Effects of stabilizer magnesium nirate on CMIT/MIT-induced respiratory toxicity.

Despite a humidifier disinfectant (HD) product containing chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) with approximately 22% magnesium nitrate as a stabilizer, no report on the effects of magnesium nitrate on the respiratory toxicity of CMIT/MIT is available. In this study, Kathon CG and Proclin 200, containing approximately 1.5% CMIT/MIT with different magnesium nitrate concentrations (22.6% and 3%, respectively), were used to compare respiratory effects after intratracheal instillation (ITI) in C57BL/6 mice. C57BL/6 mice were randomized into groups of saline control, magnesium nitrate, Kathon CG, and Proclin 200 with 1.14 mg/kg of CMIT/MIT as the active ingredient, and administration was performed 6 times in a 2-3 day-interval in 2 weeks in all groups. Differential cell count analysis, cytokine analysis, and histological analysis of lung tissue were performed to characterize the injury features. Both Kathon and Proclin 200 induced an increase in inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid, in particular, eosinophils and type 2 T helper cell (Th2)-secreted cytokines. All histopathological changes including granulomatous inflammation, mixed inflammatory cell infiltration, mucous cell hyperplasia, eosinophil infiltration, and pulmonary fibrosis were induced with similar frequency and severity in Kathon CG and Proclin 200 groups. Our results suggested that magnesium nitrate did not affect CMIT/MIT-induced lung injury in the intratracheally instilled model. Further inhalation studies are needed to determine the distribution and toxicity differences of CMIT/MIT in the lungs according to the magnesium nitrate concentration.

Comparative study of lung toxicity of E-cigarette ingredients to investigate E-cigarette or vaping product associated lung injury.

No comparative study has yet been performed on the respiratory effects of individual E-cigarette ingredients. Here, lung toxicity of individual ingredients of E-cigarette products containing nicotine or tetrahydrocannabinol was investigated. Mice were intratracheally administered propylene glycol (PG), vegetable glycerin (VG), vitamin E acetate (VEA), or nicotine individually for two weeks. Cytological and histological changes were noticed in PG- and VEA-treated mice that exhibited pathophysiological changes which were associated with symptoms seen in patients with symptoms of E-cigarette or Vaping Use-Associated Lung Injuries (EVALI) or E-cigarette users. Compared to potential human exposure situations, while the VEA exposure condition was similar to the dose equivalent of VEA content in E-cigarettes, the PG condition was about 47-137 times higher than the dose equivalent of the daily PG intake of E-cigarette users. These results reveal that VEA exposure is much more likely to cause problems related to EVALI in humans than PG. Transcriptomic analysis revealed that PG exposure was associated with fibrotic lung injury via the AKT signaling pathway and M2 macrophage polarization, and VEA exposure was associated with asthmatic airway inflammation via the mitogen-activated protein kinase signaling pathway. This study provides novel insights into the pathophysiological effects of individual ingredients of E-cigarettes.

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.

Wound Irrigation Using Wet Gauze May Reduce Surgical Site Infection Following Laparoscopic Appendectomy.

PURPOSE: This study aimed to compare the perioperative outcomes of wet gauze and conventional irrigation after laparoscopic appendectomy to determine whether wet gauze irrigation can help reduce surgical site infection (SSI). METHODS: A total of 308 patients undergoing laparoscopic appendectomy were included in this study between December 2018 and May 2020. Of these, 132 (42.9%) received gauze irrigation (group 1), and 176 patients (57.1%) received conventional irrigation (group 2). Pre-operative outcomes and complications, including SSI, were compared after propensity score matching (PSM) to adjust for baseline differences and selection bias. RESULTS: After 1:1 PSM, 92 well-matched patients in each group were evaluated. Regarding perioperative outcomes between groups 1 and 2, the rate of severe complications (Clavien-Dindo Classification grades III, IV, and V), operative time, and readmission rate did not differ between the groups. Superficial/deep SSIs were observed more frequently in group 2 (8/92 cases) than in group 1 (1/92 cases; p = 0.017). The organ/space SSIs rate was not significantly different between the two groups (1/92 group 1 and 0/92 group 2, p = 0.316). However, post-operative hospital stay was significantly longer in group 2 (2.8 ± 1.3 days) than in group 1 (1.6 ± 1.2 days; p < 0.001). In the univariate analyses, wound irrigation using wet gauze was an independent protective factor for superficial or deep SSI (p = 0.044). CONCLUSIONS: Wound irrigation using wet gauze after fascia closure has a significant beneficial effect on reducing post-operative superficial/deep SSI following laparoscopic appendectomy.

DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer.

Surgical rectus sheath block combined with multimodal pain management reduces postoperative pain and analgesic requirement after single-incision laparoscopic appendectomy: a retrospective study.

PURPOSE: This study aimed to evaluate the impact of multimodal postoperative pain management, performing a surgical rectus sheath (RS) block via ropivacaine injection into the surgical field after single-incision laparoscopic appendectomy (SILA). METHODS: Patients who underwent single-incision laparoscopic appendectomy (SILA) for acute appendicitis were divided into three groups and compared: group 1 (multimodal pain management that included intraoperative application of a surgical RS block), group 2 (conventional pain management with intravenous opioids), or group 3 (multimodal pain management without RS block). Forty, 53, and 42 patients were registered, respectively (Table 1). RESULTS: Time to start a liquid (1.2 ± 0.4 h) in group 1 was statistically significantly shorter than that in group 2 (16.3 ± 8.4 h; p < 0.001) and group 3 (4.93 ± 2.3 h; p < 0.001). The median and max postoperative VAS scores in group 1 (1.6 ± 1.2 and 2.2 ± 1.8, respectively) were statistically significantly lower than that in group 2 (3.0 ± 1.2 and 4.2 ± 1.9, respectively; p < 0.001 on both accounts) and group 3 (2.9 ± 0.6 and 3.4 ± 1.2, respectively; p < 0.001 on both accounts). The postoperative hospital stay for group 1 (17.0 ± 9.4 h) was shorter than that for group 2 (44.7 ± 27.9 h; p < 0.001) and group 3 (35.4 ± 20.9 h; p < 0.001). RS block was a significant factor for reducing length of hospital stay and postoperative pain in 24 h. CONCLUSIONS: A surgical RS block combined with multimodal pain management after SILA is a safe and effective method that results in reduced postoperative pain and shorter hospitalization.

Miconazole inhibits signal transducer and activator of transcription 3 signaling by preventing its interaction with DNA damage-induced apoptosis suppressor.

DNA damage-induced apoptosis suppressor (DDIAS) facilitates the survival of lung cancer by suppressing apoptosis. Moreover, DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) via their interaction. Here, we identified miconazole as an inhibitor of DDIAS/STAT3 interaction by screening a chemical library using a yeast two-hybrid assay. Miconazole inhibited growth, migration and invasion of lung cancer cells. Furthermore, miconazole suppressed STAT3 tyrosine Y705 phosphorylation and the expression of its target genes, such as cyclin D1, survivin and snail but had no suppressive effect on the activation of ERK1/2 or AKT, which is involved in the survival of lung cancer. As expected, no interaction between DDIAS and STAT3 occurred in the presence of miconazole, as confirmed by immunoprecipitation assays. Mouse xenograft experiments showed that miconazole significantly suppressed both tumor size and weight in an NCI-H1703 mouse model. Tyrosine phosphorylation of STAT3 at Y705 and expression of its targets, such as cyclin D1, survivin and snail, were decreased in miconazole-treated tumor tissues, as compared with those in vehicle-treated tumor tissues. These data suggest that miconazole exerts an anti-cancer effect by suppressing STAT3 activation through inhibiting DDIAS/STAT3 binding.

Micropuncture Access Set Use During Implantation of Totally Implantable Venous Access Device May Reduce Upper Extremity DVT Incidence Among Patients Undergoing Chemotherapy for Colorectal Cancer.

BACKGROUND: The aim of this study was to compare the perioperative outcomes when using a micropuncture access set (MS) to those when using a conventional puncture set (CS) for implantation of totally implantable venous access device (TAVID). METHODS: A total of 314 patients undergoing chemotherapy for colorectal cancer were included between June 2015 and July 2018. Of these, 123 (39.2%) received TAVID implantation using MS and 191 patients (60.8%) received TAVID using CS. Perioperative outcomes and complications were compared between both groups. RESULTS: Baseline characteristics, including body mass index, American Society of Anesthesiologists score, cardiovascular disease, diabetes mellitus, and hyperlipidemia, were not significantly different between the groups. Postoperative complications occurred in 25 patients (8.0%), and the rate and incidence of venous thrombosis were significantly higher in the CS group. There were no significant differences between the groups in other complications such as the rate of port site infection, deep vein thrombosis, obstruction, catheter dislocation, and skin complications (exposure). No incidence of catheter infection, port rotation, intraoperative bleeding, or pneumothorax was observed in this cohort. CONCLUSIONS: MS is a safe and feasible procedure and results in less thrombosis. MS may play an important role in improving outcomes for the implantation of TAVID.

Data on the transcriptional regulation of DNA damage induced apoptosis suppressor (DDIAS) by ERK5/MEF2B pathway in lung cancer cells.

The data included in this article are associated with the article entitled "DNA-damage-induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes ß-catenin-mediated invasion" (J.Y. Im, S.H. Yoon, B.K. Kim, H.S. Ban, K.J. Won, K.S. Chung, K.E. Jung, M. Won) [1]. Quantitative RT-PCR data revealed that genetic or pharmacological inhibition of extracellular signal-regulated kinase 5 (ERK5) suppresses DDIAS transcription in response to epidermal growth factor (EGF) in Hela cells. p300 did not interact with myocyte enhancer factor 2B (MEF2B), a downstream target of ERK5 and affect transcription of DDIAS. Moreover, DDIAS transcription is activated by ERK5/MEF2B signaling on EGF exposure in the non-small cell lung cancer cells (NSCLC) NCI-H1703 and NCI-H1299. DDIAS knockdown suppresses lung cancer cell invasion by decreasing ß-catenin protein level on EGF exposure.

DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes ß-catenin-mediated invasion.

DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates ß-catenin signaling in HeLa cells. The genetic or pharmacological inhibition of ERK5 suppressed DDIAS induction following EGF exposure and the overexpression of constitutively active MEK5 (CA-MEK5) enhanced DDIAS expression. In chromatin immunoprecipitation assays, MEF2B, a downstream target of ERK5, exhibited sequence-specific binding to a MEF2 binding site in the DDIAS promoter following treatment with EGF. The overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas the knockdown of MEF2B impaired this effect. Furthermore, DDIAS promoted invasion by increasing ß-catenin expression at the post-translational level in response to EGF, suggesting that DDIAS plays a crucial role in the metastasis of cancer cells by regulating ß-catenin expression. It is unlikely that MEF2B and NFATc1 cooperatively regulate DDIAS transcription in response to EGF. Collectively, EGF activates the ERK5/MEF2 pathway, which in turn induces DDIAS expression to promote cancer cell invasion by activating ß-catenin target genes.

DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.

In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer-specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells.

NFATc1 regulates the transcription of DNA damage-induced apoptosis suppressor.

DNA damage induced apoptosis suppressor (DDIAS), or human Noxin (hNoxin), is strongly expressed in lung cancers. DDIAS knockdown induced apoptosis in non-small cell lung carcinoma A549 cells in response to DNA damage, indicating DDIAS as a potential therapeutic target in lung cancer. To understand the transcriptional regulation of DDIAS, we determined the transcription start site, promoter region, and transcription factor. We found that DDIAS transcription begins at nucleotide 212 upstream of the DDIAS translation start site. We cloned the DDIAS promoter region and identified NFAT2 as a major transcription factor (Im et al., 2016 [1]). We demonstrated that NFATc1 regulates DDIAS expression in both pancreatic cancer Panc-1 cells and lung cancer cells.

An objective index to estimate the survival rate of primary blast lung injury.

To supply proper treatments to the primary blast lung injury (PBLI) patients, it is important to estimate the severity of the primary blast lung injury in accordance with the blast conditions. In this study, a blast-induced mechanical parameter (first principal stress) of lung was calculated using a finite element thorax model and the correlation between the survival rate of the subjects with blast-induced lung damage and an objective index that was related to the first principal stress of the lung model. This study propose the objective index for the estimation of the degree of PBLI. The results have a potential clinical application to improve the efficacy of treatment for blast injury patients.