Strategies for Overcoming Immune Evasion in Bladder Cancer.

Tumors intricately shape a highly immunosuppressive microenvironment, hampering effective antitumor immune responses through diverse mechanisms. Consequently, achieving optimal efficacy in cancer immunotherapy necessitates the reorganization of the tumor microenvironment and restoration of immune responses. Bladder cancer, ranking as the second most prevalent malignant tumor of the urinary tract, presents a formidable challenge. Immunotherapeutic interventions including intravesical BCG and immune checkpoint inhibitors such as atezolizumab, avelumab, and pembrolizumab have been implemented. However, a substantial unmet need persists as a majority of bladder cancer patients across all stages do not respond adequately to immunotherapy. Bladder cancer establishes a microenvironment that can actively hinder an efficient anti-tumor immune response. A deeper understanding of immune evasion mechanisms in bladder cancer will aid in suppressing recurrence and identifying viable therapeutic targets. This review seeks to elucidate mechanisms of immune evasion specific to bladder cancer and explore novel pathways and molecular targets that might circumvent resistance to immunotherapy.

Application of diffusive gradient in thin films probes to monitor trace levels of labile methylmercury in freshwaters.

This study aimed to optimize the methods for sampling and analyzing methylmercury (MeHg) concentrated within diffusive gradients in thin films (DGT) and its application to different water bodies. We explored the elution solution for MeHg, comprised of 1.13 mM thiourea and 0.1M HCl, optimizing its volume to 50 mL. In addition, we found that it is necessary to analyze the entire extraction solution after adjusting its pH, to ensure completion of the ethylation reaction. The DGT samplers were deployed in two distinct aquatic environments (i.e., Okjeong Lake and Nakdong River) for up to 6 weeks, and this study demonstrated to predict the time-weighted average concentration with a diffusion coefficient of 7.65 × 10-6 cm2 s-1 for MeHg in the diffusive gel. To assess the diffusive boundary layer (DBL) effects, the DGT samplers with different agarose diffusive gel thickness were deployed. The mass of MeHg accumulated in the DGT resin at a given time decreased with increasing diffusive gel thickness, because of creating longer diffusion pathways within thicker gels. The labile MeHg concentration estimated by the DGT in Okjeong Lake and Nakdong River are found in the range of 61-111 and 55-105 pg L-1, respectively, which were found to be similar to the grab sampling data. Additionally, this study evaluated depth-dependent MeHg in Okjeong Lake. The vertical profile results showed that the concentration of MeHg at the depth of 2.3 and 15.7 m are about 1.5 and 4.6 times of the DGT installed at 0.3 m of the surface layer, respectively, suggesting potential mercury methylation in deep waters. These findings have practical implications for predicting bioavailability, assessing risks, and formulating strategies for water body management and contamination remediation.

Ultrafast Triggering of Insulator-Metal Transition in Two-Dimensional VSe2.

The transition-metal dichalcogenide VSe2 exhibits an increased charge density wave transition temperature and an emerging insulating phase when thinned to a single layer. Here, we investigate the interplay of electronic and lattice degrees of freedom that underpin these phases in single-layer VSe2 using ultrafast pump-probe photoemission spectroscopy. In the insulating state, we observe a light-induced closure of the energy gap, which we disentangle from the ensuing hot carrier dynamics by fitting a model spectral function to the time-dependent photoemission intensity. This procedure leads to an estimated time scale of 480 fs for the closure of the gap, which suggests that the phase transition in single-layer VSe2 is driven by electron-lattice interactions rather than by Mott-like electronic effects. The ultrafast optical switching of these interactions in SL VSe2 demonstrates the potential for controlling phase transitions in 2D materials with light.

Pseudoalteromone A, a Ubiquinone Derivative from Marine Pseudoalteromonas spp., Suppresses Melanogenesis.

An ubiquinone derivative, pseudoalteromone A (1), has been isolated from two marine-derived Pseudoalteromonas spp., APmarine002 and ROA-050, and its anti-melanogenesis activity was investigated. The anti-melanogenic capacity of pseudoalteromone A was demonstrated by assessing the intracellular and extracellular melanin content and cellular tyrosinase activity in the B16 cell line, Melan-a mouse melanocyte cell line, and MNT-1 human malignant melanoma cell line. Treatment with pseudoalteromone A (40 µg/mL) for 72 h reduced α-melanocyte-stimulating hormone (α-MSH)-induced intracellular melanin production by up to 44.68% in B16 cells and 38.24% in MNT-1 cells. Notably, pseudoalteromone A induced a concentration-dependent reduction in cellular tyrosinase activity in B16 cell, and Western blot analyses showed that this inhibitory activity was associated with a significant decrease in protein levels of tyrosinase and tyrosinase-related protein 1 (Tyrp-1), suggesting that pseudoalteromone A exerts its anti-melanogenesis activity through effects on melanogenic genes. We further evaluated the skin-whitening effect of pseudoalteromone A in the three-dimensional (3D) pigmented-epidermis model, MelanoDerm, and visualized the 3D distribution of melanin by two-photon excited fluorescence imaging in this human skin equivalent. Collectively, our findings suggest that pseudoalteromone A inhibits tyrosinase activity and expression and that this accounts for its anti-melanogenic effects in melanocytes.

Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1's effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases.

Repetitive hyperbaric oxygen therapy for paroxysmal sympathetic hyperactivity after acute carbon monoxide poisoning.

Delayed neuropsychological sequelae (DNS) are relatively common complications of acute carbon monoxide (CO) poisoning, and usually develop within several days to weeks after the initial clinical recovery from acute CO poisoning. DNS can consist of various symptoms such as memory loss, confusion, ataxia, seizures, urinary incontinence, fecal incontinence, emotional lability, disorientation, hallucinations, mutism, cortical blindness, psychosis, parkinsonism, gait disturbances, rigidity, bradykinesia, and other motor disturbances. Paroxysmal sympathetic hyperactivity (PSH) is a potentially life-threatening disease secondary to acute acquired brain injury. It is characterized by episodic and simultaneous paroxysmal increases in sympathetic and motor activities, not rare in patients with a severe traumatic brain injury. The term PSH is clinically more accurate than the previously used ones describing such conditions as non-stimulated tachycardia, hypertension, tachypnea, hyperthermia, external posturing, diaphoresis, and paroxysmal autonomic instability with dystonia. Development of PSH typically prolongs the length of hospital stay and potentially leads to a secondary brain injury or even death. To date, the occurrence of PSH in the DNS after acute CO poisoning has not been reported in the literature. Potential mechanisms underlying the development of DNS in the deep white matter of the brain are immune-related inflammation and vasodilatation. Repetitive hyperbaric oxygen therapy, combined with methylprednisolone administration, may inhibit DNS progression by inducing cerebral oxygenation, inhibiting inflammation, and reducing cerebral edema. Herein, we report three cases in which the patients recovered from the PSH as DNS after CO poisoning after receiving repetitive hyperbaric oxygen therapy.

Stroke Incidence in Survivors of Carbon Monoxide Poisoning in South Korea: A Population-Based Longitudinal Study.

BACKGROUND Carbon monoxide (CO) poisoning is a suspected risk factor for stroke. However, the association between stroke occurrence and carbon monoxide poisoning remains unclear. This nationwide study in Korea analyzed the incidence of stroke in survivors of CO poisoning. MATERIAL AND METHODS In this nationwide, population-based longitudinal study, the database of the Health Insurance Review and Assessment Service was searched to identify patients diagnosed with CO poisoning from 2012 to 2018. Their incidence of ischemic and hemorrhagic strokes, the patterns of stroke incidences, the annual incidence rates in sequential time, the standardized incidence ratio (SIR), and the effects of hyperbaric oxygen therapy (HBOT) were analyzed. RESULTS Of the 29 301 patients diagnosed with CO poisoning during the study period, 984 (3.36%) were diagnosed with stroke after CO poisoning, with approximately 50% occurring within 1 year after CO poisoning. The overall SIR for stroke was 19.49 (95% confidence interval [CI], 17.92-21.12) during the first year, decreasing to 5.64 (95% CI, 4.75-6.66) during the second year. Overall stroke hazard ratio (HR) in the patients admitted to the ICU for CO poisoning was 2.28 (95% CI, 1.19-2.27), compared with 2.35 (95% CI, 1.94-2.84) for ischemic stroke and 1.76 (95% CI, 1.11-2.78) for hemorrhagic stroke. Cumulative HRs did not differ between patients who were and were not treated with HBOT for stroke. CONCLUSIONS CO poisoning is a high-risk factor for the development of stroke, evidenced by high incidences of stroke after CO poisoning. Practical strategies for preventing stroke after CO poisoning are needed, because stroke after CO poisoning affects adults of almost all ages, significantly increasing their socioeconomic burden.

Does Exposure to Computed Tomography Contrast Media Increase Risk of End-Stage Renal Disease?

BACKGROUND There are many studies on acute kidney injury (AKI) after exposure to contrast media in patients with chronic kidney disease (CKD). However, whether the risk of end-stage renal disease (ESRD) increases after exposure to contrast media in the long term, regardless of development of AKI after such exposure, has not been studied. MATERIAL AND METHODS The electronic health records of patients diagnosed with CKD and followed up from 2014 to 2018 at a tertiary university hospital were retrospectively collected. Patients were divided into patients who progressed to ESRD (ESRD group) and those who did not (non-ESRD group). Patients in the non-ESRD group were matched 1: 1 to those in the ESRD group by using disease risk score generation and matching. Multivariate logistic regression analysis was performed to assess the effect of contrast media exposure on progression to ESRD. RESULTS In total, 179 patients were enrolled per group; 178 (99.4%) were in CKD stage 3 or above in both groups. Average serum creatinine was 4.31±3.02 mg/dl and 3.64±2.55 mg/dl in the ESRD and non-ESRD groups, respectively (p=0.242). Other baseline characteristics were not statistically significant, except for the number of times contrast-enhanced computed tomography (CECT) was performed (0.00 [Interquartile range (IQR) 0.00-2.00] in the ESRD group and 0.00 [IQR 0.00-1.00] in the non-ESRD group [p=0.006]); in multivariate logistic regression, this number (OR=1.24, 95% CI=1.08-1.47, p=0.006) was significantly related to progression to ESRD. CONCLUSIONS The use of CECT increased the risk of ESRD 1.2-fold in advanced and stable CKD outpatients after 5-year follow-up.

Risk Stratification of Intermediate-Risk Children With Minor Head Injury.

The Pediatric Emergency Care Applied Research Network rule helps emergency physicians identify very low-risk children with minor head injury who can forgo head computed tomography. This rule contributes to reduction in lifetime risk of radiation-induced cancers while minimizing missing clinically important traumatic brain injury. However, in intermediate-risk children, decisions on whether to perform computed tomography remain at the emergency physicians' discretion. To reduce this gray zone, this review summarizes evidence for risk stratification of intermediate-risk children with minor head injury.

Inhibition of melanogenesis by sodium 2-mercaptoethanesulfonate.

Sodium 2-mercaptoethanesulfonate (mesna) is a protective agent that is widely used in medicine because of its antioxidant effects. Recently, reactive oxygen species (ROS) were shown to increase pigmentation. Thus, ROS scavengers and inhibitors of ROS production may suppress melanogenesis. Forkhead box-O3a (FoxO3a) is an antimelanogenic factor that mediates ROS-induced skin pigmentation. In this study, we aimed to investigate the whitening effect of mesna and the signaling mechanism mediating this effect. Human melanoma (MNT-1) cells were used in this study. mRNA and protein expression were measured by real-time quantitative PCR and Western blotting analysis to track changes in FoxO3a-related signals induced by mesna. An immunofluorescence assay was performed to determine the nuclear translocation of FoxO3a. When MNT-1 melanoma cells were treated with mesna, melanin production and secretion decreased. These effects were accompanied by increases in FoxO3a activation and nuclear translocation, resulting in downregulation of four master genes of melanogenesis: MITF, TYR, TRP1, and TRP2. We found that mesna, an antioxidant and radical scavenger, suppresses melanin production and may therefore be a useful agent for the clinical treatment of hyperpigmentation disorders.

Rolling up MoSe2 Nanomembranes as a Sensitive Tubular Photodetector.

Transition metal dichalcogenides, as a kind of 2D material, are suitable for near-infrared to visible photodetection owing to the bandgaps ranging from 1.0 to 2.0 eV. However, limited light absorption restricts photoresponsivity due to the ultrathin thickness of 2D materials. 3D tubular structures offer a solution to solve the problem because of the light trapping effect which can enhance optical absorption. In this work, thanks to mechanical flexibility of 2D materials, self-rolled-up technology is applied to build up a 3D tubular structure and a tubular photodetector is realized based on the rolled-up molybdenum diselenide microtube. The tubular device is shown to present one order higher photosensitivity compared with planar counterparts. Enhanced optical absorption arising from the multiple reflections inside the tube is the main reason for the increased photocurrent. This tubular device offers a new design for increasing the efficiency of transition metal dichalcogenide-based photodetection and could hold great potential in the field of 3D optoelectronics.

WZ3146 inhibits mast cell Lyn and Fyn to reduce IgE-mediated allergic responses in vitro and in vivo.

Mast cells (MCs) play an important role as effector cells that cause allergic responses in allergic diseases. For these reasons, MC is considered an attractive therapeutic target for allergic disease treatment. In this study, we investigated the inhibitory effect of WZ3146, N-[3-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide, and the mechanisms of its actions on the MC activation and IgE-mediated allergic response by using three types of MCs such as rat basophilic leukemia (RBL)-2H3 cells, mouse bone marrow mast cells (BMMCs), and human Laboratory of Allergic Diseases 2 (LAD2) cells. WZ3146 inhibited antigen-stimulated degranulation in a dose-dependent manner (IC50, ~ 0.35 µM for RBL-2H3 cells; ~ 0.39 µM for BMMCs; ~ 0.41 for LAD2 cells). WZ3146 also suppressed the production of histamine, tumor necrosis factor (TNF)-α and interleukin (IL)-6, which mediate various allergic responses, in a dose-dependent manner. As the mechanism of WZ3146 to inhibit MCs, it inhibited the activation of spleen tyrosine kinase (Syk) and the downstream signaling proteins of Syk such as linker for activation of T cell (LAT) and phospholipase (PL) Cγ1 in the signaling pathway of FcεRI. In addition, WZ3146 inhibited the activation of Akt, extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun N-terminal kinase (JNK). However, WZ3146 did not inhibit degranulation of MCs by thapsigargin or ionomycin, which increase calcium concentration in cytosol. Notably, WZ3146 inhibited the activity of Lyn and Fyn, but not Syk. In an following animal experiment, WZ3146 inhibited IgE-dependent passive cutaneous anaphylaxis (PCA) in a dose-dependent manner (ED50, ~ 20 mg/kg). Taken together, in this study we show that the pyrimidine derivative, WZ3146, inhibits the IgE-mediated allergic response by inhibiting Lyn and Fyn Src-family kinases, which are initially activated by antigen stimulation in MCs. Therefore, we propose that WZ3146 could be used as a new therapeutic agent for the treatment of allergic diseases.

Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma.

BACKGROUND: Inhaled protease allergens preferentially trigger TH2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2-favorable DCs in the airway remains unclear. OBJECTIVE: We sought to determine a subset of DCs responsible for TH2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway. METHODS: Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies. RESULTS: Protease allergens induced a remarkable accumulation of TH2-favorable programmed cell death 1 ligand 2 (PD-L2)+ DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2+ DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2+ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2+ DC population in mice lacking mast cells. CONCLUSION: Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of TH2-favorable PD-L2+ DCs in allergic asthma and suggest that targeting the PD-L2+ DC pathway might be effective in suppressing allergic T-cell responses in the airway.

The performance of diffusive gradient in thin film probes for the long-term monitoring of trace level total mercury in water.

The potential of diffusive gradient in thin film (DGT) as a long-term monitoring tool to assess trace level mercury (Hg) in surface waters was evaluated. A piston type DGT sampler and a plate-type device that could hold 15 DGTs were designed. The device contained piston type DGT samplers with varying diffusive gel thicknesses, that is, 0.5, 0.75, and 1.0 mm, respectively. Three DGT devices were deployed in a lake for 5 weeks, and two were deployed in a stream for 3 weeks. In the lake, the total Hg (THg) mass accumulated in the DGT varied between 0.05 and 0.15 ng, which increased with an increase in deployment time and decreased with an increase in agarose diffusion gel thickness. The DGT concentration in the lake water for a 2 week period was estimated to be about 0.8-1.0 ng/L, which was close to the measured value of 1.1 (± 0.13) ng/L, using the grab sampling technique. However, the DGT estimated at 4 and 6 weeks showed a concentration of about 0.5-0.7 ng/L, which is about twice as small as that measured by grab sampling. This underestimation of the THg levels in water appear to be caused by additional thicknesses of the physical diffusive boundary layer (0.15, 0.5, 1.29 mm) and biofilm, outside the DGT filter. The predicted DGT concentration in the upper stream of the Nakdong River was estimated to be about 0.8-1.4 ng/L, which is similar to the value of 1.22 (± 0.29) ng/L measured in the field by grab sampling. The concentration of THg was estimated to be about 1.0-1.2 ng/L, which is similar to the values measured by grab sampling. The additional diffusion thickness formed outside the DGT filter was 0.018 mm and 0.093 mm at 1 and 3 weeks, respectively, which is not larger than the diffusion gel thickness (0.5-1.0 mm). This was because DGT was installed in a region where the flow velocity is high, and the thickness of the diffusion boundary layer outside the filter is negligible.

Value of Additional Ultrasound Examination in Patients with Equivocal Computed Tomography Findings of Acute Appendicitis: Comparison with Computed Tomography Reassessment.

OBJECTIVES: The objective of this study was to find the diagnostic values of additional ultrasound (US) in patients with equivocal computed tomography (CT) findings of acute appendicitis, compared to CT reassessment. MATERIALS AND METHODS: Patients with equivocal CT findings of acute appendicitis (n = 115), who underwent the US, were included in the study. Two abdominal radiologists reviewed CT scans independently. They analyzed CT findings and made a diagnosis of acute appendicitis. The patients were categorized into positive and negative appendicitis based on the previous US reports. The diagnostic performance, interobserver agreement of CT findings, and appendicitis likelihood were calculated. RESULTS: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of US (100%, 92.1%, 79.5%, and 100%, respectively) were higher than those of CT reassessment (reviewer 1: 51.9%, 87.5%, 56.1%, and 85.6%; reviewer 2: 66.7%, 85.2%, 58.1%, and 89.3%, respectively). In the coexistent inflammation group, the sensitivity, specificity, PPV, and NPV of US (reviewer 1: 100%, 98%, 91.5%, and 100%; reviewer 2: 100%, 98%, 87.7%, and 100%, respectively) were higher than those of CT reassessment (reviewer 1: 27.3%, 94.1%, 49.9%, and 85.8%; reviewer 2: 14.3%, 98.0%, 50.5%, and 88.9%, respectively). CONCLUSION: In patients with equivocal CT findings of acute appendicitis, US shows better diagnostic performance than CT reassessment, and helps differentiate with periappendicitis.

Therapeutic Aspects of Carbon Monoxide in Cardiovascular Disease.

Carbon monoxide (CO) is being increasingly recognized as a potential therapeutic with important signaling functions in various diseases. Carbon monoxide-releasing molecules (CORMs) show anti-apoptotic, anti-inflammatory, and anti-oxidant effects on the tissues of organisms, thus contributing to tissue homeostasis. An increase in reactive oxygen species production from the mitochondria after exposure to CO is also considered one of the underlying mechanisms of cardioprotection, although mitochondrial inhibition is the main toxic mechanism of CO poisoning. This review highlights the mechanism of the biological effects of CO and its potential application as a therapeutic in clinical settings, including in cardiovascular diseases. This review also discusses the obstacles and limitations of using exogenous CO or CORMs as a therapeutic option, with respect to acute CO poisoning.

Sonographic Findings of Malignant Appendix Tumors in Seven Cases.

We report the sonographic features of confirmed malignant appendiceal tumors in seven cases. The histologic diagnoses of these tumors were mucinous cystadenocarcinoma (n = 2), colonic type adenocarcinoma (n = 4), and signet-ring cell carcinoma (n = 1). The 2 mucinous cystadenocarcinomas showed mucocele type, which had markedly enlarged inner luminal diameters (mean, 23 mm; range, 15-31 mm) and thick, irregular walls (mean wall thickness, 5.5 mm; range, 5-6 mm). In contrast, the 5 nonmucinous carcinomas (4 adenocarcinomas and 1 signet-ring cell carcinoma) showed nonmucocele type, which had relatively small inner luminal diameters (mean ± standard deviation [SD], 6.6 ± 4.5 mm; range, 2-15 mm) and prominent wall thickening (mean wall thickness ± SD, 6.2 ± 2.3 mm; range, 3-10 mm). Of the 5 nonmucinous tumors, only one had a discernible mass, three had thick irregular walls, two had loss of the wall layer pattern, and four had submucosal hypoechogenicity. Regardless of the histologic type, five of the seven malignant appendiceal tumors showed a severe periappendiceal fat infiltration or periappendiceal abscess, suggestive of perforation. Although the sonographic findings of the malignant appendiceal tumors were nonspecific, some of the sonographic features seen in these seven cases may help radiologists consider the possibility of underlying malignant appendiceal tumors.

Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4µ8C.

Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4µ8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4µ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4µ8C suppressed the degranulation of IgE-mediated mast cells (IC50=3.2µM) and the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in a dose-dependent manner. 4µ8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50=25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4µ8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4µ8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4µ8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4µ8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4µ8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis.

CT Predictors of Unfavorable Clinical Outcomes of Acute Right Colonic Diverticulitis.

OBJECTIVE: The purpose of this study was to retrospectively assess CT predictors of unfavorable outcomes of medical treatment in patients with right colonic diverticulitis. MATERIALS AND METHODS: Of 394 patients with right colonic diverticulitis diagnosed on the basis of CT findings from January 2010 through August 2013, we included 328 (190 men, 138 women; mean age, 41.3 ± 12.6 years) who had undergone medical treatment as inpatients. Two radiologists retrospectively reviewed the following CT findings associated with diverticulitis: number of diverticula per 10 cm of colon; length and thickness of affected colonic wall; diameter of inflamed diverticulum and abscess; presence of pericolic fluid collection, spilled feces, and contained air; and extent of fatty infiltration. Logistic regression analysis and the Cox proportional hazards regression model were used to determine significant variables predictive of unfavorable outcomes, including surgery after failed medical treatment, recurrence, and prolonged hospital stay. RESULTS: Of the 328 patients, nine underwent surgery after failed medical treatment. Of the other 319 patients, 35 had recurrence and 49 had a prolonged hospital stay. The spilled feces sign (adjusted odds ratio [OR], 111; p < 0.001) and serum WBC count (adjusted OR, 1.3; p = 0.047) were independent predictors of the need for surgery. More than five multiple diverticula per 10 cm of colon was significantly associated with recurrence (adjusted hazard ratio, 4.1; p < 0.001). Abscess larger than 4 cm (adjusted OR, 18.2; p = 0.01) and inflamed diverticulum larger than 2 cm (adjusted OR, 3.7; p = 0.001) were independent predictors of prolonged hospital stay. CONCLUSION: Some specific CT findings can be useful predictors of unfavorable clinical outcomes of right colonic diverticulitis.