Toxicological evidence integration to confirm the biological plausibility of the association between humidifier disinfectant exposure and respiratory diseases using the AEP-AOP framework.

Objectives: Exposure to humidifier disinfectants has been linked to respiratory diseases, including interstitial lung disease, asthma, and pneumonia. Consequently, numerous toxicological studies have explored respiratory damage as both a necessary and sufficient condition for these diseases. We systematically reviewed and integrated evidence from toxicological studies by applying the evidence integration method established in previous research to confirm the biological plausibility of the association between exposure and disease. Methods: We conducted a literature search focusing on polyhexamethylene guanidine phosphate (PHMG) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT), the primary ingredients in humidifier disinfectants. We selected relevant studies based on their quality and the population, exposure, comparator, outcome (PECO) statements. These studies were categorized into 3 lines of evidence: hazard information, animal studies, and mechanistic studies. Based on a systematic review, we integrated the evidence to develop an aggregate exposure pathway-adverse outcome pathway (AEP-AOP) model for respiratory damage. The reliability and relevance of our findings were assessed by comparing them with the hypothesized pathogenic mechanisms of respiratory diseases. Results: The integration of each AEP-AOP component for PHMG and CMIT/MIT led to the development of an AEP-AOP model, wherein disinfectants released from humidifiers in aerosol or gaseous form reached target sites, causing respiratory damage through molecular initiating events and key events. The model demonstrated high reliability and relevance to the pathogenesis of respiratory diseases. Conclusion: The AEP-AOP model developed in this study provides strong evidence that exposure to humidifier disinfectants causes respiratory diseases. This model demonstrates the pathways leading to respiratory damage, a hallmark of these conditions.

Preclinical and Preliminary Evaluation of Perceived Image Quality of AI-Processed Low-Dose CBCT Analysis of a Single Tooth.

This study assessed AI-processed low-dose cone-beam computed tomography (CBCT) images for single-tooth diagnosis. Human-equivalent phantoms were used to evaluate CBCT image quality with a focus on the right mandibular first molar. Two CBCT machines were used for evaluation. The first CBCT machine was used for the experimental group, in which images were acquired using four protocols and enhanced with AI processing to improve quality. The other machine was used for the control group, where images were taken in one protocol without AI processing. The dose-area product (DAP) was measured for each protocol. Subjective clinical image quality was assessed twice by five dentists, with a 2-month interval in between, using 11 parameters and a six-point rating scale. Agreement and statistical significance were assessed with Fleiss' kappa coefficient and intra-class correlation coefficient. The AI-processed protocols exhibited lower DAP/field of view values than non-processed protocols, while demonstrating subjective clinical evaluation results comparable to those of non-processed protocols. The Fleiss' kappa coefficient value revealed statistical significance and substantial agreement. The intra-class correlation coefficient showed statistical significance and almost perfect agreement. These findings highlight the importance of minimizing radiation exposure while maintaining diagnostic quality as the usage of CBCT increases in single-tooth diagnosis.

Metabolite analysis of 14C-labeled chloromethylisothiazolinone/methylisothiazolinone for toxicological consideration of inhaled isothiazolinone biocides in lungs.

5-Chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) used as preservatives in various products, including humidifier disinfectants, presents substantial health hazards. This research delves into the toxicological assessments of CMIT/MIT in the respiratory system using animal models. Through the synthesis of radiolabeled [14C]CMIT and [14C]MIT, we investigated the biological uptake and in vivo behaviors of CMIT/MIT in the respiratory tissues following intratracheal exposure. Quantitative whole-body autoradiography (QWBA) revealed significant persistence of CMIT/MIT in lung tissue. In addition, radio high-performance liquid chromatography (radio-HPLC) with tandem mass spectrometry (LC-MS/MS) was employed for metabolite profiling and identification. Notably, around 28% of the radiolabel was retained in tissue after the extraction step, suggesting covalent binding of CMIT/MIT and their metabolites with pulmonary biomolecules. This observation demonstrates the propensity of the electrophilic isothiazolinone ring in CMIT/MIT to undergo chemical interactions with biothiols in proteins and enzymes, fostering irreversible alterations of biomolecules. Such accumulations of transformations could result in direct toxicity at both cellular and organ levels. Additionally, the detection of metabolites, including a MIT dimer conjugated with glutathione (GSH), as analyzed by mass spectrometry indicates the possible reduction of cellular GSH levels and subsequent oxidative stress. This investigation offers an in-depth insight into the toxic mechanisms of CMIT/MIT, underlying their capability to engage in complex formations with biomacromolecules and induce pronounced respiratory toxicity. These results highlight the imperative for stringent safety assessments of these chemicals, advocating for improved public health and safety measures in the use of chemicals.

Three new nonenes from culture broth of marine-derived fungus Albifimbria verrucaria and their cytotoxic and anti-viral activities.

Three new nonenes, verrucanonenes A‒C (1‒3), were isolated from culture broth of marine-derived fungus Albifimbria verrucaria. These compounds were isolated using silica gel column chromatography, reversed-phase medium pressure liquid chromatography, Sephadex LH-20 column chromatography, and preparative HPLC. Their structures were determined using a spectroscopic method. Cytotoxicities of these isolated compounds to A549, DU145, HCT116, and HT1080 cancer cell lines were assessed. Compounds 1‒3 exhibited cytotoxicities to DU145 cancer cell line, with IC50 values of 23.4, 28.6, and 20.1 µM, respectively. Compound 2 decreased H1N1-induced cytopathic effects on MDCK cells in a dose-dependent manner.

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.

Three new phthalide derivatives from culture broth of Dentipellis fragilis and their cytotoxic activities.

Three new phthalide derivatives (1‒3) together with two known compounds, erinaceolactone B (4) and hericerin III (5), were isolated from the culture broth of Dentipellis fragilis. The chemical structures of 1‒5 were determined by analyses of their 1D-, 2D-NMR, and MS. The absolute configuration of 1 was determined by CD analysis. The isolated compounds were assessed for their cytotoxic activities against A549, DU145, HCT116, and HT1080 cancer cell lines. Compounds 1‒5 showed strong cytotoxic activities against DU145, with IC50 values ranging from 14.3 to 16.1 µM. Additionally, all compounds showed moderate or weak cytotoxic activities against all cell lines except for compounds 4 and 1 which showed no cytotoxic activities against A549 and HCT116 cancer cell lines, respectively. Against HT1080 cancer cell line, only compound 2 displayed moderate cytotoxic activity.

Understanding subduction infancy to mature subduction in Southwest Japan via the self-consistent formation of a weak slab interface.

The weak slab interface controls long-term subduction dynamics. A weak hydrous layer at the slab interface promotes mechanical decoupling between the forearc mantle and the subducting slab and converts a hot forearc mantle to a cold mantle. Often referred to as a cold nose, the cold forearc mantle, plays a key role in the transition from subduction infancy to mature subduction. This study was the first to numerically demonstrate the self-consistent formation of a weak hydrous layer with permeability anisotropy based on the Southwest Japan subduction zone case, where transition-related geological features were present. Our models showed that mechanical decoupling by spontaneous downdip growth of the weak hydrous layer created a cold nose by converting a hot forearc mantle to a cold mantle. The emergence of a cold nose explained the migration of the forearc-to-arc volcanic front, expressed as the formation of mid-Miocene forearc high-magnesium andesite and Quaternary arc adakite. Furthermore, the weak hydrous layer providing a pathway for free-water transport toward the mantle wedge tip elucidates slab/mantle-derived geochemical components in deep groundwater as well as large S-wave delay times and non-volcanic seismic tremors in the forearc.

Application of multiplex realtime PCR detection for hemorrhagic fever syndrome viruses.

BACKGROUND: Multiplex real-time PCR is a quick and cost effective method for detection of various gene simultaneously. HFSV (Hemorrhagic Fever Syndrome Virus) is a newly emerging infectious disease because of globalization and climate change. We tried to develop a molecular diagnostic technique for various causative viruses and evaluate its usefulness for improving public health. METHODS: Molecular diagnostic test method that qualitatively detects viruses causing viral hemorrhagic fevers hired Taq-Man Real-time RT-PCR technique. The Ct value was experimentally observed three or more times at the RNA concentration before and after the detection limit. After designing a multiplex real-time RT-PCR test for target gene of selected 17 viruses, the detection limit for each target and the presence or absence of cross-reaction and interference reaction were evaluated to determine its availability. RESULTS: Six kinds of viruses, including Crimean-Congo hemorrhagic fever virus, Omsk hemorrhagic fever virus, Sabia virus, Chapare virus, Yellow fever virus, and Variola virus (A4L gene, B12R gene), were able to confirm the detection limit of 0.5 copies/µl, and other Ebola virus, Marburg virus, Rift Valley fever virus, Kyasanur Forest disease virus, Junin virus, Guanarito virus, Machupo virus, Chikungunya virus, Hantavirus, Dengue virus types 1-4, and Lassa virus (L gene, GPC gene), and 11 kinds of viruses, the detection limit was confirmed at 5 copies/µl. No cross-reaction or interference between detected genes was observed. CONCLUSION: The virus test method developed through this study using multiplex is expected to be used for public health and quarantine as a test method that can be used when a hemorrhagic fever virus of unknown cause is introduced.

Formanilides from the culture broth of Perenniporia fraxinea.

A new formanilide dimer, fraxinin (1), and three known formanilides (2‒4) were isolated from the culture broth of Perenniporia fraxinea using silica gel and Sephadex LH-20 column chromatographies, medium-pressure liquid chromatography (MPLC), and preparative HPLC. The structures of these compounds were determined by spectroscopic methods, such as NMR and mass analysis, and by comparison of the spectra with previously reported data. The free radical scavenging activities of the isolated compounds were assessed using 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Compounds 1‒3 exhibited ABTS radical scavenging activity with IC50 values in the range of 57.2-250.2 µM. Compounds 2 and 4 marginally reduced disease incidence of powdery mildew with a control value of 42% at 1.0 mg ml-1 in cucumber leaf disk assay.

Evidence integration on health damage for humidifier disinfectant exposure and legal presumption of causation.

OBJECTIVES: Inhalation exposure to humidifier disinfectants has resulted to various types of health damages in Korea. To determine the epidemiological correlation necessary for presuming the legal causation, we aimed to develop a method to synthesize the entire evidence. METHODS: Epidemiological and toxicological studies are systematically reviewed. Target health problems are selected by criteria such as frequent complaints of claimants. Relevant epidemiologic studies are reviewed and the risk of bias and confidence level of the total evidence are evaluated. Toxicological literature reviews are conducted on three lines of evidence including hazard information, animal studies, and mechanistic studies, considering the source-to-exposure-to-outcome continuum. The confidence level of the body of evidence is then translated into the toxicological evidence levels for the causality between humidifier disinfectant exposure and health effects. Finally, the levels of epidemiological and toxicological evidence are synthesized. RESULTS: Under the Special Act revised in 2020, if the history of exposure and the disease occurred/worsened after exposure were approved, and the epidemiological correlation between the exposure and disease was verified, the legal causation is presumed unless the company proves the evidence against it. The epidemiological correlation can be verified through epidemiological investigations, health monitoring, cohort investigations and/or toxicological studies. It is not simply as statistical association as understood in judicial precedents, but a general causation established by the evidence as a whole, i.e., through weight-of-the-evidence approach. CONCLUSIONS: The weight-of-the-evidence approach differs from the conclusive single study approach and this systematic evidence integration can be used in presumption of causation.

Bioaccumulation and in vivo fate of toxic benzylalkyldimethylammonium chloride in rats via the radiotracer analysis.

Benzylalkyldimethylammonium chloride (BAC), a quaternary ammonium compound (QAC), is utilized in industrial and biomedical applications for antimicrobial purposes. Since the coronavirus disease (COVID-19) outbreak, various types of BAC-containing household chemicals have been produced. BACs have several adverse effects; however, their biological uptake, translocation, and excretion in animal models (essential for better understanding in vivo behavior and toxicological impact) remain unclear. In this study, we performed the first biodistribution and whole-body imaging studies of BAC in male Sprague Dawley rats, using two different administration routes. Quantitative whole-body autoradiography (QWBA) data obtained for intranasal 14C-labeled BAC ([14C]C12-BAC) exposure showed substantial uptake values for the respiratory organs (e.g. 346 ng g-1 of lung at 3 h post administration) and the radiotracer was transported to other internal organs. The amount of radiotracer in the heart, adrenal gland, and pancreas were 198, 1410, and 186 ng g-1 tissue respectively at 168 h following exposure. Autoradiograms obtained after intravenous injection also showed high accumulation and slow excretion in these organs. The cumulative excretion analysis revealed that approximately 6.4% of the administered radioactivity remained in rats after a week. The results indicated that continuous inhalation exposure to BAC leads to potential toxic effects in extrapulmonary organs and the respiratory tract. Thus, the radiolabeling method utilized may help assess various synthetic QACs in living subjects.

Crocin Attenuates NLRP3 Inflammasome Activation by Inhibiting Mitochondrial Reactive Oxygen Species and Ameliorates Monosodium Urate-Induced Mouse Peritonitis.

Crocin is a hydrophilic carotenoid pigment found in the stigma of Crocus sativus or the fruit of Gardenia jasminoides. In this study, we investigated the effects of Crocin on the activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome in J774A.1 murine macrophage cells and monosodium urate (MSU)-induced peritonitis. Crocin significantly inhibited Nigericin-, adenosine triphosphate (ATP)-, MSU-induced interleukin (IL)-1ß secretion, and caspase-1 cleavage without affecting pro-IL-1ß and pro-caspase-1. Crocin also suppressed gasdermin-D cleavage and lactate dehydrogenase release and enhanced cell viability, indicating that Crocin reduces pyroptosis. Similar effects were observed in primary mouse macrophages. However, Crocin did not affect poly(dA:dT)-induced absent in melanoma 2 (AIM2) and muramyl dipeptide-induced NLRP1 inflammasomes. Crocin decreased Nigericin-induced oligimerization and the speck formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Crocin also dramatically alleviated the ATP-induced production of mitochondrial reactive oxygen species (mtROS). Finally, Crocin ameliorated the MSU-induced production of IL-1ß and IL-18 and the recruitment of neutrophils during peritoneal inflammation. These results suggest that Crocin suppresses NLRP3 inflammasome activation by blocking mtROS production and ameliorates MSU-induced mouse peritonitis. Thus, Crocin may have therapeutic potential in various NLRP3 inflammasome-related inflammatory diseases.

Biodistribution and respiratory toxicity of chloromethylisothiazolinone/methylisothiazolinone following intranasal and intratracheal administration.

A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose-trachea-lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g-1 and 752 ng g-1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.

The long multi-epitope peptide vaccine combined with adjuvants improved the therapeutic effects in a glioblastoma mouse model.

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC597-104 and EphA2682-689) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells' distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8+ T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo. In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Effectiveness of cone-beam computed tomography-generated cephalograms using artificial intelligence cephalometric analysis.

Lateral cephalograms and related analysis constitute representative methods for orthodontic treatment. However, since conventional cephalometric radiographs display a three-dimensional structure on a two-dimensional plane, inaccuracies may be produced when quantitative evaluation is required. Cone-beam computed tomography (CBCT) has minimal image distortion, and important parts can be observed without overlapping. It provides a high-resolution three-dimensional image at a relatively low dose and cost, but still shows a higher dose than a lateral cephalogram. It is especially true for children who are more susceptible to radiation doses and often have difficult diagnoses. A conventional lateral cephalometric radiograph can be obtained by reconstructing the Digital Imaging and Communications in Medicine data obtained from CBCT. This study evaluated the applicability and consistency of lateral cephalograms generated by CBCT using an artificial intelligence analysis program. Group I comprised conventional lateral cephalometric radiographs, group II comprised lateral cephalometric radiographs generated from CBCT using OnDemand 3D, and group III comprised lateral cephalometric radiographs generated from CBCT using Invivo5. All measurements in the three groups showed non-significant results. Therefore, a CBCT scan and artificial intelligence programs are efficient means when performing orthodontic analysis on pediatric or orthodontic patients for orthodontic diagnosis and planning.

Semi-subterranean environment and soil metagenomic datasets of the Gyeongju Seokbinggo (stone ice storage) in South Korea.

The Seokbinggo is an ice cellar made of stone to store ice in the 1700s. The Seokbinggo, a traditional Korean stone architecture, can keep ice collected in winter until summer because the semi-subterranean structure utilizes the natural environment, and the insulation design is effective. However, these structures and scientific designs are not used as ice storage and are easily damaged by biological contamination. We present the environmental data of the inside and the metagenomic dataset of the soil samples from the Seokbinggo. Next-generation sequencing was carried out on an Illumina MiSeq platform. The raw sequence data used for analysis is available in NCBI under the Sequence Read Archive (SRA) with BioProject No. PRJNA727939 and SRA accession Nos. SRX10976613, SRX10976614, SRX10976615, SRX10976616, SRX10976617, SRX10976618, SRX10976619, SRX10976620. Environmental data, including data from Korea Meteorological Administration, is available in the Mendeley data repository with DOI: 10.17632/2r8gpg7pxn.1.

Evaluation of nurse-led social media intervention for diabetes self-management: A mixed-method study.

AIMS: This study aimed to investigate the effectiveness and understand the process of a nurse-led social media intervention for health behavior and glucose control for diabetes self-management among patients with type 2 diabetes mellitus. DESIGN: This study had an explanatory sequential mixed methods design, with a randomized controlled trial and qualitative interviews. METHODS: A total of 89 patients diagnosed with type 2 diabetes mellitus were randomly assigned to an intervention or a control group. Patients in the intervention group were invited to join the closed nurse-led social media platform that included diabetes information, action planning, unmoderated chat, and questions and answers. The outcomes of diabetes self-care behavior, hemoglobin A1c (HbA1c) percentage, fasting blood sugar level (FBS), systolic and diastolic blood pressure, and triglyceride (TG) and total cholesterol levels were measured at baseline, 3 months, and 6 months. A linear mixed model was used to analyze the effectiveness of the intervention over time. Qualitative data were collected from interviews with seven patients engaged in the intervention and analyzed using qualitative content analysis. FINDINGS: After 6 months, insulin users who were provided with the social media intervention had significantly lower FBS and TG levels than those with usual care (135.80 ± 12.37 vs. 175.82 ± 15.34 mg/dL, p = 0.049; 206.85 ± 38.26 vs. 387.50 ± 56.19 mg/dL, p = 0.013; respectively). Although a similar rate of decrease in the HbA1c level over time was observed among insulin and noninsulin users after the social media intervention, this decrease was significantly greater among noninsulin users at 3 and 6 months compared with the control group (6.38 ± 0.34 vs. 7.25 ± 0.24, p = 0.040; 6.31 ± 0.37 vs. 7.28 ± 0.26, p = 0.036; respectively). Interview with seven patients who engaged in the intervention revealed that their engagement in the intervention was primarily determined by their acceptance of the role of managing their diabetes. Being engaged in the intervention, patients benefited from information sharing and interactive support to motivate their self-care, nurses' professional advice to modify their behaviors, and action planning to make progress toward behavioral change. CONCLUSIONS: The positive outcomes of the nurse-led social media intervention indicate that the social media platform is an effective strategy to implement diabetes self-management in clinical nursing practice. CLINICAL RELEVANCE: The social media intervention would be successfully implemented by nurses to facilitate patients accepting their role in diabetes management and employing key services for diabetes information, support, professional advice, and action planning.

IL-33 Coordinates Innate Defense to Systemic Candida albicans Infection by Regulating IL-23 and IL-10 in an Opposite Way.

Invasive candidiasis has high mortality rates in immunocompromised patients, causing serious health problems. In mouse models, innate immunity protects the host by rapidly mobilizing a variety of resistance and tolerance mechanisms to systemic Candida albicans infection. We have previously demonstrated that exogenous IL-33 regulates multiple steps of innate immunity involving resistance and tolerance processes. In this study, we systematically analyzed the in vivo functions of endogenous IL-33 using Il33 -/- mice and in vitro immune cell culture. Tubular epithelial cells mainly secreted IL-33 in response to systemic C. albicans infection. Il33 -/- mice showed increased mortality and morbidity, which were due to impaired fungal clearance. IL-33 initiated an innate defense mechanism by costimulating dendritic cells to produce IL-23 after systemic C. albicans infection, which in turn promoted the phagocytosis of neutrophils through secretion of GM-CSF by NK cells. The susceptibility of Il33 -/- mice was also associated with increased levels of IL-10, and neutralization of IL-10 resulted in enhanced fungal clearance in Il33 -/- mice. However, depletion of IL-10 overrode the effect of IL-33 on fungal clearance. In Il10 -/- mouse kidneys, MHC class II+F4/80+ macrophages were massively differentiated after C. albicans infection, and these cells were superior to MHC class II-F4/80+ macrophages that were preferentially differentiated in wild-type mouse kidneys in killing of extracellular hyphal C. albicans Taken together, our results identify IL-33 as critical early regulator controlling a serial downstream signaling events of innate defense to C. albicans infection.

Role of Esophagectomy after Chemoradiation Therapy in Patients with Locally Advanced Squamous Cell Carcinoma: A Comparative Analysis Stratified by Clinical Response to Chemoradiation Therapy.

PURPOSE: This study aimed to evaluate the long-term effect of esophagectomy in patients with esophageal squamous cell carcinoma (ESCC) by comparing the chemoradiotherapy (CRT)-only group and the trimodality treatment (TMT) group who received concurrent CRT followed by surgery. MATERIALS AND METHODS: We included 412 operable ESCC patients treated with TMT or CRT between January 2005 and December 2015. The oncological outcomes of the two groups were compared using a weighted Cox proportional-hazards model with inverse probability of treatment weighting (IPTW). RESULTS: The median survival time was 64 and 32 months in the TMT (n=270) and CRT (n=142) groups, respectively (p < 0.001). After IPTW, the median overall survival (OS) remained significantly higher in the TMT group than in the CRT group (61 months vs. 32 months, p=0.016). Moreover, the TMT group showed a better local recurrence-free rate (LRFR, p < 0.001) and distant metastasis-free rate (p=0.007). In the subgroup of patients with clinical complete response (cCR), the OS was not significantly different between the two groups, both before and after IPTW adjustment (p=0.35 and p=0.93). However, among non-cCR patients, the OS was significantly higher in the TMT group (64% vs. 45%, p < 0.001). CONCLUSION: In patients with locally advanced ESCC, TMT was superior to CRT in terms of OS and LRFR. Such difference was more prominent in the non-cCR subgroup. In patients who achieved cCR, esophagectomy was effective in improving LRFR but not OS, suggesting that esophagectomy may be omitted in complete responders.

Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro. The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγnull mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo. As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.