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Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

The prediction of anatomical structures within the surgical field by artificial intelligence (AI) is expected to support surgeons’ experience and cognitive skills. We aimed to develop a deep-learning model to automatically segment loose connective tissue fibers (LCTFs) that define a safe dissection plane. The annotation was performed on video frames capturing a robot-assisted gastrectomy performed by trained surgeons. A deep-learning model based on U-net was developed to output segmentation results. Twenty randomly sampled frames were provided to evaluate model performance by comparing Recall and F1/Dice scores with a ground truth and with a two-item questionnaire on sensitivity and misrecognition that was completed by 20 surgeons. The model produced high Recall scores (mean 0.606, maximum 0.861). Mean F1/Dice scores reached 0.549 (range 0.335–0.691), showing acceptable spatial overlap of the objects. Surgeon evaluators gave a mean sensitivity score of 3.52 (with 88.0% assigning the highest score of 4; range 2.45–3.95). The mean misrecognition score was a low 0.14 (range 0–0.7), indicating very few acknowledged over-detection failures. Thus, AI can be trained to predict fine, difficult-to-discern anatomical structures at a level convincing to expert surgeons. This technology may help reduce adverse events by determining safe dissection planes.

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived newly discovered bioactive anti-inflammatory lipid mediator having diverse functions. Here, we assessed the potential of orally administered 5,6-DiHETE in promoting healing of dextran sulfate sodium (DSS)-induced colitis in mice. We measured the plasma concentrations of 5,6-DiHETE in untreated mice before and 0.5, 1, 3, and 6 h after its oral administration (150 or 600 μg/kg) in mice. Mice developed colitis by DSS (2% in drinking water for 4 days), and 5,6-DiHETE (150 or 600 μg/kg/day) was orally administered from day 9 to 14. Next, the faecal hardness and bleeding were assessed, and the dissected colons on day 14 via H&E staining. The plasma concentration of 5,6-DiHETE reached 25.05 or 44.79 ng/mL 0.5 h after the administration of 150 or 600 μg/kg, respectively, followed by a gradual decrease. The half-life of 5,6-DiHETE was estimated to be 1.25–1.63 h. Diarrhoea deteriorated after day 3 and peaked on day 5, followed by a gradual recovery. Histological assessment on day 14 showed DSS-mediated granulocyte infiltration, mucosal erosion, submucosal edema, and cryptal abscesses in mice. Oral administration of 150 or 600 μg/kg/day of 5,6-DiHETE accelerated the recovery from the DSS-induced diarrhoea and significantly ameliorated colon inflammation. The therapeutic effect of 600 μg/kg/day 5,6-DiHETE was slightly stronger than that by 150 μg/kg/day. Our study reveals attenuation of DSS-induced colitis in mice by the oral administration of 5,6-DiHETE dose-dependently, thereby suggesting a therapeutic potential of 5,6-DiHETE for inflammatory bowel disease.

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E 2 metabolite tetranor-PGEM and PGD 2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F 2 isoprostanes (F 2 -IsoPs), 8-iso PGF 2α and 2,3-dinor-8-iso PGF 2α , were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22 phox ). These observations suggest that urinary 8-iso PGF 2α and 2,3-dinor-8-iso PGF 2α can be indexes of CAC.

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) is highly effective for advanced esophageal squamous cell carcinoma, and patients with a good response sometimes desire to avoid surgery. The aim of this single-center, retrospective study was to predict the probability of residual tumors using a newly devised scoring system and identify conditions that may obviate the need for surgery. Between January 2017 and March 2024, 106 patients received NAC with DCF, followed by radical resection at our institution. After NAC, patients underwent multimodal assessments to correlate the evaluation parameters with residual tumors. A scoring system was developed by incorporating the parameters that exhibited significant differences. After calculating the scores for all patients, a receiver operating characteristic (ROC) curve was generated to determine the optimal cutoff value for predicting residual tumors. Eighteen patients achieved a pathological complete response, of whom 12 showed complete tumor disappearance, including lymph node metastases. The scoring system included the following seven parameters: endoscopic irregularity, elevation, and pink-color sign after iodine staining; identification of the main tumor, regional lymph nodes ≥5 mm in long diameter, presence of positive lymph node findings on computed tomography; and positive 18F-fluorodeoxyglucose uptake on positron emission tomography. The area under the ROC curve was 0.957, with a cutoff value of 3 for residual tumors. All patients with a score of 0 showed complete tumor disappearance. Our scoring system suggests that surgery might be safely omitted in patients with a score of 0. Comprehensive and flexible clinical decision-making is essential.

A postoperative pancreatic fistula (POPF) is a critical complication of radical gastrectomy for gastric cancer, mainly because surgeons occasionally misrecognize the pancreas and fat during lymphadenectomy. Therefore, this study aimed to develop an artificial intelligence (AI) system capable of identifying and highlighting the pancreas during robot-assisted gastrectomy. A pancreas recognition algorithm was developed using HRNet, with 926 training images and 232 validation images extracted from 62 scenes of robot-assisted gastrectomy videos. During quantitative evaluation, the precision, recall, intersection over union (IoU), and Dice coefficients were calculated based on the surgeons' ground truth and the AI-inferred image from 80 test images. During the qualitative evaluation, 10 surgeons answered two questions related to sensitivity and similarity for assessing clinical usefulness. The precision, recall, IoU, and Dice coefficients were 0.70, 0.59, 0.46, and 0.61, respectively. Regarding sensitivity, the average score for pancreas recognition by AI was 4.18 out of 5 points (1 = lowest recognition [less than 50%]; 5 = highest recognition [more than 90%]). Regarding similarity, only 54% of the AI-inferred images were correctly differentiated from the ground truth. Our surgical AI system precisely highlighted the pancreas during robot-assisted gastrectomy at a level that was convincing to surgeons. This technology may prevent misrecognition of the pancreas by surgeons, thus leading to fewer POPFs.

Thromboxane A 2 (TXA 2 ) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA 2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA 2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction and it was inhibited by Ca 2+ channel blockade or Rho kinase inhibition. Thus endogenous TXA 2 exacerbates ALI and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA 2 -TP axis, via Ca 2+ - and Rho kinase-dependent signaling.

GATA2 deficiency, a syndrome caused by heterozygous loss-of-function variants in the gene, is characterized by immunodeficiency, bone marrow failure, and predisposition to myeloid neoplasms. Its clinical presentation is highly variable, making early diagnosis challenging. Although GATA2 deficiency has been linked to systemic inflammation, gastrointestinal involvement mimicking inflammatory bowel disease (IBD) is extremely rare. This report presented the case of two adolescent boys with no family history of novel heterozygous frameshift variants. Notably, Patient 1 initially presented with clinical and endoscopic features strongly suggestive of Crohn's disease, including weight loss, perianal abscess, and characteristic intestinal ulcers, before developing acute myeloid leukemia with monosomy 7. This is a rare presentation of GATA2 deficiency manifesting initially with Crohn's disease-like symptoms. Patient 2 presented with intractable cutaneous warts and pancytopenia, later diagnosed as myelodysplastic syndrome with der(1;7)(q10;p10). Both patients harbored novel frameshift variants predicted to eliminate the DNA-binding domain, suggesting a loss-of-function mechanism. These cases expand the phenotypic spectrum of GATA2 deficiency and highlight that atypical IBD-like symptoms, including Crohn's disease-like presentations, may cause an initial manifestation. GATA2 deficiency should be considered in patients with IBD-like symptoms, refractory skin disorders, and hematological abnormalities. Early genetic testing and family screening are essential to ensuring timely diagnosis and curative hematopoietic stem cell transplantation before progression to advanced myeloid disease.

Food allergy is immediate hypersensitive reactions to ingested foods. Since early diagnosis is effective for disease control, development of an objective diagnostic index is required. Using mediator-lipidomics, we found that levels of the urinary prostaglandin D 2 (PGD 2 ) metabolite, tetranor-PGDM, reflected the severity of the allergic symptoms and intestinal mast cell hyperplasia in mice. Repeated oral challenges with ovalbumin promoted allergic symptoms in sensitized mice. Particularly, the allergic mice presented with increased numbers of intestinal mast cells, which strongly expressed hematopoietic PGD synthase (H-PGDS). The levels of urinary tetranor-PGDM increased as the disease progressed. Treatment with a mast cell inactivator or an anti-inflammatory steroid attenuated these symptoms and decreased the tetranor-PGDM urinary levels. The levels of urinary tetranor-PGDM did not correlate with the disease severity in murine models of colitis, asthma, or allergic dermatitis. Furthermore, we have shown that urinary levels of tetranor-PGDM were significantly higher in patients with food allergy than those in healthy volunteers and patients with other types of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. These findings suggest that urinary tetranor-PGDM is a useful diagnostic index of food allergy in both mice and humans.