As extracellular vesicles that play an active role in intercellular communication by transferring cellular materials to recipient cells, exosomes offer great potential as a natural therapeutic drug delivery vehicle. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IκB (srIκB), which is the dominant active form of IκBα and can inhibit translocation of nuclear factor κB into the nucleus. An optogenetically engineered exosome system (EXPLOR) that we previously developed was implemented for loading a large amount of srIκB into exosomes. We showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality and systemic inflammation in septic mouse models. In a biodistribution study, Exo-srIκBs were observed mainly in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, we found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells.

BACKGROUND.Adenosquamous carcinoma of the lung is composed of adenocarcinomatous and squamous cell carcinomatous components. The epidermal growth factor receptor (EGFR) mutations occur mostly in adenocarcinomas and rarely in squamous cell carcinoma of lung. Attempts to investigate the EGFR mutation status in each component of adenosquamous carcinoma and to characterize the patients according to mutation status may help to understand the histogenesis of adenosquamous carcinoma.METHODS.The mutation status of EGFR kinase domain from exon 18 to 21 was investigated in 25 Korean patients with adenosquamous carcinoma by polymerase chain reaction–single strand conformation polymorphism using the tissues of each component from the adenosquamous carcinoma tumor. Clinicopathologic characteristics of the patients according to the status of EGFR mutations were compared.RESULTS.EGFR mutations were identified in 11 (44%) patients: 9 mutations were in exon 19, 1 in exon 20, and 1 in exon 21. EGFR mutations were significantly more frequent (P = .005) in women (n = 8, 80%) than men (n = 3, 20%). Never‐smokers (n = 8, 62%) had EGFR mutations more commonly than smokers (n = 3, 25%; P = .111). Identical EGFR mutations in both components of adenosquamous carcinoma were confirmed by nucleotide sequencing.CONCLUSIONS.The frequency of EGFR mutation and clinicopathologic characteristics of the EGFR mutants in adenosquamous carcinoma are similar to those of Asian patients with adenocarcinomas. Identical EGFR mutations in both components suggest the possibility of monoclonality in the histogenesis of adenosquamous carcinoma. Cancer 2007;109:581–587. © 2006 American Cancer Society.

BackgroundThe development of chemo-resistance in non-small lung cancer is a major obstacle in treating patients. Hypoxia is a commonly faced microenvironment in solid tumor and suggested to be related to both autophagy and chemo-resistance.MethodsIn this study, we investigated the role of hypoxia-induced autophagy in acquiring chemo-resistance in both cancer cell (A549) and human cancer tissueResultsHypoxic exposure (1 % O2) of A549 cell stimulated autophagic induction in cancer cells, shown by increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 in Western blot, increased GFP-LC puncta in confocal microscopy, and increased number of double-membrane autophagic vacuoles in electron micrographs. Hypoxic exposure also induced resistance of cancer cells to cisplatin, and LC3B siRNA restored the sensitivity of cancer cells to chemotherapy. Furthermore, Human lung cancer tissues that experienced chemotherapy showed increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 compared with chemo-naïve cancer tissue in Western blot.ConclusionAutophagy may play an important role in acquiring resistance to chemotherapy in lung cancer and hypoxia related pathway seems to be involved in autophagy induction.

Background: While atlas segmentation (AS) has proven to be a time-saving and promising method for radiation therapy contouring, optimal methods for its use have not been well-established. Therefore, we investigated the relationship between the size of the atlas patient population and the atlas segmentation auto contouring (AC) performance. Methods: A total of 110 patients' head planning CT images were selected. The mandible and thyroid were selected for this study. The mandibles and thyroids of the patient population were carefully segmented by two skilled clinicians. Of the 110 patients, 100 random patients were registered to 5 different atlas libraries as atlas patients, in groups of 20 to 100, with increments of 20. AS was conducted for each of the remaining 10 patients, either by simultaneous atlas segmentation (SAS) or independent atlas segmentation (IAS). The AS duration of each target patient was recorded. To validate the accuracy of the generated contours, auto contours were compared to manually generated contours (MC) using a volume-overlap-dependent metric, Dice Similarity Coefficient (DSC), and a distance-dependent metric, Hausdorff Distance (HD). Results: In both organs, as the population increased from n = 20 to n = 60, the results showed better convergence. Generally, independent cases produced better performance than simultaneous cases. For the mandible, the best performance was achieved by n = 60 [DSC = 0.92 (0.01) and HD = 6.73 (1.31) mm] and the worst by n = 100 [DSC = 0.90 (0.03) and HD = 10.10 (6.52) mm] atlas libraries. Similar results were achieved with the thyroid; the best performance was achieved by n = 60 [DSC = 0.79 (0.06) and HD = 10.17 (2.89) mm] and the worst by n = 100 [DSC = 0.72 (0.13) and HD = 12.88 (3.94) mm] atlas libraries. Both IAS and SAS showed similar results. Manual contouring of the mandible and thyroid required an average of 1,044 (±170.15) seconds, while AS required an average of 46.4 (±2.8) seconds. Conclusions: The performance of AS AC generally increased as the population of the atlas library increased. However, the performance does not drastically vary in the larger atlas libraries in contrast to the logic that bigger atlas library should lead to better results. In fact, the results do not vary significantly toward the larger atlas library. It is necessary for the institutions to independently research the optimal number of subjects.

PurposeMultiple genetic factors are associated with chronic obstructive pulmonary disease (COPD). The association of gene encoding vitamin D binding protein (VDBP, GC) with COPD has been controversial. We sought to investigate the types of GC variants in the Korean population and determine the association of GC variants with COPD and lung function in the Korean population.Materials and MethodsThe study cohort consisted of 203 COPD patients and 157 control subjects. GC variants were genotyped by the restriction fragment-length polymorphism method. Repeated measures of lung function data were analyzed using a linear mixed model including sex, age, height, and pack-years of smoking to investigate the association of GC genetic factors and lung function.ResultsGC1F variant was most frequently observed in COPD (46.1%) and controls (42.0%). GC1S variant (29.0% vs. 21.4%; p=0.020) and genotype 1S-1S (8.3% vs. 3.4%; p=0.047) were more commonly detected in control than COPD. According to linear mixed model analysis including controls and COPD, subjects with genotype 1S-1S had 0.427 L higher forced expiratory volume in 1 second (FEV1) than those with other genotypes (p=0.029). However, interaction between the genotype and smoking pack-year was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014 L per smoking pack-year (p=0.001).ConclusionThis study suggested that GC polymorphism might be associated with lung function and risk of COPD in Korean population. GC1S variant and genotype 1S-1S were more frequently observed in control than in COPD. Moreover, GC1S variant was more common in non-decliners than in rapid decliners among COPD.

Human papillomavirus (HPV) infection is a co-carcinogen of lung cancer and contributes to its pathogenesis. To evaluate the prevalence of HPV infection, polymerase chain reaction (PCR) was employed to detect HPV 16, 18, and 33 DNA in tumor tissues of 112 patients with non-small cell lung cancer (NSCLC) who underwent curative surgery from Jan. 1995 to Dec. 1998 at Severance Hospital, Seoul, Korea. The patients consisted of 90 men and 22 women. Nineteen patients were under 50 years old (17%), and 92 patients (82%) were smokers. Fifty-three patients had adenocarcinomas, while 59 patients had non-adenocarcinomas. Early stage (I and II) cancer was found in 64 patients (57.1%) and advanced stage (III and IV) found in 48 (42.9%). The prevalence of HPV 16, 18, and 33 were 12 (10.7%), 11 (9.8%), and 37 (33.0%), respectively. Smoking status, sex, and histologic type were not statistically different in the presence of HPV DNA. The presence of HPV 16 was more common in younger patients and HPV 18 was more common in advanced stage patients. This study showed that the prevalence rate of HPV 16 and 18 infections in NSCLC tissue was low, suggesting HPV 16 and 18 infections played a limited role in lung carcinogenesis of Koreans. However, the higher prevalence of HPV 33 infections in Korean lung cancer patients compared to other Asian and Western countries may be important and warrants further investigation.

Related innate immune system activation and diagnostic factors of sepsis are not fully understood. The aim of this study was to analyze the clinical value of full-length tryptophanyl-tRNA synthetase (WRS) induced through inflammatory stimuli for the detection of sepsis and prediction of mortality in critically ill patients. Methods: This was a retrospective analysis of blood samples collected prospectively from patients in the medical intensive care unit (ICU) at Yonsei University College of Medicine, from March 2015 to June 2018. The ability of WRS to detect sepsis and predict mortality were compared to those of procalcitonin (PCT), C-reactive protein (CRP), and interleukin 6 (IL-6), and with Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Results: A total of 241 study patients were enrolled, of whom 190 (78.8%) had been diagnosed with sepsis on ICU admission. The areas under the receiver operating characteristics curves (AUROCs) for sepsis discrimination with WRS, PCT, CRP, and IL-6 levels, and SOFA and APACHE II scores were 0.864, 0.727, 0.625, 0.651, 0.840, and 0.754, respectively. The prediction of 28-day mortality in patients with sepsis using WRS levels was possible and non-inferior to that with the SOFA score. Conclusions: WRS secreted early in sepsis may be useful not only for the early detection of sepsis, but also for the prediction of mortality in critically ill patients.

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