Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells. MATERIALS AND METHODS: Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. RESULTS: Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis. CONCLUSION: Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.

Korean Version of the Delirium Rating Scale-Revised-98: Reliability and Validity

OBJECTIVE: The aims of the present study were 1) to standardize the validity and reliability of the Korean version of Delirium Rating Scale-Revised-98 (DRS-R98-K) and 2) to establish the optimum cut-off value, sensitivity, and specificity for discriminating delirium from other non-delirious psychiatric conditions. METHODS: Using DSM-IV criteria, 157 subjects (69 delirium, 29 dementia, 32 schizophrenia, and 27 other psychiatric patients) were enrolled. Subjects were evaluated using DRS-R98-K, DRS-K, Mini-Mental State Examination (MMSE-K), and Clinical Global Impression-Severity (CGI-S) scale. RESULTS: DRS-R98-K total and severity scores showed high correlations with DRS-K. They were significantly different across all groups (p=0.000). However, neither MMSE-K nor CGI-S distinguished delirium from dementia. All DRS-R98-K diagnostic items (#14-16) and items #1 and 2 significantly discriminated delirium from dementia. Cronbach's alpha coefficient revealed high internal consistency for DRS-R98-K total (r=0.91) and severity (r=0.89) scales. Interrater reliability (ICC between 0.96 and 1) was very high. Using receiver operating characteristic analysis, the area under the curve of DRS-R98-K total score was 0.948 between the delirium group and all other groups and 0.873 between the delirium and dementia groups. The best cut-off scores in DRS-R98-K total score were 18.5 and 19.5 between the delirium and the other three groups and 20.5 between the delirium and dementia groups. CONCLUSION: We demonstrated that DRS-R98-K is a valid and reliable instrument for assessing delirium severity and diagnosis and discriminating delirium from dementia and other psychiatric disorders in Korean patients.

A Case of Pseudoaneurysm Developed during Intensive Treatment of Status Asthmaticus: A Case Report / 대한구급학회지

Pseudoaneurysm formation in the pulmonary vasculature is a rare but fatal condition. Several etiologies have been described including trauma, complication after cardiac or other surgeries, tuberculosis, necrotizing pneumonia, congestive heart disease, atherosclerosis, cancer and vasculitis. We report a case of pseudoaneurysm found in a patient being treated with status asthmaticus, who developed complications of pneumonia and brain abscess secondary to sepsis.

Diaphragmatic Hernia of the Right Hepatic Lobe Mistaken for Diaphragmatic Paralysis in Adult / 결핵및호흡기질환

Diaphragmatic paralysis can be demonstrated through diaphragmatic elevation on chest X-ray after thoracic lung surgery or the placement of chest tubing. Additional causes of diaphragmatic paralysis are iatrogenic, mass, atelectasis, etc. For the diagnosis of diaphragmatic paralysis, it required some studies (fluoroscopy, computed tomography [CT], magnetic resonance imaging). Diaphragmatic hernia of the liver is a rare clinical entity, usually found after trauma in adults. Congenital diaphragmatic hernia in neonates requires surgery. Non-traumatic diaphragmatic hernia of the liver in an adult is a rare right-sided diaphragmatic hernia. On developing any symptoms, surgery must be performed. When diaphragmatic hernia is incidentally found in adults without trauma, it is placed under observation for a time period. We diagnosed the diaphragmatic herniation of a right hepatic lobe by 16-slice CT scan without surgery.

Two Cases of Chemical Pneumonitis Induced by Hydrocarbon Aspiration / 결핵및호흡기질환

Chemical pneumonitis induced by hydrocarbon aspiration is rare in Korea. Kerosene is a petroleum distillate with low viscosity and high volatility. We report two adult cases of chemical pneumonitis caused by the accidental aspiration of kerosene. They were treated successfully with antibiotics and systemic corticosteroids, and recovered without complications.

The Effect of Inhibition of Heme Oxygenase-1 on Chemosensitivity of Cisplatin in Lung Cancer Cells / 결핵및호흡기질환

BACKGROUND: Heme oxygenase-1 (HO-1) is known to modulates the cellular functions, including cell proliferation and apoptosis. It is known that a high level of HO-1 expression is found in many tumors, and HO-1 plays an important role in rapid tumor growth on account of its antioxidant and antiapoptotic effects. Cisplatin is a widely used anti-cancer agent for the treatment of lung cancer. However, the development of resistance to cisplatin is a major obstacle to its use in clinical treatment. We previously demonstrated that inhibiting HO-1 expression through the transcriptional activation of Nrf2 induces apoptosis in A549 cells. The aim of this study was to determine of the inhibiting HO-1 enhance the chemosensitivity of A549 cells to cisplatin. MATERIALS AND METHODS: The human lung cancer cell line, A549, was treated cisplatin, and the cell viability was measured by a MTT assay. The change in HO-1, Nrf2, and MAPK expression after the cisplatin treatment was examined by Western blotting. HO-1 inhibition was suppressed by ZnPP, which is a specific pharmacologic inhibitor of HO activity, and small interfering RNA (siRNA). Flow cytometry analysis and Western blot were performed in to determine the level of apoptosis. The level of hydrogen peroxide (H2O2) generation was monitored fluoimetrically using 2',7'-dichlorofluorescein diacetate. RESULTS: The A549 cells showed more resistance to the cisplatin treatment than the other cell lines examined, whereas cisplatin increased the expression of HO-1 and Nrf2, as well as the phosphorylation of MAPK in a time-dependent fashion. Inhibitors of the MAPK pathway blocked the induction of HO-1 and Nrf2 by the cisplatin treatment in A549 cells. In addition, the cisplatin-treated A549 cells transfected with dither the HO-1 small interfering RNA (siRNA) or ZnPP, specific HO-1 inhibitor, showed in a more significantly decrease in viability than the cisplatin-only-treated group. The combination treatment of ZnPP and cisplatin caused in a marked increase in the ROS generation and a decrease in the HO-1 expression. CONCLUSION: Cisplatin increases the expression of HO-1, probably through the MAPK-Nrf2 pathway, and the inhibition of HO-1 enhances the chemosensitivity of A549 cells to cisplatin.

Diaphragmatic Paralysis Following Cervical Herpes Zoster / 결핵및호흡기질환

Herpes zoster is well-known viral disease in immune compromised that produces inflammatory lesions in the posterior root ganglia and is characterized clinically by pain and skin eruptions along the distribution of the affected ganglia. However, motor involvement after a herpes zoster is an uncommon complication. We report a case of diaphragmatic paralysis that occurred after a herpes zoster in 63-year-old woman. The diaphragmatic paralysis occurred one month after the typical herpes zoster eruptions affecting the C3 and C4 dermatomes in the right neck, shoulder and back area.

Phase II Study of Irinotecan Plus Cisplatin as First Line therapy in Extensive Small-Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Irinotecan (topoisomerase I inhibitor) is effective as a monotherapy against small-cell lung cancer(SCLC). Cisplatin is also an important drug against SCLC. A phase II study of irinotecan combined with cisplatin was carried out to evaluate the efficacy and toxicity of this combined regimen as a first line treatment in patients with extensive SCLC. METHODS: Thirty-nine patients with previously untreated extensive SCLC were enrolled in this study. Irinotecan 60mg/m(2) was administered intravenously on days 1, 8 and 15, and in combination with cisplatin 60mg/m(2) on day 1 and every 28 days thereafter. Four cycles of chemotherapy were given to the patients. RESULTS: The overall response rate was 77% with a complete response (CR) rate of 8%. The median survival time, 1- and 2-year survival rate were 14.8 months, 60.9% and 27.6%, respectively. The median progression free survival time, 6-and 12-month progression free survival rate were 8.4 months, 75% and 18.8%, respectively. The WHO grade 3 or more toxicity encountered were leukopenia (23%), diarrhea (26%). Two patients changed their chemotherapeutic regimen and one patient died from severe diarrhea. CONCLUSION: The combination of irinotecan and cisplatin is effective as a first line therapy in extensive SCLC is effective , but has severe or fatal diarrhea as toxicity.

Heme Oxygenase-1 via Transcriptional Activation of Nrf2 Attenuates Apoptosis in Lung Cancer Cells

PURPOSE : Increasing evidences have indicated the critical role of HO-1 in cytoprotection and more diverse biological functions. HO-1 has been reported to stimulate tumor cell growth and proliferation. And several tumors, including renal cell carcinoma, prostate tumor, hepatoma, and sarcoma, express a high level of HO-1. Indeed, inhibition of HO-1 by using specific HO inhibitors demonstrated in vivo antitumor activity. However, the precise mechanism of HO-1 induction and signals in lung cancer is not clearly known yet. We aimed to analyze the role of HO-1, characterize the mechanism of HO-1 induction, the role of Nrf2 in the induction, and investigated whether inhibition of HO-1 may induce apoptosis in lung cancer cells. MATERIALS AND METHODS : Western blot and immunostaining analyses were performed to ascertain whether HO-1, Nrf2, and NFkB were expressed or not in various lung cancer cell lines. Apoptosis by HO-1 inhibition through siRNA transfection was measured by flow cytometric analysis and Western blot. And the expression of HO-1 by siRNA of Nrf2 and NFkB was examined by ARE-driven luciferase activity and Western blot. RESULTS : We demonstrated that HO-1 was expressed highly in A549 cells than other lung cancer cells. And A549 cells were transfected by HO-1 small interfering RNA (siRNA) induced apoptosis. Nrf2 siRNA, next, resulted in a decrease of HO-1 expression. However, NFkB siRNA had no influence on the expression of HO-1. CONCLUSION : Increasing HO-1 expression in A549 cells may be resulted from the transcriptional activation of Nrf2, and inhibition of Nrf2-HO-1 pathway induces apoptosis. Therefore it provides new important insights into the possible molecular mechanism of the antitumor therapy

The Role of Heme Oxygenase-1 in Lung Cancer Cells / 결핵및호흡기질환

BACKGROUND: Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the oxidative degradation of heme to form biliverdin, carbon monoxide (CO), and free iron. The current evidence has indicated a critical role of HO-1 in cytoprotection and also in other, more diverse biological functions. It is known that the high expression of HO-1 occurs in various tumors, and that HO-1 has an important role in rapid tumor growth because of its antioxidative and antiapoptotic effects. Therefore, the role of HO-1 was analyzed in human lung cancer cell lines, and especially in the A549 cell line. MATERIAL AND METHODS: Human lung cancer cell lines, i.e., A549, NCI-H23, NCI-H157 and NCI-H460, were used for this study. The expression of HO-1 in the untreated state was defined by Western blotting. ZnPP, which is the specific HO inhibitor we used, and the viability of cells were tested for by conducting MTT assaysy. The HO enzymatic activity, as determined via the bilirubin level, was also indirectly measured. Moreover, the generation of intracellular hydrogen peroxide (H2O2) was monitored fluorimetrically with using a scopoletin-horse radish peroxidase (HRP) assay and 2',7'-dichlorofluorescein diacetate (DCFH-DA). We have also transfected small HO-1 interfering RNA (siRNA) into A549 cells, and the apoptotic effects were evaluated by flow cytometric analysis and Western blotting. RESULTS: The A549 cells had a greater expression of HO-1 than the other cell lines, whereas ZnPP significantly decreased the viability of the A549 cells more than the viability of the other lung cancer cells in a dose-dependant fashion. Consistent with the viability, the HO enzymatic activity also was decreased. Moreover, intracellular H2O2 generation via ZnPP was induced in a dose-dependent manner. Apoptotic events were, then induced in the HO-1 siRNA transfected A549 cells. CONCLUSION: HO-1 provides new important insights into the possible molecular mechanism of the antitumor therapy in lung cancer.

Adjuvant Chemotherapy after Surgical Resection for Small-Cell Carcinoma of Lung / 결핵및호흡기질환

BACKGROUND: Small-cell carcinoma of lung has a tendency of rapid growth and early wide metastasis. In spite of high response rate of combination chemotherapy alone or with radiotherapy, overall long-term survival rate is very disappointed. According to autopsy findings, the common cause of failure is local recurrence in primary cancer site. So, surgical resection with combined chemotherapy has been recently attempted for very early stage of small-cell carcinoma of lung. METHODS: 10 patients (TNM I: & II: 5 cases) undergoing surgical resection for small-cell carcinoma of lung with adjuvant chemotherapy in an attempt to prolong survival. Of these, 9 patients received chemotherapy, and retrospective study was undertaken for survival (Kaplan-Meier analysis). RESULTS: Median survival time was 26 months, 2-, 5-year survival rate was 68.6%, 46.7%. If 1 patient without chemotherapy was excluded, 2-, 5-year survival rate was 76.2%, 50.8%. No survival difference was seen between patients with TNM I, II stages. CONCLUSION: Adjuvant chemotherapy after surgical resection results in prolonged survival for patients with TNM stage I, II small-cell carcinoma of lung.

A Reliability and Validity Study of the Reciprocal Attachment Questionnaire: Korean Version (RAQ-K)(I) / 신경정신의학

OBJECTIVES: The aim of this study was to develop the Reciprocal Attachment Questionnaire-Korean version (RAQ-K). METHODS: The authors tested the reliability of dimensional and pattern scales of RAQ-K with Crohnbach's alpha, test-retest reliability and interscale correlation, and construct validity with factor analysis. The subjects were Korean undergraduate students: 234 males and 249 females in the medical and nursing schools of Kyungpook National University. RESULTS: The dimensional scale of RAQ-K proved to be reliable in terms of Crohnbach's alpha coefficient except Availability and Use subscales, test-retest reliability and interscale correlation. The pattern scales of RAQ-K were reliable. Both dimensional and pattern scales were valid with two factor orthogonal rotation. CONCLUSION: The authors found RAQ-K retained available psychometric properties. But further study with some consideration to develop RAQ-K is expected. This research should assess samples of various age groups or various kinds of patients after considering two subscales. The authors stress that it is very important to consider the cultural difference between the East and the West and characteristics of Korean culture in developing a Korean version of foreign scales.

A Case of Bronchopulmonary Atypical Carcinoid Tumor with Liver Metastasis / 결핵

Bronchial carcinoid tumors are uncommon, constituting approximately 5% of all primary lung cancers. Carcinoid tumors belong to the calss of neuroendocrine tumors that consist of cells that can store and secrete neuramines and neuropeptides. Neuroendocrine tumors of the lung include three pathologic types: a low-grade malignancy, the so-called "typical carcinoid", a more aggressive tumor, the "atypical carcinoid" and the most aggressive malignant neoplasm, the small-cell carcinoma. Atypical carcinoid tumor, have a higher malignant potential, is more commonly peripheral than is the typical carcinoid tumor. Histologic features would characterize a carcionoid as hitologically atypical: increased mitotic activity, pleomorphism and irregularity of neuclei with promonent nucleoli, hyperchromatin, and abnormal nuclear-cytoplasmic ratio, areas of increased cellularity with disorganization of architecture, and areas of tumor necrosis. Metastatic involvement of regional lymph nodes and distant organ is common. The prognosis is related to size of the tumor, typical or atypical appearance, endoluminal or extraluminal growth, vascular invasion, node metastasis. Pulmonary resection is the treatement of choice for bronchial carcinoid. We experienced one case of bronchopulmonary atypical carcinoid tumor. In the case, radiologic study showed solitary lung mass with liver metastasis and the level of 5-HIAA was elevated. There was no history of cutaneous flushing, diarrhea, valvular heart disease. The authors reported a case of brochopulmonary atypical carcinoid tumor with review of literatures.