Clonal Hematopoiesis of Indeterminate Potential Is Associated with Current Smoking Status and History of Exacerbation in Patients with Chronic Obstructive Pulmonary Disease / 결핵및호흡기질환

Background@#There is limited data regarding the clinical outcomes of clonal hematopoiesis of indeterminate potential (CHIP) in patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the clinical significance of CHIP as a COPD biomarker. @*Methods@#This retrospective study was conducted on patients with COPD who were enrolled prospectively in the Seoul National University Hospital Airway Registry from January 2013 to December 2019 and underwent pulmonary function and blood tests. We evaluated the CHIP score according to smoking status and severity of airflow obstruction. @*Results@#We analyzed next-generation sequencing data to detect CHIP in 125 patients with COPD. Current smokers had a higher prevalence of CHIP in combination of DNMT3A, TET2, and PPM1D (DTP), DNA methyltransferase 3 alpha (DNMT3A), and protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) genes than in never- or ex-smokers. CHIP of DTP and DNMT3A genes was significantly associated with current smokers (adjusted odds ratio [aOR], 2.80; 95% confidence interval [CI], 1.01 to 7.79) (aOR, 4.03; 95% CI, 1.09 to 14.0). Patients with moderate-to-severe airflow obstruction had a higher prevalence of CHIP in most of the explored genes than those with mild obstruction, although the difference was not statistically significant. CHIP in ASXL transcriptional regulator 1 (ASXL1) genes was significantly associated with history of mild, severe, and total acute exacerbation. @*Conclusion@#Given that CHIP in specific genes was significantly associated with current smoking status and acute exacerbation, CHIP can be considered as a candidate biomarker for COPD patients.

Geriatric risk model for older patients with diffuse large B-cell lymphoma (GERIAD): a prospective multicenter cohort study

Background/Aims@#Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). @*Methods@#This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson’s Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). @*Results@#The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30–3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. @*Conclusions@#This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.

LKB1/STK11 Tumor Suppressor Reduces Angiogenesis by Directly Interacting with VEGFR2 in Tumorigenesis

Cervical tumors represent a prevalent form of cancer affecting women worldwide; current treatment options involve surgery, radiotherapy, and chemotherapy. Angiogenesis, the process of new blood vessel formation, is a crucial factor in cervical tumor growth. The molecular mechanisms underlying the effects of the liver kinase B1 (LKB1/STK11) tumor suppressor protein on tumor angiogenesis have not been elucidated. Therefore, we investigated the role of LKB1 in cervical tumor angiogenesis both in vitro and in vivo in this study. Our results demonstrated that LKB1 inhibited cervical tumor angiogenesis by suppressing the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α. LKB1 directly affected both carcinoma and vascular endothelial cells, resulting in a significant reduction in tumor growth and angiogenesis. Furthermore, LKB1 was found to bind to VEGF receptor 2 (VEGFR-2) and target the VEGFR-2-mediated protein kinase B/ mechanistic target of rapamycin signaling pathway in endothelial cells, thereby reducing cervical tumor growth and angiogenesis.Our study provides new insights into the molecular mechanisms underlying the anti-tumor and anti-angiogenic effects of LKB1 in cervical cancer. These findings will help develop new therapeutic strategies for cervical cancer.

Liver Kinase B1 Mediates Its Anti-Tumor Function by Binding to the N-Terminus of Malic Enzyme 3

Liver kinase B1 (LKB1) is a crucial tumor suppressor involved in various cellular processes, including embryonic development, tumor initiation and progression, cell adhesion, apoptosis, and metabolism. However, the precise mechanisms underlying its functions remain elusive. In this study, we demonstrate that LKB1 interacts directly with malic enzyme 3 (ME3) through the N-terminus of the enzyme and identified the binding regions necessary for this interaction. The binding activity was confirmed to promote the expression of ME3 in an LKB1-dependent manner and was also shown to induce apoptosis activity. Furthermore, LKB1 and ME3 overexpression upregulated the expression of tumour suppressor proteins (p53 and p21) and downregulated the expression of antiapoptotic proteins (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and B-cell lymphoma 2 (Bcl-2)). Additionally, LKB1 and ME3 enhanced the transcription of p21 and p53 and inhibited the transcription of NF-κB. Moreover, LKB1 and ME3 suppressed the phosphorylation of various components of the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B signaling pathway. Overall, these results suggest that LKB1 promotes pro-apoptotic activities by inducing ME3 expression.

Latanoprostene Bunod 0.024% w/v Treatment of Open-anlge Glaucoma: Short-term Effects, Safety, and Changes in Ocular Blood

Purpose@#To study the short-term intraocular pressure (IOP)-lowering effect and optic nerve head (ONH) blood flow improvement after switching from latanoprost 0.005% w/v to latanoprostene bunod 0.024% w/v. @*Methods@#This prospective study ran from May 2022 to December 2022 and included 40 patients with open-angle glaucoma who switched from latanoprost 0.005% w/v to latanoprostene bunod 0.024% w/v. The IOP, ONH blood flow, and conjunctival hyperemia, corneal erosion, and eyelid pigmentation status were measured 3 months after switching. We recorded all possible side effects. @*Results@#The baseline IOP significantly dropped from 17.53 ± 6.49 to 16.00 ± 8.06 mmHg at 3 months (p = 0.032). The best-corrected visual acuity did not significantly change (0.24 ± 0.19 to 0.23 ± 0.16); neither did eyelid pigmentation (1.16 ± 0.78 to 1.16 ± 0.82) nor the corneal erosion score (0.58 ± 0.85 to 0.39 ± 0.76). Conjunctival hyperemia significantly decreased from 2.00 ± 0.69 to 1.67 ± 0.63 (p = 0.010). Neither the whole-image vessel density nor the peripapillary vessel density significantly changed. However, pruritus became significantly worse after the change (p = 0.008). @*Conclusions@#In the short term, latanoprostene bunod 0.024% w/v lowered the IOP more effectively than did latanoprost 0.005% w/v. However, there was no significant change in ONH blood flow after the switch.

Machine Learning-Based Proteomics Reveals Ferroptosis in COPD PatientDerived Airway Epithelial Cells Upon Smoking Exposure

Background@#Proteomics and genomics studies have contributed to understanding the pathogenesis of chronic obstructive pulmonary disease (COPD), but previous studies have limitations. Here, using a machine learning (ML) algorithm, we attempted to identify pathways in cultured bronchial epithelial cells of COPD patients that were significantly affected when the cells were exposed to a cigarette smoke extract (CSE). @*Methods@#Small airway epithelial cells were collected from patients with COPD and those without COPD who underwent bronchoscopy. After expansion through primary cell culture, the cells were treated with or without CSEs, and the proteomics of the cells were analyzed by mass spectrometry. ML-based feature selection was used to determine the most distinctive patterns in the proteomes of COPD and non-COPD cells after exposure to smoke extract.Publicly available single-cell RNA sequencing data from patients with COPD (GSE136831) were used to analyze and validate our findings. @*Results@#Five patients with COPD and five without COPD were enrolled, and 7,953 proteins were detected. Ferroptosis was enriched in both COPD and non-COPD epithelial cells after their exposure to smoke extract. However, the ML-based analysis identified ferroptosis as the most dramatically different response between COPD and non-COPD epithelial cells, adjusted P value = 4.172 × 10−6 , showing that epithelial cells from COPD patients are particularly vulnerable to the effects of smoke. Single-cell RNA sequencing data showed that in cells from COPD patients, ferroptosis is enriched in basal, goblet, and club cells in COPD but not in other cell types. @*Conclusion@#Our ML-based feature selection from proteomic data reveals ferroptosis to be the most distinctive feature of cultured COPD epithelial cells compared to non-COPD epithelial cells upon exposure to smoke extract.

The serotype-specific prevalence of pneumococci in hospitalized pneumonia patients with COPD: a prospective, multi-center, cohort study

Background/Aims@#The overall incidence of pneumococcal pneumonia is declining. However, the change in the pathogenic distribution of community-acquired pneumonia (CAP) in chronic obstructive pulmonary disease (COPD) patients and the serotype specificity of Streptococcus pneumoniae have not been evaluated in the post-era of pneumococcal vaccination in Korea. @*Methods@#We conducted a prospective, multi-center, cohort study from seven University-affiliated hospitals. The primary objective was the identification of serotype-specific prevalence of pneumococcal pneumonia in COPD patients hospitalized for CAP. For the purpose, we conducted serotype-specific urine antigen detection (SS-UAD) assays for S. pneumoniae. The secondary objectives were other clinical characteristics of pneumonia including vaccination status. @*Results@#The total number of participants was 349. Most of them were male (95.1%) with old ages (75.55 ± 8.59 y). The positive rate for S. pneumoniae was 9.2% with SS-UAD assay and the common serotypes were 22F, 6A, and 6B. In the sputum, Pseudomonas aeruginosa (5.0%) and Haemophilus influenzae (4.0%) were common pathogens. The vaccination rate was 78.8%, 53.0%, and 25.8% for influenza, pneumococcal polysaccharide vaccine 23 (PPV 23), and pneumococcal protein- conjugated vaccine 13 (PCV 13), respectively. Thirteen patients died during hospitalization (mortality rate; 3.7%). There was no difference in the respective rate of influenza vaccination (79.2% vs. 69.2%, p = 0.288) and PCV 13 vaccination (25.6% vs. 30.8%, p = 0.443) between survivors and the deceased. @*Conclusions@#Serotypes 22F, 6A, and 6B, which are covered either by PPV 23 or by PCV 13, are still common pneumococcal serotypes in COPD pneumonia in the post-vaccination era in Korea.

Snail Promotes Cancer Cell Proliferation via Its Interaction with the BIRC3

Snail is implicated in tumour growth and metastasis and is up-regulated in various human tumours. Although the role of Snails in epithelial-mesenchymal transition, which is particularly important in cancer metastasis, is well known, how they regulate tumour growth is poorly described. In this study, the possible molecular mechanisms of Snail in tumour growth were explored. Baculoviral inhibitor of apoptosis protein (IAP) repeat-containing protein 3 (BIRC3), a co-activator of cell proliferation during tumourigenesis, was identified as a Snail-binding protein via a yeast two-hybrid system. Since BIRC3 is important for cell survival, the effect of BIRC3 binding partner Snail on cell survival was investigated in ovarian cancer cell lines. Results revealed that Bax expression was activated, while the expression levels of anti-apoptotic proteins were markedly decreased by small interfering RNA (siRNA) specific for Snail (siSnail). siSnail, the binding partner of siBIRC3, activated the tumour suppressor function of p53 by promoting p53 protein stability. Conversely, BIRC3 could interact with Snail, for this reason, the possibility of BIRC3 involvement in EMT was investigated. BIRC3 overexpression resulted in a decreased expression of the epithelial marker and an increased expression of the mesenchymal markers. siSnail or siBIRC3 reduced the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. These results provide evidence that Snail promotes cell proliferation by interacting with BIRC3 and that BIRC3 might be involved in EMT via binding to Snail in ovarian cancer cells. Therefore, our results suggested the novel relevance of BIRC3, the binding partner of Snail, in ovarian cancer development.

Effect of Mask Mandates on the Intraocular Pressure Measured via Goldmann Applanation Tonometry

Purpose@#The corona virus disease-19 (COVID-19) pandemic has resulted in mandatory masking of patients and physicians during outpatient visits. This study evaluated the changes in intraocular pressure (IOP) according to mask use. @*Methods@#This prospective study enrolled 30 healthy volunteers (60 eyes). IOP was measured via Goldmann applanation tonometry (GAT) for the subjects wearing one of four commonly used masks: dental, bi-folding Korean Filter (KF)94, tri-folding KF94, and dust masks. Subjects with IOP measurement errors of more than 5 mmHg were rechecked with another GAT type. @*Results@#The mean IOP measured via GAT before mask wearing was 13.7 ± 1.7 mmHg. It was 13.5 ± 2.1, 14.0 ± 2.3, 14.3 ± 2.5, and 13.8 ± 1.6 mmHg with the dental, bi-folding KF94, tri-folding KF94, and dust masks, respectively. There were no significant differences in IOP according to mask type (p = 0.635). IOP errors above 5 mmHg were detected in three subjects who had contact between the GAT feeler arm and tri-folding KF94 mask during IOP measurement. @*Conclusions@#The IOP as measured via GAT is artificially elevated by mechanical interference from the tri-fold KF94 mask. To minimize such mask-induced artifacts in GAT measurements, compress the patient’s mask or change the mask type to prevent any contact during measurement.

The Association Between Bacille Calmette-Guérin Vaccination and Nontuberculous Mycobacterial Pulmonary Disease

This study aimed to investigate the association between Bacille Calmette-Guérin (BCG) vaccination and nontuberculous mycobacterial pulmonary disease (NTM-PD). Patients in the prospective NTM-PD cohort were matched to healthy controls to measure the association between BCG and NTM-PD development. The clinical course of NTM-PD patients was also evaluated to investigate the association between BCG and NTM-PD progression. BCG scars were not associated with NTM-PD development (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 0.96–4.34) or progression (adjusted OR, 1.61; 95% CI, 0.92–2.81).In conclusion, BCG vaccination was not associated with the development or progression of NTM-PD.

Prevalence and impact of airway diseases on clinical outcomes in idiopathic pulmonary fibrosis

Background/Aims@#The prevalence and effects of airway diseases, including asthma, eosinophilic bronchitis (EB), chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) have not been thoroughly studied in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the prevalence of airway diseases in patients with IPF and to identify the differences in symptoms based on the presence of airway diseases. @*Methods@#This single-institution prospective cohort study was conducted from June 2017 to September 2018, at the Seoul National University Hospital. Spirometry with bronchodilator, methacholine bronchial provocation test, induced sputum with eosinophil stain, and exhaled nitric oxide were performed to confirm the presence of airway disease. The modified Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT), St. George’s Respiratory Questionnaire (SGRQ), EuroQol-5 dimension (EQ-5D) index, and cough-specific quality of life questionnaire (CQLQ) data were collected to assess symptom severity. @*Results@#Total 147 patients with IPF were screened, and 70 patients were analyzed. The prevalence of airway diseases in the participants was as follows: 5.0% had COPD, 1.7% had asthma, 3.3% had ACO, and 1.7% had EB. The mMRC, CAT, SGRQ, EQ-5D, and CQLQ scores did not differ regardless of combined airway disease. After 3 months, the SGRQ (p = 0.028) and CQLQ (p = 0.030) scores were significantly higher in patients with airway disease than in those without. @*Conclusions@#The prevalence of airway diseases in patients with IPF is low, but when airway diseases are accompanied by IPF, symptom severity and quality of life may worsen rapidly.

PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase

Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.

Loss of EMP2 Inhibits Melanogenesis of MNT1 Melanoma Cells via Regulation of TRP-2

Melanogenesis is the production of melanin from tyrosine by a series of enzyme-catalyzed reactions, in which tyrosinase and DOPA oxidase play key roles. The melanin content in the skin determines skin pigmentation. Abnormalities in skin pigmentation lead to various skin pigmentation disorders. Recent research has shown that the expression of EMP2 is much lower in melanoma than in normal melanocytes, but its role in melanogenesis has not yet been elucidated. Therefore, we investigated the role of EMP2 in the melanogenesis of MNT1 human melanoma cells. We examined TRP-1, TRP-2, and TYR expression levels during melanogenesis in MNT1 melanoma cells by gene silencing of EMP2. Western blot and RT-PCR results confirmed that the expression levels of TYR and TRP-2 were decreased when EMP2 expression was knocked down by EMP2 siRNA in MNT1 cells, and these changes were reversed when EMP2 was overexpressed. We verified the EMP2 gene was knocked out of the cell line (EMP2 CRISPR/Cas9) by using a CRISPR/Cas9 system and found that the expression levels of TRP-2 and TYR were significantly lower in the EMP2 CRISPR/Cas9 cell lines. Loss of EMP2 also reduced migration and invasion of MNT1 melanoma cells. In addition, the melanosome transfer from the melanocytes to keratinocytes in the EMP2 KO cells cocultured with keratinocytes was reduced compared to the cells in the control coculture group. In conclusion, these results suggest that EMP2 is involved in melanogenesis via the regulation of TRP-2 expression.

A Multicenter Study to Identify the Respiratory Pathogens Associated with Exacerbation of Chronic Obstructive Pulmonary Disease in Korea / 결핵및호흡기질환

Background@#Although respiratory tract infection is one of the most important factors triggering acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), limited data are available to suggest an epidemiologic pattern of microbiology in South Korea. @*Methods@#A multicenter observational study was conducted between January 2015 and December 2018 across 28 hospitals in South Korea. Adult patients with moderate-to-severe acute exacerbations of COPD were eligible to participate in the present study. The participants underwent all conventional tests to identify etiology of microbial pathogenesis. The primary outcome was the percentage of different microbiological pathogens causing AE-COPD. A comparative microbiological analysis of the patients with overlapping asthma–COPD (ACO) and pure COPD was performed. @*Results@#We included 1,186 patients with AE-COPD. Patients with pure COPD constituted 87.9% and those with ACO accounted for 12.1%. Nearly half of the patients used an inhaled corticosteroid-containing regimen and one-fifth used systemic corticosteroids. Respiratory pathogens were found in 55.3% of all such patients. Bacteria and viruses were detected in 33% and 33.2%, respectively. Bacterial and viral coinfections were found in 10.9%. The most frequently detected bacteria were Pseudomonas aeruginosa (9.8%), and the most frequently detected virus was influenza A (10.4%). Multiple bacterial infections were more likely to appear in ACO than in pure COPD (8.3% vs. 3.6%, p=0.016). @*Conclusion@#Distinct microbiological patterns were identified in patients with moderate-to-severe AE-COPD in South Korea. These findings may improve evidence-based management of patients with AE-COPD and represent the basis for further studies investigating infectious pathogens in patients with COPD.

The Impact of Tinnitus on Fibromyalgia

Objective@#. Fibromyalgia (FM) is a disorder characterized by chronic diffuse pain and enhanced pain response to stimuli and is caused by central sensitization. Tinnitus also is related to central sensitization. So we investigated the impact of tinnitus on FM. @*Methods@#. We included 22 FM patients with tinnitus and 25 FM patients without tinnitus. We assessed a range of symptoms using the Widespread Pain Index; Symptom Severity Score scale; Visual Analogue Scale of pain; and the Korean versions of the Fibromyalgia Impact Questionnaire (FIQ), the Insomnia Severity Index, and the Short-form Health Survey (SF-36). Information about the severity of tinnitus in FM patients was evaluated using the Korean version of the Tinnitus Handicap Questionnaire (THQ-K). @*Results@#. There were significant differences between the group that had mild tinnitus (THQ＜38) and the group that had moderate-to-severe tinnitus (THQ≥38) for FIQ score (p=0.025) and for the physical functioning (p=0.003), social functioning (p=0.035), and mental health (p=0.017) components of the SF-36. Also, after dividing patients into 2 groups according to insomnia severity, significant differences were observed in FIQ score (p=0.002) and in body pain (p=0.001), general health (p=0.008), vitality (p=0.003), social functioning (p=0.003), role limitation due to emotional condition (p=0.001), and mental health (p＜0.001) components of the SF-36. @*Conclusion@#. The FM patients with severe tinnitus had more functional impairments and lower quality of life than those with mild tinnitus. Severe insomnia also was accompanied by worse health status and lower quality of life.

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphateactivated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.

Adherence Improvement in Glaucoma Patients: Effects of Educational Intervention Using an Eye Drop Chart

Purpose@#To evaluate the effects of an educational intervention using an eye drop chart and supplementary education on glaucoma patients’ adherence. @*Methods@#In this multicenter prospective study, medically treated glaucoma patients were educated on the administration of eye drops using an eye drop chart. At the time of recruitment, all of the patients completed a questionnaire on demographic characteristics and adherence. Three months after the initial educational intervention, the patients were randomly divided into two groups: an education group and a control group. The education group received supplementary education. Immediately thereafter and at 6 months, all of the patients completed the questionnaire on adherence again. Changes in instillation behavior, the relationship between the adherence score and demographic characteristics, and factors contributing to an improvement in adherence and intraocular pressure were then analyzed. @*Results@#The adherence scores were significantly higher in patients with fewer medications, a higher annual income and higher educational level, and an urban residence (p = 0.038, p = 0.033, p = 0.041 and p = 0.047, respectively). Education on the administration of eye drops and use of the eye drop chart improved adherence scores from 23.05 ± 3.52 to 21.30 ± 3.95 (p = 0.021) and significantly reduced the average intraocular pressure from 14.3 ± 2.9 to 12.4 ± 3.1 mmHg (p < 0.001). Working indoors (odds ratio [OR] = 5.47, p = 0.032) and supplementary education at 3 months (OR = 4.53, p = 0.030) were also correlated with improved adherence. @*Conclusions@#An eye drop chart is an effective tool for improving adherence and intraocular pressure control in glaucoma patients. Improvement in adherence was especially notable in patients whose work predominantly involved indoor activity. The effectiveness of the eye drop chart was improved by supplementary education.

Effectiveness of Plasma and Urine Neutrophil Gelatinase-Associated Lipocalin for Predicting Acute Kidney Injury in High-Risk Patients

Background@#Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for acute kidney injury (AKI) prediction. However, studies on whether using both plasma NGAL (PNGAL) and urine NGAL (UNGAL) can improve AKI prediction are limited. We investigated the best approach to predict AKI in high-risk patients when using PNGAL and UNGAL together. @*Methods@#We enrolled 151 AKI suspected patients with one or more AKI risk factors. We assessed the diagnostic performance of PNGAL and UNGAL for predicting AKI according to chronic kidney disease (CKD) status by determining the areas under the receiver operating curve (AuROC). Independent predictors of AKI were assessed using univariate and multivariate logistic regression analyses. @*Results@#In the multivariate logistic regression analysis for all patients (N = 151), Model 2 and 3, including PNGAL (P = 0.012) with initial serum creatinine (S-Cr), showed a better AKI prediction power (R2 = 0.435, both) than Model 0, including S-Cr only (R2 = 0.390). In the non-CKD group (N = 135), the AuROC of PNGAL for AKI prediction was larger than that of UNGAL (0.79 vs 0.66, P = 0.010), whereas in the CKD group (N = 16), the opposite was true (0.94 vs 0.76, P = 0.049). @*Conclusions@#PNGAL may serve as a useful biomarker for AKI prediction in high-risk patients. However, UNGAL predicted AKI better than PNGAL in CKD patients. Our findings provide guidance for selecting appropriate specimens for NGAL testing according to the presence of CKD in AKI high-risk patients.

Effect of Chlorhexidine Mouthrinse on Prevention of Microbial Contamination during EBUS-TBNA: A Study Protocol for a Randomized Controlled Trial / 결핵및호흡기질환

Background@#Endobronchial ultrasound‒guided transbronchial needle aspiration (EBUS-TBNA) is a standard diagnostic method for mediastinal and hilar lymphadenopathy. Although rare, fatal infectious complications can occur following EBUS-TBNA. However, to date, there is a lack of effective preventive strategies to reduce these complications. We started a trial to investigate the effect of chlorhexidine mouthrinse on the prevention of microbial contamination during EBUS-TBNA. @*Methods@#This study is a single-center, parallel-group, assessor-blinded randomized controlled trial (RCT). We will enroll 112 adult participants undergoing EBUS-TBNA using a convex probe, and randomly assign them to two groups at a 1:1 ratio. The intervention group will gargle for 1 minute with 100 mL of 0.12% chlorhexidine gluconate before EBUS-TBNA, while the control group will have no mouthrinse before the procedure. Immediately after completion of EBUS-TBNA on all targeted lesions with an aspiration needle, a needle wash sample will be taken by instilling 5 mL of sterile saline into the used needle. The primary outcome is colony forming unit (CFU) counts in aerobic cultures of the needle wash samples. Secondary outcomes are CFU counts in anaerobic cultures, fever within 24 hours after EBUS-TBNA, and infectious complications within 4 weeks after EBUS-TBNA. @*Conclusion@#This trial was designed as the first RCT to investigate the effect of chlorhexidine mouthrinse on the prevention of microbial contamination during EBUS-TBNA. Results from this trial can provide clinical evidence for a simple, safe, and cost-effective strategy to prevent infectious complications following EBUS-TBNA (ClinicalTrials.gov ID: NCT04718922, registered on 22 January 2021).

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3’-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the threedimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.