 30% occupancy. Only blockade of 5-HT1A decreased motivation through changes in both expected cost and incentive; sensitivity to future workload and time delay to reward increased (cost) and reward value decreased (incentive). Blocking the 5-HT1B receptor also reduced motivation through decreased incentive, although it did not affect expected cost. These results suggest that 5-HT deficiency disrupts 2 processes, the subjective valuation of costs and rewards, via 5-HT1A and 5-HT1B receptors, thus leading to reduced motivation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: HER2 signaling might be involved in the regulation of immune cell activation in the tumor microenvironment (TME) of gastric cancer (GC). However, the relationship between HER2 status and immune cell condition in the HER2-positive GC TME is not clearly understood., Methods: To investigate the effect of HER2 signaling on the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contributes to immune cell activation in the GC TME, we evaluated the associations among the expressions of HER2, cGAS-STING, and the number of CD8 + tumor-infiltrating lymphocytes (TIL) by considering HER2 heterogeneity in HER2-positive GC tissues. We also examined the effect of HER2 signaling on the activation of STING signaling in vitro using human HER2-positive GC cell lines., Results: The expression of HER2 is highly heterogeneous in HER2-positive GC tissues, and we found that the number of CD8 + TIL in HER2 high areas was significantly lower than that in HER2 low areas in HER2-positive GC tissues. Intriguingly, the tumor cell-intrinsic expression of STING, but not cGAS, was also significantly lower in the HER2 high areas than the HER2 low areas in HER2-positive GC tissues. Moreover, in vitro experiments, we demonstrated that the blockade of HER2 signaling increased the expression of STING and its target genes, including IFNB1, CXCL9/10/11, and CCL5, in HER2-positive GC cell lines., Conclusions: Our results suggest that HER2 signaling might suppress immune cell activation in the GC TME by inhibiting STING signaling in tumor cells in HER2-positive GC., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

TGFβ signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFβ-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined ( n = 2240). TIM-3 and a TGFβ-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry ( n = 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression of HAVCR2 (TIM-3) significantly correlated with the transcriptional signatures of TGFβ, TGFβ-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3 + immune cells accumulated in TGFβ-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFβ treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.

It has been reported that tumor cell-intrinsic cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) pathway is essential for radiotherapy(RT)-induced activation of anti-tumor immune responses. However, its role in the RT- induced remodeling of the tumor microenvironment(TME)in esophageal squamous cell carcinoma(ESCC), is largely unknown. In this study, we found that the tumor cell-intrinsic cGAS-STING pathway is a critical component for RT-induced activation of immune cells in the TME through the induction of type Ⅰ interferon and C-X-C motif chemokine ligand 10 in tumor cells in ESCC. However, at the same time, the tumor cell-intrinsic cGAS-STING pathway is also involved in RT-triggered infiltration and polarization of immunosuppressive CD163+ tumor-associated macrophages (TAM) through the induction of interleukin 34 (IL-34) in tumor cells in ESCC. Our findings suggest that targeting IL-34 to impede the infiltration and polarization of CD163+ TAM could potentially enhance the efficacy of RT-induced immune cell activation in ESCC TME.

Background/aim: Development of multidisciplinary therapies including immune checkpoint inhibitors for esophageal squamous cell carcinoma (ESCC) requires a clear understanding of immunological responses induced by chemotherapy with/without radiotherapy in the tumor microenvironment., Patients and Methods: This is a retrospective analysis of paired pretreatment biopsy samples and surgically resected tumor samples of 49 patients who underwent radical surgery for ESCC with/without neoadjuvant therapy at Fukushima Medical University Hospital. The cohort included 30 patients treated with neoadjuvant chemotherapy (NAC), 11 treated with neoadjuvant chemoradiotherapy (NACRT), and eight who underwent surgery alone and did not receive neoadjuvant antitumor therapy. Chemotherapy included fluoropyrimidine- and platinum-based agents in all treated patients, and radiotherapy included 40 or 42 Gy administered in 20 or 21 fractions. Expression of CD8, human leukocyte antigen (HLA) class I-ABC, PD-L1, PD-L2, CEACAM-1, LSECtin, and p-STAT1, were determined using immunohistochemistry., Results: The frequency of tumor-infiltrating CD8 + T cells was significantly increased by NAC (p<0.05), and the expression of HLA class I-ABC on tumor cells was significantly increased by NAC and NACRT (p<0.05). Furthermore, the ESCC cells expressed PD-L1, PD-L2, and CEACAM-1, whereas the expression of PD-L1 on ESCC cells was significantly correlated with the expression of p-STAT1 in ESCC cells (p<0.05)., Conclusion: NAC and NACRT induced both positive and negative immunological responses in patients with ESCC. These results may be a part of basis for multidisciplinary therapy including immune checkpoint inhibitors for patients with advanced ESCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses pharmacologically selective actuator modules (PSAMs), which are selectively activated by pharmacologically selective effector molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex (M1) of two male macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand [ 18 F]ASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using [ 18 F]fluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging (phMRI) showed that increased brain activity in the PSAM4-expressing region began ∼13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications. SIGNIFICANCE STATEMENT Like other chemogenetic tools, the ion channel-based system called pharmacologically selective actuator module/pharmacologically selective effector molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in nonhuman primates (NHPs) is still limited. Here, we used multitracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (phMRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations., (Copyright © 2023 Hori, Nagai et al.)

Coherent Ising machine (CIM) is a network of optical parametric oscillators that can solve large-scale combinatorial optimisation problems by finding the ground state of an Ising Hamiltonian. As a practical application of CIM, Aonishi et al., proposed a quantum-classical hybrid system to solve optimisation problems of [Formula: see text]-regularisation-based compressed sensing. In the hybrid system, the CIM was an open-loop system without an amplitude control feedback loop. In this case, the hybrid system is enhanced by using a closed-loop CIM to achieve chaotic behaviour around the target amplitude, which would enable escaping from local minima in the energy landscape. Both artificial and magnetic resonance image data were used for the testing of our proposed closed-loop system. Compared with the open-loop system, the results of this study demonstrate an improved degree of accuracy and a wider range of effectiveness., (© 2023. Springer Nature Limited.)

Background: Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. The aim of this study was to assess the effect of the combination of irradiation with anti-PD-1 therapy for advanced GC., Methods: We conducted a single-arm, phase I/II trial in GC patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days) (NCT03453164). Eligible patients (n = 40) had unresectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion. The primary endpoint is the disease control rate (DCR) of non-irradiated target lesions and the secondary endpoints are the median survival time (MST), safety, and DCR of irradiated lesions., Results: We observe that the DCR for the non-irradiated target as the abscopal effect is 22.5% (90% confidence interval (CI), 12.3-36.0), and the DCR for the irradiated lesion is 40.0% (90% CI, 26.9-54.2). The median survival time is 230 days (95% CI, 157-330), and grade 3 and higher adverse events (AEs) are observed in 16 patients (39 %) with no obvious additional AEs when adding irradiation., Conclusions: The present study suggests that the combination of nivolumab with oligo-fractionated irradiation has the potential to induce a promising anti-tumor effect for advanced GC., (© 2023. Springer Nature Limited.)

In order to develop a biomarker predicting the efficacy of treatments for patients with esophageal squamous cell carcinoma (ESCC), we evaluated the subpopulation of T cells in ESCC patients treated with chemotherapy (CT), chemoradiotherapy (CRT), and nivolumab therapy (NT). Fifty-five ESCC patients were enrolled in this study, and peripheral blood samples were collected before and after CT or CRT and during NT. Frequencies of memory, differentiated, and exhausted T cells were evaluated using flow cytometry among cStages, treatment strategies, pathological responses of CT/CRT, and during NT. The frequencies of PD-1 + or TIM-3 + CD4 + T cells were significantly higher in patients with cStage IV. PD-1 + CD4 + and TIM-3 + CD8 + T-cell populations were significantly higher in patients treated with CRT but were not associated with treatment response. The frequencies of both CD4 + and CD8 + CD45RA - CD27 + CD127 + central memory T cells (T CM ) were significantly decreased during the course of NT in the progressive disease group. Taken together, the alteration in frequency of CD45RA - CD27 + CD127 + T CM during NT may be a biomarker to predict its therapeutic response in ESCC patients.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI., Competing Interests: The authors have no competing interests to declare., (Copyright: © Mimura et al.)

This systematic review and meta-analysis aimed to review the optimal timing of delivery at term for neonates with prenatally diagnosed congenital diaphragmatic hernia (CDH). We reviewed the literature up to December 19, 2022 using MEDLINE and the Cochrane Library databases. The inclusion criteria were original articles, comparative studies of CDH neonates delivered at an early term (37-38 weeks of gestation) and at full term (39 weeks of gestation or later), and comparative studies investigating outcomes of CDH neonates. Six studies met the inclusion criteria, including 985 neonates delivered at an early term and 629 delivered at full term. The cumulative rate of survival to discharge showed no significant difference between CDH neonates delivered at an early term (395/515; 76.7%) or at full term (345/467; 73.9%) (risk ratio [RR] 1.01; 95% confidence interval [CI], 0.89-1.16; p = 0.85). Furthermore, the number of neonates requiring oxygen therapy at discharge was not significantly different between CDH neonates delivered at an early term (32/370; 8.6%) and at full term (14/154; 9.1%) (RR, 0.99; 95% CI, 0.36-2.70; p = 0.99). Therefore, the optimal timing of delivery at term for neonates with CDH remains unclear., (© 2023 John Wiley & Sons Ltd.)

Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by anti-HPA alloantibody, and anti-HPA-4b is the most common cause in Japanese. Anti-HPA-5b is frequently detected in pregnant women, but it is still controversial whether anti-HPA-5b causes severe FNAIT., Case Presentation: A Japanese woman with anti-HPA-4b and anti-HPA-5b alloantibodies delivered a baby with severe FNAIT who was both HPA-4b and HPA-5b incompatible. We carefully monitored the patient's following three pregnancies (the second and the fourth siblings were HPA-4b incompatible and HPA-5b compatible; the third sibling was both HPA-4b and HPA-5b compatible). FNAIT was not observed in all three siblings, although a modest decrease in cord blood platelet count was observed in the HPA-4b incompatible siblings compared to the HPA-4b compatible sibling. Serial monitoring of anti-HPA titer showed that anti-HPA-4b markedly decreased in late pregnancy and recovered after delivery of the HPA-4b incompatible siblings, but these decreases were not observed during the mother's pregnancy with the HPA-4b compatible sibling. In contrast, anti-HPA-5b remained at a high titer during pregnancy with all three siblings., Conclusion: Our data indicate that dynamic changes of anti-HPA-4b occur during pregnancy and strongly suggest that anti-HPA-5b was mainly responsible for severe FNAIT in this case., (© 2023. Japanese Society of Hematology.)

M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2 + or HO-1 + M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H 2 O 2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Silicate spherules have been identified from the ca. 3.4 Ga-old Strelley Pool Formation (SPF) in the Pilbara Craton, Western Australia. Their origins and geochemical characteristics, including the Re and platinum-group elements of their host clastic layer and the overlying and underlying microfossil-bearing finely laminated carbonaceous cherts, were examined. The spherules have various morphologies (completely spherical to angular), sizes (∼20 to >500 μm), textures (layered, non-layered, and fibrous), mineralogy (various proportions of microcrystalline quartz, sericite, anatase and Fe-oxides), and chemistry (enriched in Ni and/or Cr), commonly with thin anatase-rich walls. Their host clastic layer is characterized by rip-up clasts, suggesting a suddenly occurring high-energy depositional environment, such as tsunamis. Although various origins other than asteroid impact were considered, none could unequivocally explain the features of the spherules. In contrast, non-layered spherical spherules that occur as individual framework grains or collectively comprise angular-shaped rock fragments appear to be more consistent with the asteroid impact origin. The calculated Re-Os age of the cherts (3331 ± 220 Ma) was consistent with the established age of the SPF (3426-3350 Ma), suggesting that the Re-Os system was not significantly disturbed by later metamorphic and weathering events.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8 + T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS - /STING - ) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS + /STING + ) in tumor cells. The frequency of cGAS + /STING + cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8 + and/or CD4 + T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC.

Background: The PI3K/AKT signaling pathway is frequently activated in gastric cancer (GC); however, AKT inhibitors are not effective in unselected GC patients in clinical trials. Mutations in AT-rich interactive domain 1A (ARID1A), which are found in approximately 30% of GC patients, activate PI3K/AKT signaling, suggesting that targeting the ARID1A deficiency-activated PI3K/AKT pathway is a therapeutic candidate for ARID1A-deficient GC., Methods: The effect of AKT inhibitors was evaluated using cell viability and colony formation assays in ARID1A-deficient and ARID1A knockdown ARID1A-WT GC cells as well as in HER2-positive and HER2-negative GC. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to determine the extent of dependence of GC cell growth on the PI3K/AKT signaling pathway., Results: AKT inhibitors decreased the viability of ARID1A-deficient cells and the inhibitory effect was greater in ARID1A-deficient/HER2-negative GC cells. Bioinformatics data suggested that PI3K/AKT signaling plays a greater role in proliferation and survival in ARID1A-deficient/HER2-negative GC cells than in ARID1A-deficient/HER2-positive cells, supporting the higher therapeutic efficacy of AKT inhibitors., Conclusions: The effect of AKT inhibitors on cell proliferation and survival is affected by HER2 status, providing a rationale for exploring targeted therapy using AKT inhibitors in ARID1A-deficient/HER2-negative GC., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Purpose: Radiation therapy (RT) has the potential to activate the tumor-microenvironment (TME) and promote the efficacy of immune checkpoint blockade therapy. Tumor cell-intrinsic expression of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role in regulations of radiation-induced activation of immune cells in the TME. However, the role of tumor cell-intrinsic cGAS-STING in radiation-mediated remodeling of the TME in esophageal squamous cell carcinoma (ESCC) is not completely understood; thus, we investigated its effect on the radiation-mediated remodeling of the TME in ESCC., Methods: We assessed the effect of tumor cell-intrinsic cGAS-STING on the expression of mediators of the immune system, including type I interferon, T-cell chemo-attractants, colony-stimulating factor-1, and interleukin 34 (IL-34), induced by radiation in ESCC cell lines. We also quantified the association between tumor cell-intrinsic expression of cGAS-STING and infiltrations of immune cells, including CD8 + T cells and CD163 + M2-tumor-associated macrophages (TAMs), in ESCC tissues before and after neoadjuvant chemo-RT (n = 47)., Results: We found that tumor cell-intrinsic expression of cGAS-STING was involved in radiation-induced infiltration of CD8 + T cells and expression of type I interferon and T-cell chemo-attractants in ESCC cells. Surprisingly, tumor cell-intrinsic cGAS-STING was also involved in radiation-triggered infiltration and/or M2-polarization of CD163 + TAMs and expression of IL-34, an important cytokine for recruitment and M2-polarization of TAMs, in ESCC cells. The number of CD163 + M2-TAMs was significantly associated with IL-34 expression in tumor cells in irradiated ESCC tissues., Conclusions: The tumor cell-intrinsic expression of cGAS-STING is essential for radiation-induced activation of immune cells in the TME, but it is also involved in the recruitment of tumor-promoting M2-TAMs in ESCC. Therefore, blocking of M2-TAM infiltration by targeting IL-34 might improve the efficacy of RT and combination therapy of RT with immune checkpoint inhibitors in ESCC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool-designer receptors exclusively activated by designer drugs (DREADDs)-for treating focal seizure in a nonhuman primate model. Acute infusion of the GABA A receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model., (© 2023. The Author(s).)

Purpose: This study aimed to elucidate the effects of neuraxial analgesia on labor in women classified based on the Robson classification system., Methods: We retrospectively reviewed the clinical data of singleton cephalic nulliparous deliveries in labor at term between January 2018 and December 2021 and compared obstetrical outcomes between deliveries with and without neuraxial analgesia in women of Robson group 1 (spontaneous labor) and group 2a (induced labor). Statistical analyses were performed using the Wilcoxon ranked-sum test, Fisher's exact test, and logistic regression model. Statistical significance was set at p < 0.05., Results: We identified 2726 deliveries during the period, of which 387 deliveries (215 with analgesia and 172 without analgesia) were in Robson group 1 and 502 deliveries (258 with analgesia and 244 without analgesia) in Robson 2a. In Robson group 1 pregnancies, the cesarean section (CS) rate was higher in those who received analgesia (15%) than in those who did not (3%) (p = 0.0001). Multivariate analysis revealed that labor with analgesia was a significant risk factor for CS (p < 0.0001). Similarly, in Robson group 2a pregnancies, we observed a higher CS rate in those with analgesia than in those without analgesia (18 vs. 11%, p = 0.042)., Conclusion: A higher CS rate was observed in deliveries with analgesia than in those without analgesia both in the Robson group 1 and group 2a pregnancies., (© 2022. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

In this paper, we describe the three datasets that were used to train, validate, and test deep learning models to detect microfossil fish teeth. The first dataset was created for training and validating a Mask R-CNN model to detect fish teeth in the images taken using the microscope. The training set contained 866 images and one annotation file; the validation set contained 92 images and one annotation file. The second dataset was created for training and validating EfficientNet-V2 models; it included 17,400 images of teeth and 15,036 images that contained only noise (particles other than teeth). The third dataset was created to evaluate the performance of a system that combines a Mask R-CNN model and an EfficientNet-V2 model; it contained 5177 images with annotation files for the locations of 431 teeth within the images., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

On November 9, 1963, a coal dust explosion occurred at the Miike Mikawa Coal Mine (Omuta, Kyushu Region of Japan). This resulted in a massive release of carbon monoxide (CO) gas that resulted in 458 fatalities and 839 victims of CO poisoning. After the accident, the Department of Neuropsychiatry, Kumamoto University School of Medicine (including the authors) immediately began to conduct periodic medical examinations of the victims. Such a long-term follow up of so many CO-poisoned patients is globally unprecedented. When the Miike Mine was closed in March of 1997, 33 years after the disaster, we conducted the final follow-up study., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Although cancer immunotherapy using immune checkpoint inhibitors (ICIs) has been recognized as one of the major treatment modalities for malignant diseases, the clinical outcome is not uniform in all cancer patients. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells that possess various strong immunosuppressive activities involving multiple immunocompetent cells that are significantly accumulated in patients who did not respond well to cancer immunotherapies. We reviewed the perspective of MDSCs with emerging evidence in this review. Many studies on MDSCs were performed in malignant diseases. Substantial studies on the participation of MDSCs on non-malignant diseases such as chronic infection and autoimmune diseases, and physiological roles in obesity, aging, pregnancy and neonates have yet to be reported. With the growing understanding of the roles of MDSCs, variable therapeutic strategies and agents targeting MDSCs are being investigated, some of which have been used in clinical trials. More studies are required in order to develop more effective strategies against MDSCs.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R 2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8 + TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8 + TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8 + TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8 + TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8 + TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8 + TILs and immune-active TME., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Deficient mismatch repair (dMMR)/microsatellite instability (MSI)-H colorectal cancer (CRC) has high immunogenicity. Although the cyclic GMP-AMP synthase( cGAS)-stimulator of interferon genes( STING) pathway activation has considerably contributed to the high number of CD8+ tumor-infiltrating lymphocytes (TILs), its role in dMMR/MSI-H CRC is largely unknown. In this study, we investigated the association between cGAS-STING expression and CD8+ TILs in CRC. Data analysis using the TCGA dataset CRC cohort showed that cGAS, STING, and CD8 gene expression levels were significantly higher in the MSI group. Immunohistochemistry examination of resected clinical CRC samples showed that cGAS-STING expression in tumor cells was high in the MSI CRC, and CD8+ TILs was also significantly infiltrated in the MSI group. Moreover, significant CD8+ TILs infiltration was observed in CRC with high cGAS and STING expression levels. The results suggest that dMMR/MSI -H CRC has maintained a high cGAS-STING expression, which may contribute to abundant CD8+ TILs.