Ameliorating effect of CpG-ODN (oligodeoxynucleotide) against radiation-induced lung injury in mice.

While radiation-induced lung injury (RILI) is known to be progressed by Th2 skewed, pro-inflammatory immune response, there have been few therapeutic attempts through Th1 immune modulation. We investigated whether the immunostimulant CpG-oligodeoxynucleotide (CpG-ODN) would be effective against RILI by way of measuring reactive oxygen species (ROS) and nitric oxides (NO), histopathology, micro-three-dimensional computer tomography (CT), and cytokine profiling. We found that KSK CpG-ODN (K-CpG) significantly reduced histopathological fibrosis when compared to the positive control (PC) group (p < 0.01). The levels of ROS production in serum and splenocyte of PC group were significantly higher than that of K-CpG group (p < 0.01). The production of nitric oxide (NO) in CpG-ODNs group was higher than that of PC group. Last, cytokine profiling illustrated that the protein concentrations of Th1-type cytokines such as IL-12 and TNF-α as well as Th2-type cytokine IL-5 in K-CpG group inclined to be significantly (p < 0.001 or p < 0.01) higher than those of in PC group. Collectively, our study clearly indicates that K-CpG is effective against RILI in mice by modulating the innate immune response. To our knowledge, this is the first note on anti-RILI effect of human type, K-CpG, clinically implying the potential of immunotherapy for RILI control.

Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer.

Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations.

The differentiation of malignant mesotheliomas and benign mesothelial proliferations is crucial in determining patient care and prognosis. But, this distinction can be extremely difficult, particularly in small biopsies. Recently, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and glucose transporter 1 (GLUT-1) have been reported as specific and sensitive markers in the distinction of mesotheliomas from benign mesothelial proliferations. The purpose of this study is to evaluate the utility of IMP3, GLUT-1, and epithelial membrane antigen (EMA) immunohistochemistry for distinguishing mesotheliomas from benign mesothelial proliferations. Immunoexpression of IMP3, GLUT-1, and EMA was evaluated in 88 malignant mesotheliomas, 35 adenomatoid tumors, and 20 benign lung tissues with reactive mesothelial cells. The sensitivity for IMP3, GLUT-1, and EMA was 37%, 21%, and 41%, respectively. The specificity for IMP3, GLUT-1, and EMA was 100%. When IMP3, GLUT1, and EMA combined, the sensitivity was 66% for IMP3/EMA staining, 53% for GLUT-1/EMA staining, and 45% for IMP3/GLUT-1. Use of IMP3 and EMA together is more helpful to distinguish malignant mesotheliomas from benign mesothelial proliferations than the use of IMP3 or EMA alone.

Expression of adiponectin receptor 1 is indicative of favorable prognosis in non-small cell lung carcinoma.

Lung cancer is a major cause of cancer-related death worldwide. It is believed that obesity-related malignancies such as breast, endometrial, colorectal, and kidney carcinomas have lower plasma level and/or tissue expression of adiponectin receptors. However, the association between adiponectin receptors and lung cancer, a non obesity-related malignancy, is still unknown. We evaluated the tissue expression of adiponectin receptor (AdipoR) 1 and AdipoR2 in 83 cases of non-small cell lung carcinoma (NSCLC) and matched non-neoplastic lung tissues by immunohistochemistry and real-time polymerase chain reaction (PCR). Clinicopathological data, including smoking history, smoker's bronchiolitis, emphysema, lymph node metastasis, and T-stage were collected and evaluated. Expression of immunohistochemically stained AdipoR1 and AdipoR2 was observed in all samples of non-neoplastic lung tissues. Both receptors showed higher mRNA expression in non-neoplastic than neoplastic tissues (p < 0.05). In NSCLC tissues, AdipoR1 immunohistochemical expression was not observed in most of patients with squamous cell carcinoma and current smoking history (31/42, p = 0.04 and 25/29, p = 0.003, respectively). Additionally, AdipoR1 mRNA expression was significantly lower in patients with lymph node metastasis (p = 0.05). Meanwhile, AdipoR2 immunohistochemical stain expression was inversely correlated with T-stage (p = 0.05) and AdipoR2 mRNA expression was significantly lower in patients with smoker's bronchiolitis (p = 0.01) and emphysema (p = 0.03). Patients with expression of AdipoR1 had longer overall survival. AdipoR2 expression was not correlated with patients' survival. In conclusion, we suggest that expression of AdipoR1 is indicative of favorable prognosis and may be used as prognostic marker in NSCLC.

A decade of malignant mesothelioma surveillance in Korea.

BACKGROUND: The objectives of this study were to examine trends in mesothelioma incidence over a decade and to identify histories of asbestos exposure among cases in Korea. METHODS: In 2001, The Korea Occupational Safety and Health Agency organized a nationwide cardiopulmonary pathology group and established a malignant mesothelioma surveillance system covering all general hospitals in Korea. Mesothelioma cases were reported to this surveillance system with information about age, gender, location, occupational history, asbestos exposure environment, date of diagnosis, diagnostic method, histopathologic subtype, occurrence site, and other clinical information. Additionally, an epidemiological survey was conducted using a structured verbal questionnaire to allow further evaluation of asbestos exposures. RESULTS: A total of 399 cases of malignant mesothelioma were reported in the last decade, translating to approximately 40 annual cases, and an annual average incidence rate of 0.83 cases per million. Of the 152 patients interviewed by occupational physicians, 56 had occupational asbestos exposure histories (36.8%). Their occupations and industries included construction (19.7%), automobile repair (5.9%), asbestos textile, shipbuilding and repair, refinery work, boiler making, and asbestos cement work. Another 31 patients had environmental asbestos exposure histories. CONCLUSIONS: Surveillance data indicate that malignant mesothelioma incidence in Korea is, thus far, lower than that of other developed countries, and that construction and environmental asbestos exposure were the main identifiable causes of malignant mesothelioma.

Immunohistochemical distribution of toll-like receptor 4 in preterm human fetal membrane.

AIM: Toll-like receptor 4 (TLR-4) is the major receptor used for recognition of specific gram negative bacteria by the host immune system. The role of TLR-4 has been revealed in preterm parturition. This study aims to demonstrate the immunohistochemical expression of TLR-4 with regard to histological layers and anatomical regions of the human fetal membranes. MATERIAL AND METHODS: Fetal membranes were obtained from the uterine fundus and low segment. Immunohistochemical staining for TLR-4 and hematoxylin and eosin stain were performed. RESULTS: The chorion expressed significantly higher levels of TLR-4 than the amnion (P=0.001). There was no difference in the expression of TLR-4 between the uterine fundus and the uterine low segment (P=0.942). There was no significant difference in TLR-4 expression according to the presence of histological chorioamnionitis (P=0.444). TLR-4 expression decreased significantly with the progression of gestation (P=0.002). CONCLUSIONS: The level of expression of TLR-4 did not differ according to anatomic location, but did differ according to the histological layer of the human fetal membranes and gestational age. These results suggest that TLR-4 may be involved in preterm parturition.

Imaging Assessment of Visceral Pleural Surface Invasion by Lung Cancer: Comparison of CT and Contrast-Enhanced Radial T1-Weighted Gradient Echo 3-Tesla MRI.

OBJECTIVE: To compare the diagnostic performance of contrast-enhanced radial T1-weighted gradient-echo 3-tesla (3T) magnetic resonance imaging (MRI) and computed tomography (CT) for the detection of visceral pleural surface invasion (VPSI). Visceral pleural invasion by non-small-cell lung cancer (NSCLC) can be classified into two types: PL1 (without VPSI), invasion of the elastic layer of the visceral pleura without reaching the visceral pleural surface, and PL2 (with VPSI), full invasion of the visceral pleura. MATERIALS AND METHODS: Thirty-three patients with pathologically confirmed VPSI by NSCLC were retrospectively reviewed. Multidetector CT and contrast-enhanced 3T MRI with a free-breathing radial three-dimensional fat-suppressed volumetric interpolated breath-hold examination (VIBE) pulse sequence were compared in terms of the length of contact, angle of mass margin, and arch distance-to-maximum tumor diameter ratio. Supplemental evaluation of the tumor-pleura interface (smooth versus irregular) could only be performed with MRI (not discernible on CT). RESULTS: At the tumor-pleura interface, radial VIBE MRI revealed a smooth margin in 20 of 21 patients without VPSI and an irregular margin in 10 of 12 patients with VPSI, yielding an accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F-score for VPSI detection of 91%, 83%, 95%, 91%, 91%, and 87%, respectively. The McNemar test and receiver operating characteristics curve analysis revealed no significant differences between the diagnostic accuracies of CT and MRI for evaluating the contact length, angle of mass margin, or arch distance-to-maximum tumor diameter ratio as predictors of VPSI. CONCLUSION: The diagnostic performance of contrast-enhanced radial T1-weighted gradient-echo 3T MRI and CT were equal in terms of the contact length, angle of mass margin, and arch distance-to-maximum tumor diameter ratio. The advantage of MRI is its clear depiction of the tumor-pleura interface margin, facilitating VPSI detection.

Malignant rhabdoid tumor of the kidney combined with multicystic dysplasia in a 5-year-old child.

Multicystic dysplastic kidney (MCDK) is a relatively common developmental anomaly in infants and children and has a good prognosis. In contrast, a malignant rhabdoid tumor of the kidney (MRTK) is one of the most lethal neoplasms of early life. However, the presentation of such a lethal tumor combined with multicystic dysplasia has not been reported to date. In this report, we describe a case of MRTK in a 5-yr-old girl who also had multicystic dysplasia. She was previously diagnosed with MCDK at birth due to a huge palpable mass on the right side of the abdomen. The right kidney was extensively replaced by numerous grossly dilated, variable-sized cysts. Microscopically, the tumor cells show a diffusely infiltrative growth pattern, which revealed large non-cohesive, round-to-polygonal tumor cells with vesicular nuclei. Some tumor cells had eccentric nuclei and large, round, eosinophilic cytoplasmic inclusions. There were metanephrons present, with the central ureteric bud and peripheral branches surrounded by condensing mesenchyma, immature glomeruli, and metaplastic cartilage in the adjacent parenchyma. To our knowledge, this is the first combined case of the two aforementioned diseases and this case may, in fact, suggest a new disease entity.

LOX family and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that develops in the pleural and outer layer of tissues surrounding the lungs. MPM is primarily caused by occupational exposure to asbestos and results in a poor prognosis. Effective therapeutics as well as early diagnostics for the MPM are still lacking. To identify potential diagnostic biomarkers for MPM, we performed bioinformatics analysis of public database. METHODS: Utilizing databases from Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO), we identified several potential candidates that could act as MPM biomarkers. We carried out additional molecular analyses of these potential markers using MPM patient tissue samples via quantitative polymerase chain reaction. RESULTS: We identified Lysyl oxidase (LOX), Lysyl oxidase homologs 1&2 (LOXL1& LOXL2) Zinc Finger Protein, FOG Family Member 2 (ZFPM2) as potential diagnostic biomarkers for MPM. In this study, we found that the LOX family and ZFPM2 showed comparable diagnostic ability to Fibulin-3 or mesothelin (MSLN) and would be better potential biomarkers than Sulfatase 1 (SULF1), Thrombospondin 2 (THBS2) and Cadherin 11 (CDH11). CONCLUSIONS: LOX family and ZPFM2 were identified as novel MPM diagnostic biomarkers which could strengthen MPM clinical diagnostic capabilities.

A variety of bacterial aetiologies in the lower respiratory tract at patients with endobronchial tuberculosis.

Recently, our understanding of the elusive bacterial communities in the lower respiratory tract and their role in chronic lung disease has increased significantly. However, little is known about the respiratory microorganisms in patients with endobronchial tuberculosis (EBTB), which is a chronic inflammatory disease characterized by destruction of the tracheobronchial tree due to Mycobacterium tuberculosis (MTB) infection. We retrospectively reviewed data for histopathologically and microbiologically confirmed EBTB patients diagnosed at a tertiary referral hospital in South Korea between January 2013 and January 2019. Bacterial cultures were performed on bronchial washing from these patients at the time of EBTB diagnosis. A total of 216 patients with EBTB were included in the study. The median age was 73 years and 142 (65.7%) patients were female. Bacteria were detected in 42 (19.4%) patients. Additionally, bacterial co-infection was present in 6 (2.8%) patients. Apart from MTB, the most common microorganisms identified were Staphylococcus aureus (n = 14, 33.3%) followed by Klebsiella species (n = 12, 28.6%; 10 Klebsiella pneumoniae, 2 Klebsiella oxytoca), Streptococcus species (n = 5, 11.9%), Enterobacter species (n = 4, 9.5%), and Pseudomonas aeruginosa (n = 3, 7.1%). A variety of microorganisms were isolated from the bronchial washing indicating that changes in microorganism composition occur in the airways of patients with EBTB. Further studies are needed to investigate the clinical significance of this finding.

Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: The Damaging Effects of Air Pollution.

Air pollution poses a great environmental risk to health. Outdoor fine particulate matter (particulate matter with an aerodynamic diameter < 2.5 µm) exposure is the fifth leading risk factor for death in the world, accounting for 4.2 million deaths and > 103 million disability-adjusted life years lost according to the Global Burden of Disease Report. The World Health Organization attributes 3.8 million additional deaths to indoor air pollution. Air pollution can harm acutely, usually manifested by respiratory or cardiac symptoms, as well as chronically, potentially affecting every organ in the body. It can cause, complicate, or exacerbate many adverse health conditions. Tissue damage may result directly from pollutant toxicity because fine and ultrafine particles can gain access to organs, or indirectly through systemic inflammatory processes. Susceptibility is partly under genetic and epigenetic regulation. Although air pollution affects people of all regions, ages, and social groups, it is likely to cause greater illness in those with heavy exposure and greater susceptibility. Persons are more vulnerable to air pollution if they have other illnesses or less social support. Harmful effects occur on a continuum of dosage and even at levels below air quality standards previously considered to be safe.

Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 2: Air Pollution and Organ Systems.

Although air pollution is well known to be harmful to the lung and airways, it can also damage most other organ systems of the body. It is estimated that about 500,000 lung cancer deaths and 1.6 million COPD deaths can be attributed to air pollution, but air pollution may also account for 19% of all cardiovascular deaths and 21% of all stroke deaths. Air pollution has been linked to other malignancies, such as bladder cancer and childhood leukemia. Lung development in childhood is stymied with exposure to air pollutants, and poor lung development in children predicts lung impairment in adults. Air pollution is associated with reduced cognitive function and increased risk of dementia. Particulate matter in the air (particulate matter with an aerodynamic diameter < 2.5 µm) is associated with delayed psychomotor development and lower child intelligence. Studies link air pollution with diabetes mellitus prevalence, morbidity, and mortality. Pollution affects the immune system and is associated with allergic rhinitis, allergic sensitization, and autoimmunity. It is also associated with osteoporosis and bone fractures, conjunctivitis, dry eye disease, blepharitis, inflammatory bowel disease, increased intravascular coagulation, and decreased glomerular filtration rate. Atopic and urticarial skin disease, acne, and skin aging are linked to air pollution. Air pollution is controllable and, therefore, many of these adverse health effects can be prevented.

Optical diagnosis of cervical intraepithelial neoplasm (CIN) using polarization-sensitive optical coherence tomography.

We present a polarization-sensitive optical coherence tomography (PS-OCT) technique that can quantify the polarization changes (the degrees of circular polarization, DOCP) caused by the scattering changes induced by cervical intraepithelial neoplasia (CIN). The axial and lateral resolutions of our PS-OCT system are 13 microm and 15 microm, respectively. Uterine cervical conization tissue samples from 18 patients were examined, and 71 areas were imaged for in vitro studies; about 2-4 areas per sample were imaged and processed for diagnosis. The scanned areas had a size of 2 mm (axial) X 2 mm (lateral) X 4 mm (transversal). We quantified the slope of the axial decay of the DOCP signal near the cervical epithelium by a linear fitting procedure. The excised samples were then investigated by two pathologists, and their histological findings were later compared with the PS-OCT results. Our results show that the sensitivity and specificity are 94.7% and 71.2%, respectively.

TRAP1 Inhibition Increases Glutamine Synthetase Activity in Glutamine Auxotrophic Non-small Cell Lung Cancer Cells.

BACKGROUND/AIM: Cancer cells are distinct in terms of glutamine dependence. Here we investigated the different susceptibility of glutamine-independent and glutamine-dependent non-small cell lung cancer (NSCLC) to treatment with tumor necrosis factor receptor-associated protein 1 (TRAP1) inhibitor gamitrinib-triphenylphosphonium (G-TPP). MATERIALS AND METHODS: Cell viability and proliferation under glutamine deprivation and G-TPP treatment were determined by the MTT and colony-formation assays. Protein and mRNA expression were determined by western blot and quantitative polymerase chain reaction. Colorimetric-based assay was performed to check for glutamine synthetase (GS) activity. RESULTS: NSCLC cells showed diverse adaptation under glutamine-depleted condition and were categorized into glutamine-independent and glutamine-dependent cells. Treatment with G-TPP particularly increased GS activity and induced cell death due to energy shortage indicated by phosphorylated AMP-activated protein kinase (AMPK) in glutamine-dependent cells. CONCLUSION: This finding provides better understanding of TRAP1-mediated glutamine metabolism through GS activity, and evidence that TRAP1 could be a promising therapeutic target for glutamine-addicted cancer.

WITHDRAWN:A Clinicopathologic Study of 220 Cases of Pulmonary Sclerosing Pneumocytoma in Korea: A Nationwide Survey.

Ahead of Print article withdrawn by publisher.

Multidetector CT Findings and Differential Diagnoses of Malignant Pleural Mesothelioma and Metastatic Pleural Diseases in Korea.

OBJECTIVE: To compare the multidetector CT (MDCT) features of malignant pleural mesothelioma (MPM) and metastatic pleural disease (MPD). MATERIALS AND METHODS: The authors reviewed the MDCT images of 167 patients, 103 patients with MPM and 64 patients with MPD. All 167 cases were pathologically confirmed by sonography-guided needle biopsy of pleura, thoracoscopic pleural biopsy, or open thoracotomy. CT features were evaluated with respect to pleural effusion, pleural thickening, invasion of other organs, lung abnormality, lymphadenopathy, mediastinal shifting, thoracic volume decrease, asbestosis, and the presence of pleural plaque. RESULTS: Pleural thickening was the most common CT finding in MPM (96.1%) and MPD (93.8%). Circumferential pleural thickening (31.1% vs. 10.9%, odds ratio [OR] 3.670), thickening of fissural pleura (83.5% vs. 67.2%, OR 2.471), thickening of diaphragmatic pleura (90.3% vs. 73.4%, OR 3.364), pleural mass (38.8% vs. 23.4%, OR 2.074), pericardial involvement (56.3% vs. 20.3%, OR 5.056), and pleural plaque (66.0% vs. 21.9%, OR 6.939) were more frequently seen in MPM than in MPD. On the other hand, nodular pleural thickening (59.2% vs. 76.6%, OR 0.445), hilar lymph node metastasis (5.8% vs. 20.3%, OR 0.243), mediastinal lymph node metastasis (10.7% vs. 37.5%, OR 0.199), and hematogenous lung metastasis (9.7% vs. 29.2%, OR 0.261) were less frequent in MPM than in MPD. When we analyzed MPD from extrathoracic malignancy (EMPD) separately and compared them to MPM, circumferential pleural thickening, thickening of interlobar fissure, pericardial involvement and presence of pleural plaque were significant findings indicating MPM than EMPD. MPM had significantly lower occurrence of hematogenous lung metastasis, as compared with EMPD. CONCLUSION: Awareness of frequent and infrequent CT findings could aid in distinguishing MPM from MPD.

Erratum: Multidetector CT Findings and Differential Diagnoses of Malignant Pleural Mesothelioma and Metastatic Pleural Diseases in Korea.

[This corrects the article on p. 545 in vol. 17, PMID: 27390546.].

Comparison of EGFR mutation detection between the tissue and cytology using direct sequencing, pyrosequencing and peptide nucleic acid clamping in lung adenocarcinoma: Korean multicentre study.

BACKGROUND: The importance of sensitive methods for the detection of epidermal growth factor receptor (EGFR) mutation is emphasized. The aim of this study is to perform comparative and concordance analyses of direct sequencing, pyrosequencing and peptide nucleic acid (PNA) clamping for detecting EGFR gene mutations using archived tissue and cytology specimens. METHODS: Samples from a total of 112 cases, which were diagnosed with adenocarcinoma of the lung at nine hospitals in Korea were collected. Using the above three methods, the concordance rates of EGFR mutations in exons 18, 19, 20 and 21 were analysed and validated in comparative tissue and cytology specimens. RESULTS: Comparison of EGFR mutation detection between the tissue and cytology had a high concordance rate. The diagnostic performance of pyrosequencing and PNA clamping in tissue was higher than that of direct sequencing as well as cytology. Additionally, among some of the patients who had EGFR wild type by single method, EGFR mutations were detected by other methods. Cytology specimens had a diagnostic performance for the detection of EGFR mutations. CONCLUSIONS: Cytology specimens had a diagnostic performance for the detection of EGFR mutations that was comparable to that of tissues. For detecting EGFR mutations, pyrosequencing or PNA clamping was more sensitive than direct sequencing. In EGFR mutation negative patients who are difficult to obtain tissue, repeating test using pyrosequencing or PNA clamping is recommended to improve the detection rate of EGFR mutation than only one, especially in cytology.