Development of Drug Efficacy Testing Platform for Glomerulonephritis.

We developed a 3D glomeruli tissue chip for glomerulonephritis (GN) testing, featuring a gravity-driven glomerular filtration barrier (GFB) with human podocytes and endothelial cells with a bidirectional flow in the bottom channel. Using puromycin-induced GN, we observed decreased cell viability, increased albumin permeability, and reduced WT1 and nephrin compared to the normal GFB. Tacrolimus restored cell viability, reduced albumin permeability, and increased WT1 expression. Using serum from five membranous nephropathy (MN) patients, we created MN models using a GFB-mimicking chip. A notable decline in cell viability was observed in the serum-induced MN1 and MN2 models. However, tacrolimus restored it. Albumin permeability was reduced in the MN1, MN2, and MN5 models by tacrolimus treatment. MN1 displayed the best clinical response to tacrolimus, exhibiting increased expression of WT1 in chip-based evaluations after tacrolimus treatment. We successfully evaluated the efficacy of tacrolimus using puromycin-induced and serum-induced GN models on a chip that mimicked the structure and function of the GFB. The GFB-mimicking chip holds promise as a personalized platform for assessing drug efficacy using patient serum samples.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

Management of Immunosuppressive Therapy in Kidney Transplant Recipients with Sepsis: A Multicenter Retrospective Study.

BACKGROUND: Up to 6% of kidney transplant recipients (KTRs) experience life-threatening complications requiring intensive care unit (ICU) admission, and one of the most common medical complications requiring ICU admission is infection. This study aimed to evaluate the effect of immunosuppressive therapy (IST) modification on prognosis of KTRs with sepsis. METHODS: We conducted a multicenter retrospective study in 4 university-affiliated hospitals to evaluate the effect of adjusting the IST in KTRs with sepsis. Only patients who either maintained IST after ICU admission or those who underwent immediate (within 24 h of ICU admission) reduction or withdrawal of IST following ICU admission were included in this study. "Any reduction" was defined as a dosage reduction of any IST or discontinuation of at least 1 IST. "Complete withdrawal of IST" was defined as concomitant discontinuation of all ISTs, except steroids. RESULTS: During the study period, 1596 of the KTRs were admitted to the ICU, and 112 episodes of sepsis or septic shock were identified. The overall in-hospital mortality rate was 35.7%. In-hospital mortality was associated with higher sequential organ failure assessment score, simplified acute physiology score 3, non-identical human leukocyte antigen relation, presence of septic shock, and complete withdrawal of IST. After adjusting for potential confounding factors, complete withdrawal of IST remained significantly associated with in-hospital mortality (adjusted coefficient, 1.029; 95% confidence interval, 0.024-2.035) and graft failure (adjusted coefficient, 2.001; 95% confidence interval, 0.961-3.058). CONCLUSIONS: Complete IST withdrawal was common and associated with worse outcomes in critically ill KTRs with sepsis.

Comparison between Real-Time Ultrasound-guided Percutaneous Dilatational Tracheostomy and Surgical Tracheostomy in critically ill Patients: A Randomized Controlled Trial.

OBJECTIVES: Tracheostomy is an important procedure for critically ill patients in the intensive care unit (ICU), and percutaneous dilatational tracheostomy (PDT) has gained popularity due to its safety and effectiveness. However, there are limited data comparing ultrasound-guided PDT (US-PDT) with surgical tracheostomy (ST). In our previous study, we reported that US-PDT had similar safety and effectiveness to ST, with a shorter procedure time. However, the study design was retrospective, and the sample size was small. Therefore, we conducted a randomized controlled trial to demonstrate the safety and efficacy of US-PDT compared to ST. METHODS: A total of 70 patients who underwent either US-PDT (n=35) or ST (n=35) were enrolled in the study between October 20, 2020 and July 26, 2022. The patients were randomly assigned to their respective procedures. The data collected included patient clinical characteristics, procedure time and details, complications, duration of ICU stay, time taken for weaning from mechanical ventilation, and hospital mortality. RESULTS: The procedure time of US-PDT was shorter than that of ST (4.0±2.2 minutes vs. 10.1±4.6 minutes). The incision length of US-PDT was also shorter than that of ST (1.5±0.5 cm vs. 1.8±0.4 cm). There were no statistically significant differences in demographics, procedure details, complications, length of ICU stay, ventilator weaning time, and hospital mortality. CONCLUSION: US-PDT has a similar complication rate and shorter procedure time compared with ST. It can be safely and effectively performed in critically ill patients and can serve as a potential alternative to ST.

The Wnt/ß-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression.

Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/ß-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/ß-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/ß-catenin antagonist IWP-2 inhibited nuclear ß-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/ß-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor ß-cat/TCF to the Cyp2e1 promoter, thus exacerbating DILI. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00180-6.

Incidental Extramammary Findings on Preoperative Breast MRI in Breast Cancer Patients: A Pictorial Essay.

Breast cancer is one of the most common cancers and causes several complications in females. Currently, MRI is a necessary method for preoperative studies in patients with breast cancer. A high frequency of breast MRI can lead to an increase in the number of incidental extramammary findings. Moreover, it can provide accurate preoperative workup; therefore, the prognosis of patients can be improved. Herein, we provide several extramammary findings, including the mediastinum, lung, upper abdomen, bone, and soft tissue, correlating with US, chest CT, liver MRI, PET-CT, and bone scan.

Various congenital anomalies and anatomical variations of the spleen: a multimodality pictorial review.

There are various congenital anomalies and anatomical variations of the spleen (CAAVS). CAAVS are common and are often associated with systemic anomalies. Widespread use of computed tomography and magnetic resonance imaging in a variety of clinical situations has increased the detection of CAAVS. However, CAAVS are frequently overlooked and are occasionally misdiagnosed as pathologic disease entities. This article aimed to review the various manifestations of CAAVS with radiologic findings.

Distinguishing nontuberculous mycobacterial lung disease and Mycobacterium tuberculosis lung disease on X-ray images using deep transfer learning.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTM-LD) and Mycobacterium tuberculosis lung disease (MTB-LD) have similar clinical characteristics. Therefore, NTM-LD is sometimes incorrectly diagnosed with MTB-LD and treated incorrectly. To solve these difficulties, we aimed to distinguish the two diseases in chest X-ray images using deep learning technology, which has been used in various fields recently. METHODS: We retrospectively collected chest X-ray images from 3314 patients infected with Mycobacterium tuberculosis (MTB) or nontuberculosis mycobacterium (NTM). After selecting the data according to the diagnostic criteria, various experiments were conducted to create the optimal deep learning model. A performance comparison was performed with the radiologist. Additionally, the model performance was verified using newly collected MTB-LD and NTM-LD patient data. RESULTS: Among the implemented deep learning models, the ensemble model combining EfficientNet B4 and ResNet 50 performed the best in the test data. Also, the ensemble model outperformed the radiologist on all evaluation metrics. In addition, the accuracy of the ensemble model was 0.85 for MTB-LD and 0.78 for NTM-LD on an additional validation dataset consisting of newly collected patients. CONCLUSIONS: In previous studies, it was known that it was difficult to distinguish between MTB-LD and NTM-LD in chest X-ray images, but we have successfully distinguished the two diseases using deep learning methods. This study has the potential to aid clinical decisions if the two diseases need to be differentiated.

Gadoxetate disodium-enhanced MRI for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: late portal venous phase may improve identification of enhancing capsule.

PURPOSE: To investigate added value of late portal venous phase (LPVP) for identification of enhancing capsule (EC) on gadoxetate disodium-enhanced MRI (GD-MRI) for diagnosing hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD). METHODS: This retrospective study comprised 116 high-risk patients with 128 pathologically proven HCCs who underwent GD-MRI including arterial phase, conventional portal venous phase (CPVP, 60 s), LPVP (mean, 104.4 ± 6.7 s; range, 90-119 s), and transitional phase (TP, 3 min). Two independent radiologists assessed the presence of major HCC features, including EC on CPVP and/or TP (CPVP/TP) and EC on LPVP. The frequency of EC was compared on GD-MRI between with and without inclusion of LPVP. The radiologists assigned Liver Imaging Reporting and Data System (LI-RADS) v2018 categories before and after identifying EC on LPVP. RESULTS: Of the total 128 HCCs, 74 and 73 revealed EC on CPVP/TP for reviewer 1 and 2, respectively. After inclusion of LPVP, each reviewer identified seven more EC [Reviewer 1, 57.8% (74/128) vs. 63.3% (81/128); Reviewer 2, 57.0% (73/128) vs. 62.5% (80/128); P = 0.016, respectively]. Sensitivities of LR-5 assignment for diagnosing HCCs were not significantly different in GD-MRI with or without LPVP for EC identification [Reviewer 1, 71.9% (92/128) vs. 72.7% (93/128); Reviewer 2, 75.0% (96/128) vs. 75.8% (97/128); P = 1.000, respectively]. CONCLUSION: Including the LPVP in GD-MRI may improve identification of EC of HCC in patients with CLD. However, LI-RADS v2018 using GD-MRI showed comparable sensitivity for diagnosing HCC regardless of applying LPVP for EC.

Cellular signaling crosstalk between Wnt signaling and gap junctions inbenzo[a]pyrene toxicity.

Gap junctional intercellular communication (GJIC) is considered a key biological mechanism to maintain homeostasis in cell differentiation and growth. In addition, as another major signaling pathway associated with cell proliferation and differentiation, Wnt/ß-catenin signaling appears to trigger several cellular responses against injury. The purpose of the present study was to investigate the effects of a known toxic agent, benzo[a]pyrene (BaP), on the regulation and interaction between GJIC and Wnt/ß-catenin signaling. BaP treatment resulted in GJIC inhibition and decreases the major GJIC protein connexin 43 (Cx43) in WB-F344 rat liver epithelial cells. We also found BaP-mediated downregulation of Wnt/ß-catenin signaling related to the PI3K-Akt pathway. To identify the relationship between GJIC and Wnt/ß-catenin signaling, we treated WB-F344 cells with the Wnt agonist CHIR99021 and found that it inhibited GJIC while causing a significant reduction in Cx43 expression at both the mRNA and protein levels, through the repression of promoter activity. This Wnt agonist-mediated GJIC inhibition was confirmed using a small interfering RNA directed against the Wnt antagonist Dact2, indicating that Wnt/ß-catenin signaling negatively regulates GJIC. Despite the inverse correlation between Wnt/ß-catenin signaling and Cx43 promoter activation as indicated by downregulation of ß-catenin nuclear translocation and upregulation of Cx43 promoter activation involving HNF3ß, BaP treatment decreased the Cx43 protein expression, which was associated with protein degradation, possibly through protein kinase C activation. In conclusion, our results revealed the mechanism of BaP-induced inhibition of GJIC and Wnt/ß-catenin signaling. More importantly, linking Wnt/ß-catenin signaling to Cx protein expression will have profound implications in understanding the relationships among different major signaling pathways associated with cell proliferation and differentiation in toxicity.

Chlorpromazine as Treatment for Refractory Agitation Associated with Pediatric Delirium.

OBJECTIVE: Delirium and agitation can be devastating and prolong the length of hospitalization. As part of our continuous improvement efforts, we implemented the use of intermittent chlorpromazine therapy to target refractory agitation associated with hyperactive or mixed delirium (RAA-D). The purpose of this study was to evaluate the effectiveness of chlorpromazine on RAA-D and delirium symptoms as well as any adverse effects in critically ill children. METHODS: Retrospective chart review was conducted for children admitted to the pediatric intensive care unit who were treated with chlorpromazine for RAA-D from March 2017 to January 2019. The primary end point was to determine differences in Cornell Assessment for Pediatric Delirium (CAPD) and State Behavioral Scale (SBS) scores 24 hours before and after chlorpromazine administration. The secondary end points were the 24-hour cumulative dosing of narcotic and sedative agents before and after chlorpromazine administration and adverse events associated with chlorpromazine use. RESULTS: Twenty-six patients were treated with chlorpromazine for RAA-D; 16 (61.5%) were male with a median age of 14.5 months (IQR, 6-48). The mean CAPD (n = 24) and median SBS (n = 23) scores were significantly lower 24 hours after chlorpromazine use when compared to baseline scores, 12 vs 8.9 (p = 0.0021) and 1 vs -1, (p = 0.0005) respectively. No significant adverse effects were observed. CONCLUSIONS: Chlorpromazine use in critically ill children with RAA-D was helpful for managing symptoms without adverse events. Further investigation is needed to evaluate the use of chlorpromazine to treat RAA-D to avoid long-term use of an antipsychotic.

MRI Findings Suggestive of Metastatic Axillary Lymph Nodes in Patients with Invasive Breast Cancer.

Purpose: This study aimed to investigate the diagnostic performance of features suggestive of nodal metastasis on preoperative MRI in patients with invasive breast cancer. Materials and Methods: We retrospectively reviewed the preoperative breast MRI of 192 consecutive patients with surgically proven invasive breast cancer. We analyzed MRI findings of axillary lymph nodes with regard to the size, long/short ratio, cortical thickness, shape and margin of the cortex, loss of hilum, asymmetry, signal intensity (SI) on T2-weighted images (T2WI), degree of enhancement in the early phase, and enhancement kinetics. Receiver operating characteristic (ROC) analysis, chi-square test, t test, and McNemar's test were used for statistical analysis. Results: Increased shorter diameter, uneven cortical shape, increased cortical thickness, loss of hilum, asymmetry, irregular cortical margin, and low SI on T2WI were significantly suggestive of metastasis. ROC analysis revealed the cutoff value for the shorter diameter and cortical thickness as 8.05 mm and 2.75 mm, respectively. Increased cortical thickness (> 2.75 mm) and uneven cortical shape showed significantly higher sensitivity than other findings in McNemar's test. Irregular cortical margins showed the highest specificity (100%). Conclusion: Cortical thickness > 2.75 mm and uneven cortical shape are more sensitive parameters than other findings, and an irregular cortical margin is the most specific parameter for predicting axillary metastasis in patients with invasive breast cancer.

Cerebellar Gray Matter Volume and its Role in Executive Function, and Attention: Sex Differences by Age in Adolescents.

Objective: This research measures the regional GMV (rGMV) of the cerebellum, attention, Executive Function (EF) and we aimed to identify their correlation and sex differences in children and adolescents. Methods: Subjects comprised 114 children (male = 62, female = 52, 12.44 ± 2.99 years old) from South Korea. Participants were divided into three groups by age (age 6-9, 10-13, and 14-17). The Stroop Color and Word Test (SCWT), Wisconsin Card Sorting Test (WCST), and Advanced Test of Attention (ATA) were used to estimate executive function. Magnetic resonance imaging (MRI) images were analyzed with Regional Voxel-Based Morphometry Analysis. Results: The correlations between cerebellar rGMV and SCWT, WCST, and ATA subcategories showed difference by age and sex. In 6-9 age group, girls showed more overall correlations with cerebellar regions than boys, in WCST Categories Completed and ATA results. In age 10-13 group, more regions of cerebellum corresponded to SCWT subcategories in girls. Nevertheless, more correlation between cerebellar rGMV, WCST subcategories and some ATA subtests were observed in boys in the same age group. In the adolescent group, aged 14-17, boys showed more correlation with cerebellar rGMV, while girls showed little correlation. Conclusion: This study highlights that sex-different cerebellum maturation in adolescence might be correlated with EF and attention. These results provides evidence that cerebellum modulates higher cognitive functioning during child development.

Comparison Between Real-Time Ultrasound-Guided Percutaneous Tracheostomy and Surgical Tracheostomy in Critically Ill Patients.

Background: Ultrasound-guided percutaneous dilatational tracheostomy (US-PDT) has been adapted for use in intensive care units (ICU). US-PDT is comparable to bronchoscopy-assisted tracheostomy. However, compared to surgical tracheostomy (ST), its safety and effectiveness have not been well studied. Objectives: To determine the efficacy and safety of US-PDT compared to ST. Materials and Methods: A total of 90 patients who underwent US-PDT (n = 36) or ST (n = 54) between July 2019 and September 2020 were enrolled. US-PDT was performed in the ICU without a surgical assistant or bronchoscope. Data were collected retrospectively and analyzed regarding clinical characteristics, procedure times and details, complications, and mortality rate. Results: The success rate of US-PDT was 97.4% and the procedure time was shorter than ST (5.2 ± 3.1 vs. 10.5 ± 5.0 min). There were no significant differences in clinical characteristics and procedure details. There was no procedure-related mortality in either of the groups. Conclusions: US-PDT is time-efficient and as safe as ST. Based on our results, US-PDT may be considered a potential alternative to ST in high-risk patients and in those who cannot be transported.

Efficacy of steroid treatment for sudden sensorineural hearing loss in patients with vestibular schwannoma.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) has several aetiologies and may be a presenting symptom of vestibular schwannoma (VS). OBJECTIVES: The aim of this study was to investigate the recovery rate after steroid treatment and the prognostic factors of SSNHL with VS. MATERIALS AND METHODS: This was a retrospective observational study wherein 32 patients with VS who presented with SSNHL were analysed at a tertiary referral centre. Hearing gain and prognostic factors were the main outcome measures for steroid treatment intervention. RESULTS: Among the 1698 patients presenting with SSNHL, VS was found in 43 (2.5%) patients. Eleven cases (34.3%) showed good recovery, with significant improvements in the pure-tone audiometry values. Even though age was a significant factor, there were no associations between steroid response and initial hearing level, presence of vertigo, tumour size, and tumour extension. CONCLUSIONS AND SIGNIFICANCE: Our study showed that hearing recovery of SSNHL does not exclude a VS diagnosis. We suggest that steroid treatment be considered in patients with VS presenting SSNHL.

Risk factors and clinical impact of COVID-19-associated pulmonary aspergillosis: Multicenter retrospective cohort study.

BACKGROUND/AIMS: The risk factors and clinical impacts of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remain controversial, and no data have been reported in Korea. This study aimed to investigate the epidemiology and importance of CAPA diagnostic efforts and to identify the predictors of CAPA and the impacts on clinical outcomes. METHODS: Between January 2020 and May 2021, data of severely to critically ill COVID-19 patients were extracted from seven hospitals of the Catholic Medical Center through a clinical data warehouse. Corticosteroid use was subcategorized into total cumulative dose, early 7-day dose, mean daily dose, and duration of use. RESULTS: A total of 2,427 patients were screened, and 218 patients were included. CAPA was diagnosed in 4.6% (10/218) of all hospitalized and 11.2% (10/89) of intensive care unit patients. Total cumulative dose (over 1,000 mg as methylprednisolone) and daily high-dose corticosteroid use (over 60 mg/day) were independent predictors but not early 7-day high-dose corticosteroid use (over 420 mg/week) (odds ratio [OR], 1.731; 95% confidence interval [CI], 0.350 to 8.571) nor prolonged use (OR, 2.794; 95% CI, 0.635 to 13.928). In-hospital overall mortality was 11.9% (26 of 218). CAPA itself did not affect the outcome; rather, daily high-dose steroid use significantly increased the 30-day mortality (hazard ratio, 5.645; 95% CI, 1.225 to 26.091). CONCLUSION: CAPA was not uncommon, especially in critically ill patients. Daily high-dose corticosteroid use was the predictor of CAPA and associated with high mortality rates. High-dose corticosteroids use after early inflammatory phase should be avoided, and active surveillance methods for CAPA are essential for those high-risk patients.

Association of weight change following smoking cessation with the risk of tuberculosis development: A nationwide population-based cohort study.

BACKGROUND: Smoking or weight loss is a risk of tuberculosis (TB) development. However, the impact of weight change after smoking cessation on the occurrence of TB remains elusive. We aimed to determine the relationship between weight change after smoking cessation and the risk of TB development. METHODS: We conducted a population-based cohort study using the national database in Republic of Korea. Of the 10,490,491 subjects who underwent health check-up in 2009, we enrolled 9,953,124 subjects without a previous TB history and followed them until 2017. We divided all study participants into the following three groups: never, former, and current smokers. The primary endpoint was newly developed TB. RESULTS: Among 9,953,124 subjects analyzed, 5,922,845 (59.5%) were never smokers, 1,428,209 (14.4%) were former smokers, and 2,602,080 (26.1%) were current smokers. The risk of TB development was significantly higher in current smokers than in never smokers (adjusted hazard ratio (aHR) 1.158; 95% confidence interval [CI] 1.131-1.186). Among current smokers, individuals who stopped smoking and maintained weight after baseline evaluation had a significantly lower risk of TB development compared with those who continued to smoke (aHR 0.771; 95% CI 0.741-0.892). However, even after smoking cessation, individuals who lost weight were at a significantly higher risk of TB development compared with those who continued to smoke (aHR 1.327; 95% CI 1.119-1.715). CONCLUSIONS: Our findings suggest that smoking is a risk factor for TB and weight maintenance (neither gaining or losing) after quitting smoking might reduce the risk of TB development.

Impaired Lung Function and Lung Cancer Incidence: A Nationwide Population-Based Cohort Study.

BACKGROUND: It is unclear whether the presence of minimal lung function impairment is an independent risk factor for the development of lung cancer in general populations. METHODS: We conducted a population-based cohort study using nationally representative data from the Korean National Health and Nutrition Examination Survey and the Korean National Health Insurance Service. RESULTS: Of 20,553 participants, 169 were diagnosed with lung cancer during follow-up (median, 6.5 years). Participants with obstructive lung function impairment had increased risk of lung cancer (aHR: 2.51; 95% CI: 1.729-3.629) compared with those with normal lung function. The lower was the quartile or decile of forced expiratory volume in one second (FEV1) or the FEV1/forced vital capacity (FVC) ratio, the significantly higher was the incidence rate of lung cancer (p for trend < 0.0001). With FEV1 values in the lowest quartile (Q4), the incidence of lung cancer was significantly increased regardless of FVC (FEV1 Q4 and FVC values in the higher three quartiles Q1-3: aHR 1.754; 95% CI 1.084-2.847, FEV1 Q4 and FVC Q4: aHR 1.889; 95% CI 1.331-2.681). CONCLUSION: Our findings suggest that minimal lung function impairment, as expressed by lower FEV1 or FEV1/FVC value, may be associated with increased risk of lung cancer.

Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo.

Oxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague-Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects, which may be attributed to the inactivation of the NF-κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti-inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.

Egr1 Gene Expression as a Potential Biomarker for In Vitro Prediction of Ocular Toxicity.

Animal models are used for preclinical toxicity studies, and the need for in vitro alternative methods has been strongly raised. Our study aims to elucidate the potential mechanism of change in EGR1 expression under situations of toxic injury and to develop an Egr1 promoter-luciferase gene reporter assay for an in vitro alternative method for toxicity prediction in drug discovery. We first found an increase in early growth response-1 (EGR1) mRNA/protein expressions in the liver and kidney of cisplatin-treated injured rats. Additionally, the EGR1 protein level was also elevated under situations of ocular injury after sodium lauryl sulfate (SLS) eye drops. These in vivo observations on injury-related EGR1 induction were confirmed by in vitro studies, where human corneal epithelial cells were treated with representative irritants (SLS and benzalkonium chloride) and 17 chemicals having different UN GHS irritant categories. Additionally, our results suggest the involvement of ERK, JNK, p38 MAPK pathways in EGR1 elevation in response to gamma-butyrolactone-induced injury. As EGR1 is considered to be a pivotal factor in proliferation and regeneration, siRNA-mediated knockdown of Egr1 promoted cytotoxic potential through a delay of injury-related recovery. More importantly, the elevation of promoter activities was observed by various irritants in cells transfected with Egr1 promoter-reporter vector. In conclusion, Egr1 can be a potential biomarker in a promoter-reporter system to improve the accuracy of in vitro predictions for ocular irritation.