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Abstract We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

BackgroundMolecular screening using next-generation sequencing (NGS) in the pathologic evaluation of lung cancer is considered the standard in clinical practice; hence, we evaluated the diagnostic yields of various sampling methods for NGS.MethodsNGS data from patients with lung cancer at the Pusan National University Hospital (Busan, South Korea), admitted October, 2020–April, 2023, was obtained. The sampling methods by which NGS data was obtained were divided into surgical and nonsurgical. Surgical methods included thoracoscopic surgery, surgical biopsy from the metastatic site, and lymph node excisional biopsy, whereas nonsurgical methods included bronchoscopy procedures and medical thoracoscopic biopsy.ResultsIn total, we obtained 319 patients’ NGS data:150 (47.0%) and 169 (53.0%) was obtained using surgical and nonsurgical methods, respectively. The overall diagnostic yield of NGS analysis was 97.5% for all samples. There were no significant differences in the success rates of deoxyribonucleic acid sequencing between surgical and nonsurgical sampling methods (98.0% vs. 96.4%, p = 0.313). On the other hand, the success rate of ribonucleic acid (RNA) sequencing was significantly lower in the surgical method group (78.0% vs. 92.3%; p < 0.001). Multivariate analysis showed that surgical sampling significantly correlated with RNA sequencing failure (Odd Ratio 4.128, 95% Confidence Interval 1.681–10.133, p = 0.002).ConclusionsSmall samples obtained using nonsurgical procedures are suitable for NGS analysis in clinical practice. However, surgical sampling showed a relatively lower success rate for RNA sequencing than nonsurgical sampling. This information may help in the development of protocols to reduce RNA degradation during the surgical process.

After the successful development of targeted therapy and immunotherapy for the treatment of advanced-stage non-small cell lung cancer (NSCLC), these innovative treatment options are rapidly being applied in the adjuvant setting for early-stage NSCLC. Some adjuvants that have recently been approved include osimertinib for epidermal growth factor receptor-mutated tumors and atezolizumab and pembrolizumab for selected patients with resectable NSCLC. Numerous studies on various targeted therapies and immunotherapy with or without chemotherapy are currently ongoing in the adjuvant setting. However, several questions regarding optimal strategies for adjuvant treatment remain unanswered. The present review summarizes the available literature, focusing on recent advances and ongoing trials with targeted therapy and immunotherapy in the adjuvant treatment of early-stage NSCLC.

Abstract Objectives Polo-like kinase 1 (Plk1) is an important mitotic protein. In particular, this protein is highly overexpressed in many types of tumors and has been identified as a potential biomarker for the treatment and diagnosis of tumors. Plk1 is composed of two domains, an N-terminal kinase domain and a C-terminal polo-box domain (PBD). Presently, inhibitors with improved selectivity and specificity for Plk1 are unavailable. Therefore, we aimed to develop an inhibitor targeting the C-terminal PBD present only in Plk1. Methods & results In this study, three derivatives targeting PBD for Plk1 were designed by protein–protein interactions, which showed high levels of selectivity and specificity for Plk1 PBD, and were evaluated to inhibit tumor cell proliferation through an apoptotic process during tumor cell division. The investigation of the in vitro and in vivo antitumor effects of these inhibitors demonstrated that one of the new small molecules, 1, is a promising anticancer agent. Conclusion Our findings can provide new insights for the design of novel Plk1 peptide inhibitors in the future.

Objectives: Bone health in early adulthood, as individuals approach peak bone mass, plays a critical role in preventing osteoporosis later in life. This study aimed to investigate the associations between lifestyle and dietary factors, anthropometric measurements, and urinary bone resorption markers in young adults. Methods: A cross-sectional study was conducted with 100 healthy Korean adults (50 men and 50 women) in their 20s and early 30s. Bone mineral density (BMD), anthropometric measurements, dietary intake (24-hour recall), and urinary bone resorption indicators (deoxypyridinoline and N-terminal telopeptide of type I collagen) were analyzed. Variables were compared between the osteopenia and osteoporosis groups (OSTEO group: 30% men and 60% women) and the healthy control group. Results: Men in the OSTEO group were significantly taller than those in the control group (P < 0.05). Women in the OSTEO group had significantly lower body weight and body composition (muscle and body fat) than those in the normal group (P < 0.01). Men in the OSTEO group had a significantly higher intake of animal calcium (Ca) than those in the normal group (P < 0.05). Women in the OSTEO group had significantly higher dietary fiber, vitamin A, Ca, plant Ca, and potassium intake than did those in the normal group (P < 0.05). There were no significant differences in caffeinated beverage consumption, eating habits, or urinary bone resorption indicators between the OSTEO and control groups of either sex. Conclusions: In our study of young South Korean adults, we observed low bone density levels, with particularly low BMD in taller men and underweight women. We found a higher nutrient intake in the OSTEO group, indicating the possibility of reverse causality, a phenomenon often found in cross-sectional studies. Therefore, there is a need to further elucidate dietary factors related to osteoporosis in young adults through prospective cohort studies involving a larger population.

Since the introduction of low-dose computed tomography (CT) screening for patients at high risk of lung cancer, the detection rate of suspicious lung cancer has increased. In addition, there have been many advances in therapeutics targeting oncogenic drivers in non-small cell lung cancer. Therefore, accurate pathological diagnosis of lung cancer, including molecular diagnosis, is increasingly important. This review examines the problems in the pathological diagnosis of suspected lung cancer. For successful pathological diagnosis of lung cancer, clinicians should determine the appropriate modality of the diagnostic procedure, considering individual patient characteristics, CT findings, and the possibility of complications. Furthermore, clinicians should make efforts to obtain a sufficient amount of tissue sample using non- or less-invasive procedures for pathological diagnosis and biomarker analysis.

Abstract Background This study investigated the association between quantitative and qualitative protein intake and grip strength (GS) in the South Korean population to explore nutritional management for the prevention of sarcopenia. Methods This cross-sectional study was based on data from a nationally representative sample of the South Korean elderly population, consisting of 1,531 men and 1,983 women aged 65 years and older who participated in the Korean National Health and Nutrition Examination Survey from 2016 to 2019. Low GS was defined as GS

Background The present study evaluated the association between participation in a rehabilitation program during a hospital stay and 1-year survival of patients requiring at least 21 days of mechanical ventilation (prolonged mechanical ventilation [PMV]) with various respiratory diseases as their main diagnoses that led to mechanical ventilation. Methods Retrospective data of 105 patients (71.4% male, mean age 70.1±11.3 years) who received PMV in the past 5 years were analyzed. Rehabilitation included physiotherapy, physical rehabilitation, and dysphagia treatment program that was individually provided by physiatrists. Results The main diagnosis leading to mechanical ventilation was pneumonia (n=101, 96.2%) and the 1-year survival rate was 33.3% (n=35). One-year survivors had lower Acute Physiology and Chronic Health Evaluation (APACHE) II score (20.2±5.8 vs. 24.2±7.5, p=0.006) and Sequential Organ Failure Assessment score (6.7±5.6 vs. 8.5±2.7, p=0.001) on the day of intubation than non-survivors. More survivors participated in a rehabilitation program during their hospital stays (88.6% vs. 57.1%, p=0.001). The rehabilitation program was an independent factor for 1-year survival based on the Cox proportional hazard model (hazard ratio, 3.513; 95% confidence interval, 1.785 to 6.930; p

Background/Aims Despite the obvious benefits of adding immune checkpoint inhibitors to platinum-etoposide chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC), real-world data remain scarce. Methods This retrospective study included 89 patients with ES-SCLC treated with platinum-etoposide chemotherapy alone (chemo-only group; n = 48) or in combination with atezolizumab (atezolizumab group; n = 41) and compared the survival outcomes between these two groups. Results Overall survival (OS) was significantly longer in the atezolizumab group than in the chemo-only group (15.2 months vs. 8.5 months; p = 0.047), whereas the median progression-free survival was almost the same (5.1 months vs. 5.0 months) in both groups (p = 0.754). Subsequent multivariate analysis revealed that thoracic radiation (hazard ratio [HR], 0.223; 95% confidence interval [CI], 0.092–0.537; p = 0.001) and atezolizumab administration (HR, 0.350; 95% CI, 0.184–0.668; p = 0.001) were favorable prognostic factors for OS. In the thoracic radiation subgroup, patients who received atezolizumab demonstrated favorable survival outcomes and no grade 3–4 adverse events (AEs). Conclusions The addition of atezolizumab to platinum-etoposide resulted in favorable outcomes in this real-world study. Thoracic radiation was associated with improved OS and acceptable AE risk in combination with immunotherapy in patients with ES-SCLC.

Abstract Molecular insights into chemical safety are very important for sustainable development as well as risk assessment. This study considers how to manage future upcoming harmful agents, especially potentially cholinergic chemical warfare agents (CWAs). For this purpose, the structures of known cholinergic agents were encoded by molecular descriptors. And then each drug target interaction (DTI) was learned from the encoded structures and their cholinergic activities to build DTI classification models for five cholinergic targets with reliable statistical validation (ensemble-AUC: up to 0.790, MCC: up to 0.991, accuracy: up to 0.995). The collected classifiers were transformed into 2D or 3D array type meta-predictors for multi-task: (1) cholinergic prediction and (2) CWA detection. The detection ability of the array classifiers was verified under the imbalanced dataset between CWAs and none CWAs (area under the precision-recall curve: up to 0.997, MCC: up to 0.638, F1-score of none CWAs: up to 0.991, F1-score of CWAs: up to 0.585).

Abstract Virtual screening has significantly improved the success rate of early stage drug discovery. Recent virtual screening methods have improved owing to advances in machine learning and chemical information. Among these advances, the creative extraction of drug features is important for predicting drug–target interaction (DTI), which is a large-scale virtual screening of known drugs. Herein, we report Kullbeck–Leibler divergence (KLD) as a DTI feature and the feature-driven classification model applicable to DTI prediction. For the purpose, E3FP three-dimensional (3D) molecular fingerprints of drugs as a molecular representation allow the computation of 3D similarities between ligands within each target (Q–Q matrix) to identify the uniqueness of pharmacological targets and those between a query and a ligand (Q–L vector) in DTIs. The 3D similarity matrices are transformed into probability density functions via kernel density estimation as a nonparametric estimation. Each density model can exploit the characteristics of each pharmacological target and measure the quasi-distance between the ligands. Furthermore, we developed a random forest model from the KLD feature vectors to successfully predict DTIs for representative 17 targets (mean accuracy: 0.882, out-of-bag score estimate: 0.876, ROC AUC: 0.990). The method is applicable for 2D chemical similarity.

Abstract Lung cancer is the second most commonly reported type of cancer worldwide. Approximately 80–85% of lung cancer occurrences are accounted by non-small cell lung cancer (NSCLC). Polo-like kinase-1 (Plk1) plays multiple roles in cell cycle progression and its overexpression is observed in majority of malignancies, including NSCLC. A combination of frontline drugs and inhibitors targeting the Plk kinase domain (KD) has been used to overcome drug resistance in NSCLC. Plk1 KD inhibitors are highly prone to cross-reactivity with similar kinases, eventually leading to undesirable side effects. Moreover, there have been no reports of Plk1 PBD inhibitors showing antitumorigenic effects on NSCLC cells or animal models so far. To address this issue herein, for the first time, our recently reported Plk1 PBD inhibitor KBJK557 was evaluated for the anticancer potential against NSCLC cells. KBJK557 displayed notable cytotoxic effects in A549, PC9, and H1975 cells. Mechanistic investigations revealed that KBJK557-treated cells underwent G2/M cell cycle arrest, triggering subsequent apoptosis. In vivo antitumorigenic activity in xenograft mice model demonstrates that KBJK557-treated mice showed a considerable decrease in tumor size, proving the significances of Plk1 in lung cancer. Collectively, this study demonstrates that KBJK557 can serve as a promising drug candidate for treating the lung cancer through Plk1 PBD inhibition.

We propose a self-supervised machine learning (ML) algorithm for sequence-type classification of brain MRI using a supervisory signal from DICOM metadata (i.e., a rule-based virtual label). A total of 1787 brain MRI datasets were constructed, including 1531 from hospitals and 256 from multi-center trial datasets. The ground truth (GT) was generated by two experienced image analysts and checked by a radiologist. An ML framework called ImageSort-net was developed using various features related to MRI acquisition parameters and used for training virtual labels and ML algorithms derived from rule-based labeling systems that act as labels for supervised learning. For the performance evaluation of ImageSort-net (MLvirtual), we compare and analyze the performances of models trained with human expert labels (MLhumans), using as a test set blank data that the rule-based labeling system failed to infer from each dataset. The performance of ImageSort-net (MLvirtual) was comparable to that of MLhuman (98.5% and 99%, respectively) in terms of overall accuracy when trained with hospital datasets. When trained with a relatively small multi-center trial dataset, the overall accuracy was relatively lower than that of MLhuman (95.6% and 99.4%, respectively). After integrating the two datasets and re-training them, MLvirtual showed higher accuracy than MLvirtual trained only on multi-center datasets (95.6% and 99.7%, respectively). Additionally, the multi-center dataset inference performances after the re-training of MLvirtual and MLhumans were identical (99.7%). Training of ML algorithms based on rule-based virtual labels achieved high accuracy for sequence-type classification of brain MRI and enabled us to build a sustainable self-learning system.

Target identification is a crucial process in drug development, aiming to identify key proteins, genes, and signal pathways involved in disease progression and their relevance in potential therapeutic interventions. While C-C chemokine receptor 8 (CCR8) has been investigated as a candidate anti-cancer target, comprehensive multi-omics analyzes across various indications are limited. In this study, we conducted an extensive bioinformatics analysis integrating genomics, proteomics, and transcriptomics data to establish CCR8 as a promising anti-cancer drug target. Our approach encompassed data collection from diverse knowledge resources, gene function analysis, differential gene expression profiling, immune cell infiltration assessment, and strategic prioritization of target indications. Our findings revealed strong correlations between CCR8 and specific cancers, notably Breast Invasive Carcinoma (BRCA), Colon Adenocarcinoma (COAD), Head and Neck Squamous Cell Carcinoma (HNSC), Rectum adenocarcinoma (READ), Stomach adenocarcinoma (STAD), and Thyroid carcinoma (THCA). This research advances our understanding of CCR8 as a potential target for anti-cancer drug development, bridging the gap between molecular insights and creating opportunities for personalized treatment of solid tumors.

Abstract Objectives The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non‐small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations. Materials and methods Electronic records of patients with EGFR‐mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan–Meier method and log‐rank test. Multivariate analyses were performed using the Cox proportional hazards model. Results Of the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval [CI]: 27.7−45.6) in group A and 20.8 months (95% CI: 19.4−24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0−13.9) overall and 15.7 months (95% CI: 13.9−17.3) in group A. The 2‐ and 3‐year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively. Conclusion Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies.

Abstract In drug discovery, rapid and accurate prediction of protein–ligand binding affinities is a pivotal task for lead optimization with acceptable on-target potency as well as pharmacological efficacy. Furthermore, researchers hope for a high correlation between docking score and pose with key interactive residues, although scoring functions as free energy surrogates of protein–ligand complexes have failed to provide collinearity. Recently, various machine learning or deep learning methods have been proposed to overcome the drawbacks of scoring functions. Despite being highly accurate, their featurization process is complex and the meaning of the embedded features cannot directly be interpreted by human recognition without an additional feature analysis. Here, we propose SMPLIP-Score (Substructural Molecular and Protein–Ligand Interaction Pattern Score), a direct interpretable predictor of absolute binding affinity. Our simple featurization embeds the interaction fingerprint pattern on the ligand-binding site environment and molecular fragments of ligands into an input vectorized matrix for learning layers (random forest or deep neural network). Despite their less complex features than other state-of-the-art models, SMPLIP-Score achieved comparable performance, a Pearson’s correlation coefficient up to 0.80, and a root mean square error up to 1.18 in pK units with several benchmark datasets (PDBbind v.2015, Astex Diverse Set, CSAR NRC HiQ, FEP, PDBbind NMR, and CASF-2016). For this model, generality, predictive power, ranking power, and robustness were examined using direct interpretation of feature matrices for specific targets.

The translocator protein (TSPO) is an interesting biological target for molecular imaging and therapy because the overexpression of TSPO is associated with microglial activation caused by neuronal damage or neuroinflammation, and these activated microglia are involved in various central nervous system (CNS) diseases. The TSPO is a target for neuroprotective treatment, which is used with the aim of reducing microglial cell activation. The novel N,N-disubstituted pyrazolopyrimidine acetamides scaffold (GMA 7–17), which bears a fluorine atom and is directly linked to the phenyl moiety, was synthesized, and each of the novel ligands was characterized in vitro. All of the newly synthesized ligands displayed picomolar to nanomolar affinity for the TSPO. Particularly, an in vitro affinity study led to the discovery of 2-(5,7-diethyl-2-(4-fluorophenyl)pyrazolo [1,5-a]pyrimidin-3-yl)-N-ethyl-N-phenylacetamide GMA 15 (Ki = 60 pM), a novel TSPO ligand that exhibits a 61-fold enhancement in affinity compared to the reference standard DPA-714 (Ki = 3.66 nM). Molecular dynamic (MD) studies of the highest affinity binder, GMA 15, were carried out to check its time-dependent stability with the receptor compared to DPA-714 and PK11195. The hydrogen bond plot also indicated that GMA 15 formed higher hydrogen bonds compared to DPA-714 and PK11195. We anticipate that further optimization to enhance the potency in a cellular assay needs to be followed, but our strategy of identifying potential TSPO binding novel scaffolds may open up a new avenue to develop novel TSPO ligands suited for potential molecular imaging and a wide range of therapeutic applications.

Background This study compared the treatment outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) before and after the implementation of public–private mix (PPM). Factors affecting treatment success were also investigated. Methods Data from culture-confirmed pulmonary MDR-TB patients who commenced MDR-TB treatment at Pusan National University Hospital between January 2003 and December 2017 were retrospectively reviewed. Patients were divided into two groups in terms of PPM status: pre-PPM period, patients who commenced MDR-TB treatment between 2003 and 2010; and post-PPM period, patients treated between 2011 and 2017. Results A total of 176 patients were included (64 and 112 in the pre- and post-PPM periods, respectively). 36.9% of the patients were resistant to a fluoroquinolone or a second-line injectable drug, or both. The overall treatment success rate was 72.7%. The success rate of post-PPM patients was higher than that of pre-PPM patients (79.5% vs. 60.9%, p=0.008). Also, loss to follow-up was lower in the post-PPM period (5.4% vs. 15.6%, p=0.023). In multivariate regression analysis, age ≥65 years, body mass index ≤18.5 kg/m2, previous TB treatment, bilateral lung involvement, and extensively drug-resistant (XDR)- or pre-XDR-TB were associated with poorer treatment outcomes. However, the use of bedaquiline or delamanid for ≥1 month increased the treatment success. Conclusion The treatment success rate in MDR-TB patients was higher in the post-PPM period than in the pre-PPM period, particularly because of the low rate of loss to follow-up. To ensure comprehensive patient-centered PPM in South Korea, investment and other support must be adequate.

As a non-covalent interaction of a chiral scaffold in catalysis, pnicogen bonding of epi-cinchonidine (epi-CD), a cinchona alkaloid, was simulated to consider whether the interaction can have the potential controlling enantiotopic face like hydrogen bonding. Among five reactive functional groups in epi-CD, two stable complexes of the hydroxyl group (X-epi-CD1) at C17 and of the quinoline ring (X-epi-CD2) at N16 with pnictide family analytes [X = substituted phosphine (PX), i.e., F, Br, Cl, CF3, CN, HO, NO2, and CH3, and pnictide family analytes, i.e., PBr3, BiI3, SbI3, and AsI3] were predicted with intermolecular interaction energies, charge transfer (QMulliken and QNBO), and band gap energies of HOMO–LUMO (Eg) at the B3LYP/6-31G(d,p) level of density functional theory. It was found that the dominant site of pnicogen bonding in epi-CD is the quinoline ring (N16 atom) rather than the hydroxyl group (O36 atom). In addition, the UV-Vis spectra of the complex were calculated by time-dependent density functional theory (TD-DFT) at the B3LYP/6-31+G(d,p) level and compared with experimental measurements. Through these calculations, two intermolecular interactions (H-bond vs. pnicogen bond) of epi-CD were compared.

Background Tuberculosis (TB) causes substantial health burden to the Korean military. This study aims to assess the impact of infectious TB cases on close and casual contacts in the Korean Army settings based on contact investigation data. Methods Six Army units with infectious TB cases from September 2012 to May 2013 were enrolled in the study. We analyzed the clinical data from close and casual contacts screened using the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube to identify latent tuberculosis infection (LTBI) cases. For the control group, 286 military conscripts with no reported TB exposure were tested by TST only. Results Of the 667 contacts of index cases, LTBI cases identified were as follows: 21.8% of close contacts of smear-positive cases (71/326), 8.5% of casual contacts of smear-positive cases (26/305), and 2.8% of close contacts of smear-negative cases (1/36). In the control group, 16.8% showed positivity in TST. In a multivariate analysis, having stayed in the same room or next room with TB patients was identified as a risk factor of LTBI. Conclusion Using the data from TB contact investigations in the Korean Army units, we found an overall LTBI rate of 14.7% among the contacts screened. This study demonstrates that contacts living in the same building, especially the same room or next room, with TB patients are at a high risk of acquiring LTBI, serving as additional evidence for defining close and casual contacts of a TB patient with regard to Army barrack settings.

Background/Aims Matrix-assisted laser desorption/ionization time-of-f light mass spectrometry (MALDI-TOF MS) is a new diagnostic tool for microorganism identification. The clinical usefulness of this approach has not been widely examined in Korea. This retrospective pre–post-intervention quasi-experimental study examined the effect of MALDI-TOF MS on patients with multidrug-resistant (MDR) bacteremia in the intensive care unit (ICU). Methods All consecutive patients with MDR bacteremia in the ICU of a tertiary care hospital between March 2011 and February 2013 and between March 2014 and February 2016 were enrolled. MALDI-TOF MS was introduced between these periods. In the pre-intervention and intervention groups, microorganisms were identified by conventional means and by MALDI-TOF MS, respectively. The groups were compared in terms of time from venipuncture to microorganism identification and antimicrobial susceptibility test results. Results In total, 187 patients (mean age, 61.0 years; 56.7% male) were enrolled. Of these, 97 and 90 were in the pre-intervention and intervention groups, respectively. The intervention group had a significantly shorter time from venipuncture to microorganism identification and antimicrobial susceptibility test results (82.5 ± 21.6 hours vs. 92.3 ± 40.4 hours, p = 0.038). The antibiotics were adjusted in 52 patients (26 each in the pre-intervention and intervention groups) based on these results. These groups did not differ in terms of time from venipuncture to antibiotic adjustment, and multivariate regression analysis showed that MALDI-TOF MS–based microorganism identification was not associated with 28-day mortality. Conclusions Our study showed that MALDI-TOF MS accelerated microorganism identification in patients with MDR bacteremia, but did not inf luence 28-day mortality.

Background The presence of EGFR mutation in patients with advanced non‐small cell lung cancer (NSCLC) plays an important role in determining the appropriate treatment, response, and survival. Therefore, this study attempted to predict the prognosis of NSCLC patients using data from quantitative mutation measurements. Methods The data of patients with advanced NSCLC who underwent EGFR mutation testing using the peptide nucleic acid (PNA) mediated clamping method at the Pusan National University Hospital from October 2015 to December 2017 were retrospectively analyzed. The efficiency of PNA clamping was determined by measuring the threshold cycle (Ct) value. The ΔCt−1 value (standard Ct value minus sample Ct value) was calculated to quantify EGFR mutation. Results During the study period, 71 patients were treated with EGFR‐tyrosine kinase inhibitors. The cutoff point for the ΔCt−1 value derived from the receiver operating characteristic curve was 5.32. A survival benefit was observed in the group with an ΔCt−1 value > 5.32 or with a common EGFR mutation type compared to the group with an ΔCt−1 value < 5.32. Conclusion EGFR mutation testing using PNA clamping may predict patient survival, especially in patients with common EGFR mutations, such as exon 19 deletion or L858R. A higher ΔCt−1 value correlates with better survival.

Primary renal neuroendocrine tumor (NET) is an extremely rare disease with fewer than 100 reported cases to date. Among them, only three involved the renal pelvis, to our knowledge. Here, we report another rare case of primary NET in the renal pelvis of a 33-year-old man. Initial computed tomography (CT) scanning of the abdomen and pelvis revealed a necrotic mass with peritumoral infiltration at the left renal pelvis and ureteropelvic junction causing urinary tract obstruction. A follow-up CT scan revealed an intratumoral hemorrhage. The patient then underwent nephrectomy. The results of a subsequent histopathological examination were consistent with a well-differentiated NET. No lymph nodes or paraganglia were found within the tumor, and further imaging revealed no other primary or metastatic lesions. Therefore, the patient was diagnosed with primary NET in the renal pelvis. We discuss this rare case and briefly review the current NET literature.

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.

Abstract Non-enzymatic lipid peroxidation of the skin-lipid bilayer causes perturbations that affect the biomembrane structure, function, and permeability of reactive oxygen species (ROS). In the present study, we employed molecular dynamics simulations to study the effect of lipid peroxidation on the bilayer structural properties and permeability of various ROS. The oxidized skin-lipid bilayer was composed of ceramide, cholesterol, free fatty acid, and 5α-hydroperoxycholesterol (5α-CH). The simulation showed that, upon oxidation, the oxidized group (−OOH) of 5α-CH migrates towards the aqueous phase and the backbone of 5α-CH tilts, which causes the membrane to expand laterally. Measurements of the permeability of all ROS along the oxidized skin-lipid bilayer revealed a decreased breaching barrier for all the species as the degree of peroxidation increased, with a resulting easy passage across the membrane. The insights from the simulations indicate that lipid peroxidation might perturb the membrane barrier, thereby inflicting oxidative stress that leads to apoptosis. This study helps to understand oxidative stress at the atomic level. To our knowledge, this is the first reported molecular dynamics simulation study on oxidized skin-lipid bilayer and permeability of ROS.

S100A9 is a potential therapeutic target for various disease including prostate cancer, colorectal cancer, and Alzheimer's disease. However, the sparsity of atomic level data, such as protein-protein interaction of S100A9 with RAGE, TLR4/MD2, or CD147 (EMMPRIN) hinders the rational drug design of S100A9 inhibitors. Herein we first report predictive models of S100A9 inhibitory effect by applying machine learning classifiers on 2D-molecular descriptors. The models were optimized through feature selectors as well as classifiers to produce the top eight random forest models with robust predictability and high cost-effectiveness. Notably, optimal feature sets were obtained after the reduction of 2,798 features into dozens of features with the chopping of fingerprint bits. Moreover, the high efficiency of compact feature sets allowed us to further screen a large-scale dataset (over 6,000,000 compounds) within a week. Through a consensus vote of the top models, 46 hits (hit rate = 0.000713%) were identified as potential S100A9 inhibitors. We expect that our models will facilitate the drug discovery process by providing high predictive power as well as cost-reduction ability and give insights into designing novel drugs targeting S100A9.

Background Patients with acute respiratory failure secondary to tuberculous destroyed lung (TDL) have a poor prognosis. The aim of the present retrospective study was to develop a mortality prediction model for TDL patients who require mechanical ventilation. Methods Data from consecutive TDL patients who had received mechanical ventilation at a single university-affiliated tertiary care hospital in Korea were reviewed. Binary logistic regression was used to identify factors predicting intensive care unit (ICU) mortality. A TDL on mechanical Ventilation (TDL-Vent) score was calculated by assigning points to variables according to β coefficient values. Results Data from 125 patients were reviewed. A total of 36 patients (29%) died during ICU admission. On the basis of multivariate analysis, the following factors were included in the TDL-Vent score: age ≥65 years, vasopressor use, and arterial partial pressure of oxygen/fraction of inspired oxygen ratio

Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people. Recently, we reported a 3-azido-3-deoxythymidine (AZT)-based amphipathic small molecule, ADG-2e that revealed a notable potency against tumor metastasis. To evaluate the anticancer potential of ADG-2e, we assessed its anticancer potency in vitro and in vivo. Anticancer screening of ADG-2e against cervical cancer cells, HeLa CCL2, and BT549 mammary gland ductal carcinoma showed significant inhibition of cancer cell proliferation. Furthermore, mechanistic investigations revealed that cancer cell death presumably proceeded through an oncosis mechanistic pathway because ADG-2e treated cells showed severe damage on the plasma membrane, a loss of membrane integrity, and leakage of α-tubulin and β-actin. Finally, evaluation of the antitumorigenic potential of ADG-2e in mouse xenograft models revealed that this compound potentially inhibits cancer cell proliferation. Collectively, these findings suggest that ADG-2e can evolve as an anticancer agent, which may represent a model for nucleoside-based small molecule anticancer drug discovery.

BackgroundThis study investigated the time to appropriate treatment and factors affecting late treatment initiation in patients with multidrug-resistant tuberculosis (MDR-TB) in South Korea.MethodsData from patients with culture-confirmed pulmonary MDR-TB who received treatment at Pusan National University Hospital (PNUH) between January 2010 and July 2018 were reviewed retrospectively. Patients were divided into two groups according to the first institution they visited [patients who were transferred to PNUH after diagnosis of MDR-TB (Group A) and patients who were initially diagnosed with TB at PNUH (Group B)].ResultsA total of 100 patients were included (53 in Group A and 47 in Group B). The percentage of patients in whom line probe assays (LPAs) for isoniazid and rifampin or Xpert MTB/RIF assays were performed was higher in Group B than in Group A [20.8 vs. 57.4% (P < 0.001) and 17.0 vs. 46.8% (P = 0.001), respectively]. The median time from the first visit to appropriate treatment initiation was longer in Group A (102.0 vs. 77.0 days, P = 0.002). However, a subgroup analysis of patients with pre-extensively or extensively drug-resistant TB (pre-XDR- or XDR-TB) revealed that the time to appropriate treatment did not differ between Groups A and B. Although the time to appropriate treatment decreased during the study period in both Groups A and B, this trend was not evident in patients with pre-XDR- or XDR-TB in Group B. Based on multivariate analyses, performance of LPAs for isoniazid and rifampin, performance of Xpert MTB/RIF assays, and the presence of uncomplicated MDR-TB were protective against delays in appropriate treatment initiation.ConclusionsThe time to appropriate treatment in patients with MDR-TB in South Korea was not acceptable, particularly for patients diagnosed outside of PNUH and for patients with pre-XDR- or XDR-TB. The use of rapid molecular drug susceptibility tests in various healthcare settings and introduction of second-line LPAs are required.

BackgroundRadial probe endobronchial ultrasound using a guide sheath (EBUS-GS) is used to diagnose peripheral lung cancer. The aim was to identify the accuracy of molecular analysis that were performed with EBUS-GS specimens in patients with non-small cell lung cancer (NSCLC).MethodFrom December 2015 to September 2017, we retrospectively studied 91 patients with peripheral NSCLC who underwent surgery after EBUS-GS. Epidermal growth factor receptor (EGFR) mutational and anaplastic lymphoma kinase (ALK) translocation status obtained from surgical specimens served as the references.ResultsCompared to the reference data, EGFR mutational testing of EBUS-GS specimens was in 97% agreement, and the κ coefficient was 0.931 (P< 0.001). In addition, on ALK translocation testing, the results of all 91 patients were in agreement with the reference data (concordance rate of 100%, κ coefficient 1.000; P< 0.001).ConclusionWe found that EBUS-GS could be used for molecular diagnosis, such as EGFR mutational and ALK translocation status, in patients with peripheral NSCLC.

We aimed to investigate the presence of the phenicol–oxazolidinone resistance gene poxtA in linezolid-resistant enterococci from food-producing animals and analyze its molecular characteristics. We collected 3941 Enterococcus faecium and 5088 E. faecalis isolates from all provinces of South Korea from 2008 to 2018. We found linezolid resistance in 0.79% (94/3941) of E. faecium and 1.22% (62/5088) of E. faecalis isolates. Overall, 23.1% (36/156) of the linezolid-resistant isolates had the poxtA gene, including 31 E. faecium and five E. faecalis isolates. The poxtA-positive enterococci were mainly isolated from chicken (86.1%; 26/36). Fifteen poxtA-harboring isolates co-carried another linezolid-resistance gene, optrA. Eight E. faecium isolates had an N130K mutation in the ribosomal protein L4, while no mutations were observed in E. faecalis isolates. The poxtA gene was transferred into 10 enterococci by conjugation. Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) analysis indicated that poxtA-carrying isolates were heterogeneous. Three E. faecium isolates belonged to CC17 (ST32, ST121, and ST491). To our knowledge, this is the first report on the poxtA gene in Korea. Prudent use of antimicrobials and active surveillance on antimicrobial resistance are urgently needed to reduce the risk of dissemination of the linezolid-resistant isolates in humans and animals.

Purpose: The purpose of this study was to analyze the characteristics of initially missed and rebiopsy-detected prostate cancers following 12-core transrectal biopsy. Methods: A total of 45 patients with prostate cancers detected on rebiopsy and 45 patients with prostate cancers initially detected on transrectal ultrasound-guided biopsy were included in the study. For result analysis, the prostate was divided into six compartments, and the cancer positive rates, estimated tumor burden, and agreement rates between biopsy and surgical specimens, along with clinical data, were evaluated. Results: The largest mean tumor burden was located in the medial apex in both groups. There were significantly more tumors in this location in the rebiopsy group (44.9%) than in the control group (30.1%, P=0.015). The overall sensitivity of biopsy was significantly lower in the rebiopsy group (22.5% vs. 43.4%, P

A light-weight, flexible electromagnetic interference (EMI) shield was prepared by creating a layer-structured metal-polymer composite film consisting of electrospun nylon 66 nanofibers with silver films. The EMI shielding effectiveness (SE), specific SE, and absolute SE of the composite were as high as 60.6 dB, 67.9 dB cm3/g, and 6792 dB cm2/g in the X- and Ku-bands, respectively. Numerical and analytical calculations suggest that the energy of EM waves is predominantly absorbed by inter-layer multiple reflections. Because the absorbed EM energy is dissipated as heat, the thermal conductivity of absorption-dominant EMI shields is highly significant. Measured thermal conductivity of the composite was found to be 4.17 Wm−1K−1 at room temperature, which is higher than that of bulk nylon 66 by a factor of 16.7. The morphology and crystallinity of the composite were examined using scanning electron microscopy and differential scanning calorimetry, respectively. The enhancement of thermal conductivity was attributed to an increase in crystallinity of the nanofibers, which occurred during the electrospinning and subsequent hot pressing, and to the high thermal conductivity of the deposited silver films. The contribution of each fabrication process to the increase in thermal conductivity was investigated by measuring the thermal conductivity values after each fabrication process.

3D similarity is useful in predicting the profiles of unprecedented molecular frameworks that are 2D dissimilar to known compounds. When comparing pairs of compounds, 3D similarity of the pairs depends on conformational sampling, the alignment method, the chosen descriptors, and the similarity coefficients. In addition to these four factors, 3D chemocentric target prediction of an unknown compound requires compound–target associations, which replace compound-to-compound comparisons with compound-to-target comparisons. In this study, quantitative comparison of query compounds to target classes (one-to-group) was achieved via two types of 3D similarity distributions for the respective target class with parameter optimization for the fitting models: (1) maximum likelihood (ML) estimation of queries, and (2) the Gaussian mixture model (GMM) of target classes. While Jaccard–Tanimoto similarity of query-to-ligand pairs with 3D structures (sampled multi-conformers) can be transformed into query distribution using ML estimation, the ligand pair similarity within each target class can be transformed into a representative distribution of a target class through GMM, which is hyperparameterized via the expectation–maximization (EM) algorithm. To quantify the discriminativeness of a query ligand against target classes, the Kullback–Leibler (K–L) divergence of each query was calculated and compared between targets. 3D similarity-based K–L divergence together with the probability and the feasibility index, (Fm), showed discriminative power with regard to some query–class associations. The K–L divergence of 3D similarity distributions can be an additional method for (1) the rank of the 3D similarity score or (2) the p-value of one 3D similarity distribution to predict the target of unprecedented drug scaffolds.

In recent years, the role of reactive oxygen species (ROS) in regulating cancer cell apoptosis, inflammation, cell ischemia, and cell signaling pathways has been well established. The most common sources of intracellular ROS are the mitochondrial electron transport system, NADH oxidase, and cytochrome P450. In this study, we investigated the dynamics and permeability of ROS using molecular dynamics (MD) simulations on native skin-lipid bilayer membranes. Native skin-lipid bilayers are composed of ceramide, cholesterol, and free fatty acid in an almost equal molar ratio (1:1:1). Dynamic distribution studies on ROS, i.e., hydrogen peroxide (H2O2) and O2 (1O2 by analogy), revealed that these species interact with cholesterol as a primary target in lipid peroxidation of the skin-lipid bilayer. Moreover, the permeability of ROS, i.e., H2O2, hydroxyl radicals (HO), hydroperoxy radical (HOO), and O2, along the skin-lipid bilayer was measured using free energy profiles (FEPs). The FEPs showed that in spite of high-energy barriers, ROS traveled through the membrane easily. Breaching the free energy barriers, these ROS permeated into the membrane, inflicting oxidative stress, and causing apoptosis. Collectively, the insight acquired from simulations may result in a better understanding of oxidative stress at the atomic level.

The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs 20a-20ab have been synthesized via “on water” ultrasound-assisted irradiation conditions in excellent yields (upto 98%). All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC50 values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 μg/mL taking ascorbic acid (IC50 = 4.57 μg/mL) as standard reference. In this study, compounds 20b and 20t, the most active compound of the series, showed IC50 values of 6.89 ± 0.07 μg/mL and 4.74 ± 0.08 μg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (20c, 20j, 20m, 20n, 20r, 20u, 20z, and 20aa) were found more potent than standard reference BHT (C0.5FRAP = 546.0 ± 13.6 μM). The preliminary cytotoxic study reveals the non-toxic nature of active compounds 20b and 20t in non-cancerous 3T3 fibroblast cell lines in MTT assay up to 250 μg/mL concentration. The results were validated via carrying out in silico molecular docking studies of promising compounds 20a, 20b, and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.

We aimed to develop a decision tree model to improve diagnostic performance of positron emission tomography/computed tomography (PET/CT) to detect metastatic lymph nodes (LN) in non-small cell lung cancer (NSCLC). 115 patients with NSCLC were included in this study. The training dataset included 66 patients. A decision tree model was developed with 9 variables, and validated with 49 patients: short and long diameters of LNs, ratio of short and long diameters, maximum standardized uptake value (SUVmax) of LN, mean hounsfield unit, ratio of LN SUVmax and ascending aorta SUVmax (LN/AA), and ratio of LN SUVmax and superior vena cava SUVmax. A total of 301 LNs of 115 patients were evaluated in this study. Nodular calcification was applied as the initial imaging parameter, and LN SUVmax (≥3.95) was assessed as the second. LN/AA (≥2.92) was required to high LN SUVmax. Sensitivity was 50% for training dataset, and 40% for validation dataset. However, specificity was 99.28% for training dataset, and 96.23% for validation dataset. In conclusion, we have developed a new decision tree model for interpreting mediastinal LNs. All LNs with nodular calcification were benign, and LNs with high LN SUVmax and high LN/AA were metastatic Further studies are needed to incorporate subjective parameters and pathologic evaluations into a decision tree model to improve the test performance of PET/CT.

The use of circulating tumor cells (CTCs) as an early diagnostic biomarker and prognostic indicator after surgery or chemotherapy has been suggested for various cancers. This study aimed to evaluate CTCs in patients who underwent gastrectomy for gastric cancer and to explore their clinical usefulness in the early diagnosis of gastric cancer.A total of 116 patients with gastric cancer who underwent gastrectomy and 31 healthy volunteers were prospectively included between 2014 and 2015. Peripheral blood samples were collected before gastrectomy, and CTCs were examined using a centrifugal microfluidic system with a new fluid-assisted separation technique.After creating a receiver operating characteristic curve to identify the discriminative CTC value needed differentiate patients with gastric cancer from healthy volunteers, sensitivity and specificity were nearly optimized at a CTC threshold of 2 per 7.5 mL of blood. Of the 102 persons with a CTC level ≥2 per 7.5 mL of blood, 99 (97.1%) had gastric cancer, and of the 45 persons with a CTC level

Lung adenocarcinomas can be classified into terminal respiratory unit (TRU) and non-TRU types. We previously reported that non-TRU-type adenocarcinoma has unique clinical and morphological features as compared to the TRU type. Here we investigated whether micro (mi)RNA expression profiles can be used to distinguish between these two subtypes of lung adenocarcinoma. The expression of 1205 human and 144 human viral miRNAs was analyzed in TRU- and non-TRU-type lung adenocarcinoma samples (n = 4 each) by microarray. Results were validated by quantitative real-time (qRT-)PCR and in situ hybridization. A comparison of miRNA profiles revealed 29 miRNAs that were differentially expressed between TRU- and non-TRU adenocarcinoma types. Specifically, hsa-miR-494 and ebv-miR-BART19 were up regulated by > 5-fold, whereas hsa-miR-551b was down regulated by > 5-fold in the non-TRU relative to the TRU type. The miRNA signature was confirmed by qRT-PCR analysis using an independent set of paired adenocarcinoma (non-TRU-type, n = 21 and TRU-type, n = 12) and normal tissue samples. Non-TRU samples showed increased expression of miR-494 (p = 0.033) and ebv-miR-BART19 (p = 0.001) as compared to TRU-type samples. Both miRNAs were weakly expressed in the TRU type but strongly expressed in the non-TRU type. Neither subtype showed miR-551b expression. TRU- and non-TRU-type adenocarcinomas have distinct miRNA expression profiles, suggesting that tumorigenesis in lung adenocarcinoma occur via different pathways.

BackgroundThe aim of this study was to investigate the neuroprotective effects of sevoflurane after severe forebrain ischemic injury. We also examined the relationship between the duration of ischemia and neuronal cell death.MethodsMale Sprague-Dawley rats (300-380 g) were subjected to 6 (each n = 6) or 10 min (each n = 10) of near-complete forebrain ischemia while anesthetized with either 50 mg/kg of zoletil given intraperitoneally or inhaled sevoflurane (2.3%). Ischemia was induced by bilateral common carotid artery occlusion plus hemorrhagic hypotension (26-30 mmHg). Histologic outcomes were measured 7 days after ischemia in CA1 pyramidal cells of the rat hippocampus.ResultsThe mean percentage of necrotic cells in the hippocampal CA1 area decreased in the sevoflurane group compared to the zoletil group (25% vs. 40% after 6 min ischemia, respectively: P = 0.004 and 44% vs. 54% after 10 min of ischemia, respectively P = 0.03). The percentage of apoptotic cells was similar in all groups. The percentage of necrotic cells in each anesthetic groups was significantly higher in the 10 min ischemia group compared to the 6 min ischemia group (P = 0.004 in the sevoflurane group, P = 0.03 in the zoletil group).ConclusionsThe present data show that sevoflurane has neuroprotective effects in rats subjected to near-complete cerebral ischemia. Longer duration of ischemia is associated with more neuronal injury when compared to ischemia of shorter duration.

The dopamine D3 receptor is an important CNS target for the treatment of a variety of neurological diseases. Selective dopamine D3 receptor antagonists modulate the improvement of psychostimulant addiction and relapse. In this study, five and six featured pharmacophore models of D3R antagonists were generated and evaluated with the post-hoc score combining two survival scores of active and inactive. Among the Top 10 models, APRRR215 and AHPRRR104 were chosen based on the coefficient of determination (APRRR215: R2training = 0.80; AHPRRR104: R2training = 0.82) and predictability (APRRR215: Q2test = 0.73, R2predictive = 0.82; AHPRRR104: Q2test = 0.86, R2predictive = 0.74) of their 3D-quantitative structure–activity relationship models. Pharmacophore-based virtual screening of a large compound library from eMolecules (>3 million compounds) using two optimal models expedited the search process by a 100-fold speed increase compared to the docking-based screening (HTVS scoring function in Glide) and identified a series of hit compounds having promising novel scaffolds. After the screening, docking scores, as an adjuvant predictor, were added to two fitness scores (from the pharmacophore models) and predicted Ki (from PLSs of the QSAR models) to improve accuracy. Final selection of the most promising hit compounds were also evaluated for CNS-like properties as well as expected D3R antagonism.

Opuntia humifusa is a type of cactus whose fruits have been used in folk medicine for the treatment of several diseases. In the present study, we aimed to determine whether O. humifusa fruit water extract (OHE) has inhibitory effects against solar ultraviolet (sUV)-induced matrix metalloproteinase-1 (MMP-1) expression. In ex vivo human skin, we found that OHE suppressed sUV radiation-induced MMP-1 expression. The inhibitory effect of OHE was confirmed in human dermal fibroblasts. OHE treatment reduced sUV-induced MMP-1 expression by suppressing reactive oxygen species (ROS) generation and phosphorylation of c-Jun, a component of transcription factor activator protein 1 (AP-1). On the other hand, OHE recovered the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and type 1 collagen production attenuated by sUV. As upstream signaling pathways for AP-1, MKK4-JNK, MEK-ERK, and MKK3/6-p38 phosphorylation were downregulated by OHE treatment. In addition, OHE exhibited DPPH radical scavenging activity. These findings demonstrate that OHE has a preventive effect against sUV-induced skin damage via suppression of pathways triggered by ROS.

BackgroundNeck flexion has been shown to increase cranial spread of contrast agent when a small fixed volume was injected into the high thoracic epidural space. The purpose of this study was to evaluate the effect of volume of contrast medium on its distribution through the high thoracic epidural space during neck extension and flexion using the rabbit model.MethodsAn epidural catheter was introduced into the epidural space of New Zealand white rabbits with the tip located at the T3-4 intervertebral level. The neck was extended or flexed (n = 8 for each group), and the contrast medium was injected with the volume increasing by increments of 0.1 ml/kg, up to 0.3 ml/kg. The spread of contrast medium was determined by counting the number of vertebral body units using lateral epidurographic images.ResultsIn both groups, the total spread of contrast medium was similar, increasing continuously with injected volume. The cranial spread was greater in the flexion group than the extension group. However, the caudal spread was greater in the extension than in the flexion group. In the extension group, the contrast medium spread caudally about twice as far as it spread cranially, but there was no statistically significant difference between cranial and caudal spread in the flexion group.ConclusionsIn the high thoracic epidural space of rabbit, the contrast medium of varying doses showed limited cranial spread. The flexion of the neck increased cranial spread and extension of the neck increased caudal spread.

Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Recent advances in the understanding of the biology of tumors and in highly sensitive detection technologies for molecular analysis offer targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. However, our understanding of an individual patient’s lung cancer is often limited by tumor accessibility because of the high risk and invasive nature of current tissue biopsy procedures. “Liquid biopsy”, the analysis of circulating biomarkers from peripheral blood, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), offers a new source of cancer-derived materials that may reflect the status of the disease better and thereby contribute to more personalized treatment. In this review, we examined the clinical significance and uniqueness of CTCs and ctDNA from NSCLC patients, isolation and detection methods developed to analyze each type of circulating biomarker, and examples of clinical studies of potential applications for early diagnosis, prognosis, treatment monitoring, and prediction of resistance to therapy. We also discuss challenges that remain to be addressed before such tools are implemented for routine use in clinical settings.

Guidewire-associated complications that occur during the process of central venous catheterization include its kinking, looping, knotting and breakage. The removal of a looped or knotted guidewire is problematic because it can cause vessel damage, major hemorrhage, or embolization of a fractured guidewire. We report a case of guidewire kinking and its successful removal under fluoroscopic guidance.

To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells.

The antifungal activity of allicin and its synergistic effects with the antifungal agents flucytosine and amphotericin B (AmB) were investigated in Candida albicans (C. albicans). C. albicans was treated with different conditions of compounds alone and in combination (allicin, AmB, flucytosine, allicin + AmB, allicin + flucytosine, allicin + AmB + flucytosine). After a 24-hour treatment, cells were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM) to measure morphological and biophysical properties associated with cell death. The clearing assay was conducted to confirm the effects of allicin. The viability of C. albicans treated by allicin alone or with one antifungal drug (AmB, flucytosine) in addition was more than 40% after a 24-hr treatment, but the viability of groups treated with combinations of more than two drugs was less than 32%. When the cells were treated with allicin alone or one type of drug, the morphology of the cells did not change noticeably, but when cells were treated with combinations of drugs, there were noticeable morphological changes. In particular, cells treated with allicin + AmB had significant membrane damage (burst or collapsed membranes). Classification of cells according to their cell death phase (CDP) allowed us to determine the relationship between cell viability and treatment conditions in detail. The adhesive force was decreased by the treatment in all groups compare to the control. Cells treated with AmB + allicin had a greater adhesive force than cells treated with AmB alone because of the secretion of molecules due to collapsed membranes. All cells treated with allicin or drugs were softer than the control cells. These results suggest that allicin can reduce MIC of AmB while keeping the same efficacy.