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Tumor tissue is composed of tumor cells and surrounding non-tumor endothelial and immune cells, collectively known as the tumor microenvironment. Tumor cells manipulate tumor microenvironment to obtain sufficient oxygen and nutrient supply, and evade anti-tumor immunosurveillance. Various types of signaling molecules, including cytokines, chemokines, growth factors, and lipid mediators, are secreted, which co-operate to make up the complex tumor microenvironment. Prostaglandins, cyclooxygenase metabolites of arachidonic acid, are abundantly produced in tumor tissues. Ever since treatment with nonsteroidal anti-inflammatory drugs showed anti-tumor effect in mouse models and human patients by inhibiting whole prostaglandin production, investigators have focused on the importance of prostaglandins in tumor malignancies. However, most studies that followed focused on the role of an eminent prostaglandin, prostaglandin E2, in tumor onset, growth, and metastasis. It remained unclear how other prostaglandin species affected tumor malignancies. Recently, we identified prostaglandin D2, a well-known sleep-inducing prostaglandin, as a factor with strong anti-angiogenic and anti-tumor properties, in genetically modified mice. In this review, we summarize recent studies focusing on the importance of prostaglandins and their metabolites in the tumor microenvironment.

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.

Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53 . Osteoprogenitor-specific p53 -deleted mice ( OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53 -deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53- deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.

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.

We examined the effect of poly-γ-glutamic acid flocculant (PGAF) on the removal of ultrafine cement (UFC) particles stabilized by a poly-carboxylate co-polymer, which is a superplasticizer (SP). The flocculation–sedimentation treatment with PGAF successfully removed the SP-stabilized cement particles through the gravitational settling of the formed flocs. The removal efficiency reduced with the increase in the ionic strength, probably because of the shrunk form of poly-γ-glutamic acid (γ-PGA) at high ionic strengths. Increasing the mixing intensity during rapid mixing improved the removal efficiency. A series of flocculation–sedimentation experiments provided a diagram showing the relationship between ionic strengths and the addition amount of PGAF. Our results suggest that PGAF is a good candidate for the purification of cement suspension by flocculation–sedimentation, and a better removal performance can be obtained at lower ionic strengths with intense rapid mixing. From the diagram of the control charts presented in this study, we can determine the optimal addition amount of PGAF for achieving the target removal rate for cement suspension under any ionic strength.

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.

The upper critical field of a cuprate high-temperature superconductor, La 1.84 Sr 0.16 CuO 4 , was investigated by high-frequency self-resonant contactless electrical conductivity measurements in magnetic fields up to 102 T. An irreversible transition was observed at 85 T ( T  = 4.2 K), defined as the upper critical field. The temperature-dependent upper critical field was argued on the basis of the Werthamer-Helfand-Hohenberg theory. The Pauli-limiting pair-breaking process with a small contribution of the spin-orbit coupling explained the first-order phase transition exhibiting a hysteresis observed at low temperatures.

Intraoral vertical ramus osteotomy (IVRO) is used to treat mandibular prognathism and temporomandibular disorders. However, the improvement of temporomandibular disorders after IVRO is considered to be due to the anterior and downward movement of the mandibular condyle, which may lead to condylar sag, and in the worst case, condylar luxation. In this retrospective cohort study, we examined factors potentially associated with condylar sag. Univariate analysis indicated that condylar sag was significantly associated with the following factors: magnitude of setback ( P  = 0.001), less than 3 mm setback ( P  < 0.001), presence of temporomandibular joint (TMJ) symptoms ( P  = 0.002), Wilkes classification ( P  = 0.039), occlusal cant correction ≥ 2 mm ( P  = 0.018), and mandibular condyle deformation ( P  < 0.001). Setback magnitude ( P  = 0.032) and TMJ symptoms ( P  = 0.007) remained significant in the multivariate analysis. In the receiver operating characteristic curve, the setback magnitude cut-off value for condylar sag after IVRO was 3.25 mm. Thus, the incidence of condylar sag after IVRO is increased with a smaller setback magnitude (≤ 3.25 mm) and the presence of TMJ symptoms. These factors should be evaluated by surgeons during treatment planning for IVRO to estimate condylar sag, and it may be possible to predict the risk of condylar luxation.

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.

Medication-related osteonecrosis of the jaw is currently classified only by clinical staging, with no imaging-based qualitative classification available. To establish foundational data for a new classification method that could help guide treatment decisions and predict prognosis, this study investigated the computed tomography findings commonly observed in patients with medication-related osteonecrosis of the jaw and their frequencies. Computed tomography scans from 784 patients across 19 medical institutions were analyzed for the presence of osteolysis, sequestrum separation, periosteal reactions, mixed-type osteosclerosis, and the bone-within-bone appearance. Clinical factors associated with each finding were also examined. Osteolysis appeared as localized in 55.1% of cases, extended in 27.7%, and advanced in 13.8%. In contrast, 3.4% of patients showed no osteolysis. This non-osteolytic pattern was more common among patients treated with denosumab. Sequestrum separation was seen in 34.7% of patients, most frequently among those with osteoporosis. Periosteal reactions were observed in 5.9% of cases as the attached type, 12.4% as the gap type, and 5.6% as the irregular type. Mixed-type osteosclerosis occurred in 31.9% of cases, most often in the mandibles of patients with malignant tumors. The bone-within-bone appearance was observed in 3.1% of cases. Patients with sequestrum separation had more favorable treatment outcomes. In contrast, those without osteolysis and those with periosteal reactions, mixed-type osteosclerosis, or bone-in-bone appearance were more likely to have poorer outcomes. This multicenter study clarified the prevalence of several key computed tomography features in medication-related osteonecrosis of the jaw, highlighting their potential relevance to clinical outcomes. These findings lay the groundwork for future research into their prognostic and therapeutic implications to support the development of a new imaging-based classification system.