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Malignancy and tuberculosis are common causes of lymphocytic exudative pleural effusion. However, it is occasionally difficult to differentiate malignant pleural effusion from tuberculous pleural effusion. Vascular endothelial growth factor (VEGF) is a critical cytokine in the pathogenesis of malignant pleural effusion. Endocan is a dermatan sulfate proteoglycan that is secreted by endothelial cells. Importantly, endocan mediates the vascular growth-promoting action of VEGF. The aim of this study was to evaluate the diagnostic significance of VEGF and endocan in pleural effusion. We thus measured the levels of VEGF and endocan in the pleural effusion and serum samples of patients with lung cancer (n = 59) and those with tuberculosis (n = 32) by enzyme-linked immunosorbent assay. Lung cancer included 40 cases of adenocarcinoma, 13 of squamous cell carcinoma, and 6 of small cell carcinoma. Pleural effusion VEGF levels were significantly higher in the malignant group than in the tuberculosis group (2,091.47 ± 1,624.80 pg/mL vs. 1,291.05 ± 1,100.53 pg/mL, P < 0.05), whereas pleural effusion endocan levels were similar between the two groups (1.22 ± 0.74 ng/mL vs. 0.87 ± 0.53 ng/mL). The areas under the curve of VEGF and endocan were 0.73 and 0.52, respectively. Notably, the VEGF levels were similar in malignant pleural effusion, irrespective of the histological type of lung cancer. Moreover, no significant difference was found in the serum VEGF and endocan levels between patients with lung cancer and those with tuberculosis. In conclusion, high VEGF levels in pleural effusion are suggestive of malignant pleural effusion.

We report first case of pulmonary siderosis appearing as a consolidation upon radiological examination and being misdiagnosed as pneumonia. A 59-year-old man visited our hospital with a cough and sputum that had persisted for more than a month. He had undergone chest computed tomography (CT) after abnormal findings on chest X-ray at other hospitals. Based on the chest CT results, he was diagnosed with pneumonia. He was then administered antibiotics for 3 weeks, but there was no improvement. We identified the patient's occupational history first, and then performed bronchoalveolar lavage and chest CT-guided transthoracic lung biopsy. The obtained specimen showed alveolar, macrophage-containing, Prussian blue-positive iron particles. Based on the results, we diagnose/d the patient with pulmonary siderosis. We advised him to discontinue his job. He is currently undergoing observation, and has not shown any special symptoms. Keywords: Pulmonary siderosis, Bronchoalveolar lavage, Transthoracic lung biopsy

Histone deacetylase (HDAC) inhibition offers the potential for anti-cancer effects in a variety of cancers, since HDAC plays an important role in cancer development and progression. Thus, we demonstrated the therapeutic efficacy of the new HDAC inhibitor, CG200745, in comparison with existing HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA) in non-small lung cancer cells. Compared with SAHA, CG200745 had inhibited cell viability and HDACs expression, and induced apoptosis, ROS and mitochondrial dysfunction. CG200745 also significantly reduced tumor volume in vivo compared with SAHA. We observed increased apoptosis and ROS after treatment with survivin siRNA and CG200745, whereas overexpression of survivin protected against apoptosis and ROS by CG200745. We next demonstrated that CG200745 reduced the acetylation of survivin and that survivin is present in the nucleus. CG200745 showed a decrease in the stability of survivin. Furthermore, CG200745 increased expression of actylated-p53 and decreased activity of survivin promoter. We found that -189 ~ -11 plays an important role in the p53 binding site of the survivin promoter, and binding of p53, is increased depending on the CG200745 concentration. Collectively, these data shows that CG200745 induces apoptosis more than SAHA through down-regulation of survivin in NSCLC cells. CG200745 reduces the stability of survivin by inhibiting deacetylation of survivin, and decreases the promoter activity of survivin by acetylating p53.

Background: Oleanolic acid acetate (OAA) is a triterpenoid compound derived from Vigna angularis and is known to have various effects such as tumor suppression, kidney protection, and anti-inflammatory effect. However, research on the inhibition mechanisms of OAA in fibrosis is limited. In this study, we investigated the effects of OAA on bleomycin-induced pulmonary fibrosis in mice and its underlying mechanism in vivo and in vitro. Methods: The in vivo effect of OAA was evaluated by measuring histological changes, mRNA, BALF, collagen content and protein expression in bleomycin-indcued pulmonary fibrosis mice. The in vitro effect of OAA was evaluated proliferation, mRNA and protein expression of A549 and NIH3T3 cells were analyzed by CCK-8, real-time PCR and Western blot respectively. Mice were treated with bleomycin and OAA was orally administered for 14 days after bleomycin injection, and A549 and NIH3T3 cells were induced by TGF-b1 for 48 hours. Results: OAA treatment reduced inflammatory cell count, cytokine level and soluble protein accumulation in bronchoalveolar lavage fluid, and ameliorated weight loss and lung weight, lung histopathological abnormality and pulmonary collagen deposition. OAA also inhibited the expression of EMT and fibrotic markers in vivo and in vitro. Moreover, levels of TGF-β1, p-Smad2, and p-Smad3 in vivo and in vitro decreased after OAA treatment. Conclusion: OAA inhibits bleomycin-induced pulmonary fibrosis by inhibiting EMT and may be a novel therapeutic drug for the treatment of idiopathic pulmonary fibrosis.

// Byong-Ki Cha 1, * , Young-Suk Kim 2, * , Ki-Eun Hwang 2 , Kyung-Hwa Cho 2 , Seon-Hee Oh 3 , Byoung-Ryun Kim 4 , Hong-Young Jun 5 , Kwon-Ha Yoon 6 , Eun-Taik Jeong 2 , Hak-Ryul Kim 2 1 Department of Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonbuk, Korea 2 Departments of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine 344-2 shinyong-dong Iksan, Jeonbuk, Korea 3 Department of Premedicine, School of Medicine, Chosun University, Gwangju, Korea 4 Department of Obstetrics & Gynecology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 5 Imaging Science Research Center, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 6 Departments of Radiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea * These authors have contributed equally to this work Correspondence to: Hak-Ryul Kim, email: kshryj@wku.ac.kr Keywords: celecoxib, sulindac, EMT, SIRT1, lung cancer Received: December 16, 2015 Accepted: July 26, 2016 Published: August 09, 2016 ABSTRACT The non-steroidal anti-inflammatory drugs (NSAIDs) celecoxib and sulindac have been reported to suppress lung cancer migration and invasion. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. However, its role in inhibition of lung cancer cell epithelial-mesenchymal transition (EMT) by NSAIDs is not clearly known. We attempted to investigate the potential use of NSAIDs as inhibitors of TGF-β1-induced EMT in A549 cells, and the underlying mechanisms of suppression of lung cancer migration and invasion by celecoxib and sulindac. We demonstrated that celecoxib and sulindac were effective in preventing TGF-β1-induced EMT, as indicated by upregulation of the epithelial marker, E-cadherin, and downregulation of mesenchymal markers and transcription factors. Moreover, celecoxib and sulindac could inhibit TGF-β1-enhanced migration and invasion of A549 cells. SIRT1 downregulation enhanced the reversal of TGF-β1-induced EMT by celecoxib or sulindac. In contrast, SIRT1 upregulation promoted TGF-β1-induced EMT. Taken together, these results indicate that celecoxib and sulindac can inhibit TGF-β1-induced EMT and suppress lung cancer cell migration and invasion via downregulation of SIRT1. Our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse TGF-β1-induced EMT and to prevent lung cancer cell migration and invasion.

BACKGROUND/AIMS Brain and bone metastases are common in patients with lung cancer. The development of metastasis is associated with poor survival in lung cancer patients. Although tumor morphologic features on radiographs are routinely assessed for differentiation between benign and malignant lung nodules, they are not used to predict metastasis. We assessed morphologic features of pulmonary adenocarcinomas with brain/bone metastasis on computed tomography (CT) to identify related factors for metastasis. METHODS We performed a retrospective analysis of initial chest CT findings (size, type of contour, percentage of necrosis, enhancement, presence or absence of calcification, and air cavity) from 2009 to 2010 of patients with brain or bone metastasis and compared the findings with those of patients without metastases. RESULTS In total, 128 patients were included (78 men, 52 women; mean age 69 years; range, 36 to 87). Nineteen patients had brain metastases and 32 had bone metastases. Morphologic features associated with brain metastasis included size ≥ 50 mm (odds ratio [OR], 3.37; 95% confidence interval [CI], 1.24 to 9.17; p = 0.013), necrosis ≥ 30% (OR, 4.51; 95% CI, 1.62 to 12.55; p =0.002), and presence of calcification (OR, 3.97; 95% CI, 1.16 to 13.55; p = 0.035). Morphologic features associated with bone metastasis included necrosis ≥ 30% (OR, 4.639; 95% CI, 1.98 to 10.82; p < 0.001) and T 3 to 4 stage (OR, 2.53; 95% CI, 1.07 to 6.00; p = 0.031). CONCLUSIONS We found that necrosis ≥ 30% was associated with pulmonary adenocarcinoma with brain and bone metastasis at initial chest CT morphologic feature. To validate these results, further research should be conducted.

We report an unusual case of obstructive pneumonia due to an unknown eosinophilic mucoid impaction of the bronchi (MIB). A 54-year-old woman visited our hospital for investigation of abnormal shadows visible on a chest radiograph. Chest computed tomography and bronchoscopic examination revealed pneumonia due to MIB. Histopathological examination of biopsied mucosal tissue revealed extensive eosinophilic infiltration. With the exclusion of medical diseases that can cause eosinophilia, pneumonia due to eosinophilic mucoid impaction of the bronchi was diagnosed. The cause of the eosinophilia remained unknown. The pneumonia and mucoid impaction resolved after oral steroid therapy. (Korean J Med 2015;89:699-703)

The tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial heat shock protein that has been related to drug resistance in some tumors. Epithelial-mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. The aim of the present study was to determine the role of TRAP1 on EMT in lung cancer cell lines and to evaluate the prognostic role of TRAP1 in NSCLC patients. We developed an in vitro model of acquired resistance to gefitinib by continuously treating HCC827 with escalating doses. The effects of TRAP1 on EMT and lung cancer migration and invasion in gefitinib resistance (GR) cells were examined by western blotting and confocal microscopy. Downregulation of TRAP1 through siRNA or G-TPP inhibited GR-induced EMT, as indicated by upregulation of E-cadherin, and downregulation of mesenchymal markers and transcriptional factors. TRAP1 expression was analysed by immunohistochemistry in a series of 97 NSCLC patients. TRAP1 expression correlates with poor outcome in NSCLC patients. We next showed that TRAP1 downregulation enhanced the reversal of TGF-β1-induced EMT and hypoxia-induced EMT. Furthermore, TRAP1 downregulation attenuated migration and invasion of HCC827GR cells. In conclusions, these results suggested that TRAP1 downregulation could overcome gefitinib resistance in NSCLC via EMT reversal in tumor microenvironment.

TNF receptor-associated protein 1 (TRAP1) has been reported to be upregulated in some tumors, and protected against apoptosis and oxidative stress. This study was designed to investigate overcoming gefitinib resistance in NSCLC through a mechanism-based approach using gamitrinib variant containing triphenylphosphonium (G-TPP), TRAP1 inhibitor. We developed an in vitro model of acquired resistance to gefitinib. The effects of G-TPP on apoptosis and ROS-dependent mitochondrial dysfunction in HCC827GR cells were examined by annexin V binding assay, MitoSoX, and immunoblot analysis. and we tested the effects of pretreated with NAC or DPI, free radical scavenger. In addition, TRAP1 and antioxidant MnSOD were respectively knocked down or overexpressed to determine its role in modulating ROS-mediated apotosis signals by G-TPP. Downregulation of TRAP1 through siRNA or G-TPP enhanced ROS-mediated apoptosis whereas TRAP1 overexpression attenuated ROS-mediated apoptosis induced by gefitinib. On the other hand, pretreatment with NAC or DPI prevents apoptosis induced by gefitinib and G-TPP. We next showed that the combination of gefitinib and G-TPP resulted in decreased expression of MnSOD in HCC827GR cells, not HCC827 cells. MnSOD siRNA and combined with gefitinib and G-TPP resulted in a greater apoptosis. In contrast, overexpression of MnSOD could confer protection against the apoptosis reduced by gefitinib and G-TPP. TRAP1 downregulation could overcome gefitinib resistance in NSCLC via ROS-mediated apoptotic pathway. Moreover, enhanced apoptosis by gefitinib and G-TPP in HCC827GR cells was due, at least in part, to the down-regulation of MnSOD.

Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N-acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation.

The antibiotic salinomycin was recently identified as an antitumor drug for the treatment of several types of solid tumors. However, the effects of salinomycin on the migratory and invasive properties of non-small cell lung cancer (NSCLC) are unclear. This study was aimed to investigate the inhibitory effect and accompanying mechanisms of salinomycin on epithelial-to-mesenchymal transition (EMT) and cell migration induced by transforming growth factor-β1 (TGF-β1). In human A549 and H460 NSCLC, salinomycin strongly blocked the enhancement of cell migration by TGF-β1-induced EMT through recovering the loss of E-cadherin and suppressing the induction of mesenchymal markers as well as the upregulation of TGF-β1-mediated AMPK/SIRT signaling activity. We demonstrated that salinomycin was effective in preventing TGF-β1-induced EMT, as indicated by upregulation of the epithelial marker, E-cadherin, and downregulation of mesenchymal markers and transcription factors. Moreover, salinomycin could inhibit TGF-β1-enhanced migration and invasion of A549 and H460 cells. MMP-2 and MMP-9 downregulation enhanced the reversal of TGF- β1-induced EMT by salinomycin. In contrast, AMPK/SIRT upregulation promoted TGF- β1-induced EMT. Salinomycin can inhibit TGF-β1-induced EMT and suppress lung cancer cell migration and invasion via downregulation of MMP-2 and MMP-9. Our findings implicate overexpressed AMPK/SIRT1 as a potential therapeutic target to reverse TGF-β1-induced EMT and to prevent lung cancer cell migration and invasion.

Background Shikonin, a natural naphthoquinone pigment purified from Lithospermum erythrorhizon, induces necroptosis in various cancer types, but the mechanisms underlying the anticancer activity of shikonin in lung cancer are not fully understood. This study was designed to clarify whether shikonin causes necroptosis in non-small cell lung cancer (NSCLC) cells and to investigate the mechanism of action. Methods Multiplex and caspase 8 assays were used to analyze effect of shikonin on A549 cells. Cytometry with annexin V/PI staining and MTT assays were used to analyze the mode of cell death. Western blotting was used to determine the effect of shikonin-induced necroptosis and autophagy. Xenograft and orthotopic models with A549 cells were used to evaluate the anti-tumor effect of shikonin in vivo. Results Most of the cell death induced by shikonin could be rescued by the specific necroptosis inhibitor necrostatin-1, but not by the general caspase inhibitor Z-VAD-FMK. Tumor growth was significantly lower in animals treated with shikonin than in the control group. Shikonin also increased RIP1 protein expression in tumor tissues. Autophagy inhibitors, including methyladenine (3-MA), ATG5 siRNA, and bafilomycin A, enhanced shikonin-induced necroptosis, whereas RIP1 siRNA had no effect on the apoptotic potential of shikonin. Conclusions Our data indicated that shikonin treatment induced necroptosis and autophagy in NSCLC cells. In addition, the inhibition of shikonin-induced autophagy enhanced necroptosis, suggesting that shikonin could be a novel therapeutic strategy against NSCLC.

Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib–simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/β-catenin signaling-dependent down-regulation of survivin and apoptosis induction.

Aims Lung cancer remains the leading cause of cancer mortality worldwide. Despite their poor prognosis, patients with lung cancer are increasingly being admitted to the medical intensive care unit (MICU) for treatment of critical illnesses. The aim of this study was to assess the outcome of patients with lung cancer who are admitted to an MICU and to identify the measurable predictors of their MICU outcome. Methods We conducted retrospective analysis on 97 patients with lung cancer admitted to the MICU between 2007 and 2011. Results The mean age ± standard deviation was 71.8 ± 6.8 years. Of the 97 patients (82 male), 73 patients (75%) had non-small cell lung cancer stage IIIB, IV and 24 patients (25%) had small cell lung cancer. The intensive care unit mortality and in-hospital mortality rates were 53.6 and 61.8%. The main reasons for MICU admission were pneumonia (n = 51) and complication of cancer management (n = 45). The predictors of poor MICU outcome were history of diabetes mellitus (P = 0.028), Acute Physiology and Chronic Health Evaluation II score (P = 0.018), need for mechanical ventilation (P = 0.014), use of vasoactive agents (P

First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for patients with advanced non-small cell lung cancer who were selected on the basis of EGFR mutations have improved the progression-free survival with acceptable toxicity compared to standard chemotherapy. However, acquired resistance to EGFR-TKIs has been identified as an important clinical problem. Transformation to small cell lung cancer (SCLC) is a rare mechanism of resistance to EGFR-TKI therapy. We describe the case of a 61-year-old man who presented transformation from adenocarcinoma to SCLC as the manifestation of acquired resistance after EGFR-TKI treatment. He underwent chemotherapy with etoposide and cisplatin and achieved a complete response.

Clostridium difficile infection (CDI) is a common nosocomial infection. Lung cancer patients have a high risk of developing CDI because of continuous antibiotic treatment or chemotherapy, prolonged hospitalization, and general weakness. This study aimed to analyze predisposing or associated risk factors for CDI in lung cancer patients receiving chemotherapy. This study was a retrospective review of 188 lung cancer patients who were admitted to the Wonkwang University Hospital between 2008 and 2009. Of the 188 patients, 44 were diagnosed with CDI. The albumin levels were significantly lower and the performance status (PS) score was significantly higher in lung cancer patients with CDI than in those without CDI (P < 0.05). In conclusion, clinicians should consider the possibility of CDI occurrence in lung cancer patients receiving chemotherapy, particularly in those with low albumin levels and high PS scores, because most lung cancer patients have a high risk of developing CDI.

Shikonin, purified from the Chinese medicinal herb, Lithospermum erythrorhizon , induces necroptosis in a variety of cancers although, the mechanisms underlying the anticancer activity of shikonin in lung cancer are not fully understood. This study was designed to clarify whether shikonin can cause necroptosis in non-small cell lung cancer (NSCLC) cells and investigate the mechanism of action. Multiplex and caspase 8 assays were used to analyze effect of shikonin on A549 cells while cytometry with annexin V/PI staining and the MTT assay were used to analyze the mode of cell death. Western blot analysis was used to determine the effect of shikonin-induced necroptosis and autophagy. Xenograft and orthotopic models with A549 cells were used to evaluate the anti-tumor effect of shikonin in vivo. A549 cells were treated with shikonin to evaluate the effect on autophagy and necroptosis. Most of the cell death induced by shikonin could be rescued by the specific necroptosis inhibitor necrostatin-1, but not by the general caspase inhibitor Z-VAD-FMK. Tumor growth was significantly reduced in animals treated with shikonin compared to a control group. Shikonin also increased the protein levels of RIP1 in tumor tissues. Autophagy inhibitors including methyladenine (3-MA), ATG5 siRNA, and bafilomycin A enhanced shikonin-induced necroptosis whereas RIP1 siRNA had no effect on the apoptotic potential of shikonin. In conclusion, our data indicated that shikonin treatment induced necroptosis and autophagy in NSCLC cells. In addition, inhibition of shikonin-induced autophagy enhanced necroptosis, suggesting that shikonin could be a novel therapeutic strategy against NSCLC.

YKL-40 (a chitinase-like protein) is an inflammatory biomarker that is associated with lung injury pathogenesis. We aimed to identify the diagnostic values of YKL-40 in pleural effusions and to evaluate circulating YKL-40 levels during multiple etiological pulmonary/pleural diseases and the role of YKL-40 as a monitoring marker of inflammatory pulmonary disease.Pleural YKL-40 (n=197), YKL-39 (the most homologous chitinase-like protein to human YKL-40), and conventional pleural marker levels were measured in patients with pulmonary/pleural disease. Additionally, serum YKL-40 and YKL-39 levels were analyzed in both patients and controls (n=432) and serially monitored in patients with asthma (n=27) or pneumonia (n=22).Pleural YKL-40 levels were higher than those in the serum and highest in tuberculous pleural effusions (TPEs; 1181 ng/mL), followed by parapneumonic, malignant, and cardiogenic effusions (560 ng/mL). The diagnostic accuracy of pleural YKL-40 (0.78) for discriminating between tuberculous and malignant effusion was comparable to or greater than those of YKL-39, total protein, C-reactive protein and CYFRA 21-1, and lower than those of adenosine deaminase (p0.05) and carcinoembriogenic antigen (p=0.05). Serum YKL-40 levels were higher in the pneumonia group than in the cancer, asthma, or control groups. Following treatment, serum YKL-40 levels were more greatly reduced in pneumonia patients than in asthma patients. Serum YKL-39 levels did not differ between patients and controls.Pleural YKL-40 levels are elevated in TPEs and have fairly good diagnostic efficacy for detecting TPEs. However, adenosine deaminase is more efficient for detecting TPEs than pleural YKL-40. Serum YKL-40 levels are highest during pneumonia compared to common pulmonary/pleural diseases and are more useful for monitoring pneumonia than asthma.

Malignant fibrous histiocytoma (MFH), a type of sarcoma, is a malignant neoplasm with uncertain origins that arise from both the soft tissues and the bone. The occurrence of MFH on the chest wall is extremely rare. We hereby report a case of a 72-year-old woman who was incidentally detected with MFH after a traffic accident.

Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.

Residual pleural thickening (RPT) is the most frequent complication associated with pleural tuberculosis, and may occur even after successful anti-tuberculosis medications. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases capable of degrading all components of the extracellular matrix. The proteolytic action of MMPs may be involved in the pathogenesis of tuberculosis. MMP-9, secreted by monocytes and lymphocyte, may lead to long-term fibrosis. The aim of the present study was to determine whether MMP-2 and/or MMP-9 and their specific inhibitors, tissue inhibitors of metalloproteinase 1 (TIMP-1) and TIMP-2, could be used to predict RPT. This retrospective study enrolled 52 patients diagnosed with pleural tuberculosis. Levels of MMP-2, MMP-9, TIMP-1, and TIM-2 were determined in the pleural fluid by ELISA. The RPT was measured on chest X-ray at the completion of treatment and the final follow-up. The average periods of anti-tuberculosis medication and the follow-up after completion of treatment were 6.7 and 7.6 months, respectively. MMP-2 or MMP-9 levels had no significant correlation to RPT. The patients with RPT > 2 mm at the completion of anti-tuberculosis medication and the final follow-up had higher TIMP-1 levels (p = 0.00 and p = 0.001, respectively). However, patients with RPT > 2 mm at the completion of anti-tuberculosis medication had lower TIMP-2 levels (p = 0.005). In a logistic regression model, elevated TIMP-1 levels at the completion of anti-tuberculosis medications were associated with RPT. In conclusion, higher TIMP-1 levels are responsible for the development of RPT and may be helpful for predicting RPT in pleural tuberculosis.

// Ki-Eun Hwang 1, * , Young-Suk Kim 1, * , Jae-Wan Jung 1 , Su-Jin Kwon 1 , Do-Sim Park 2 , Byong-Ki Cha 3 , Seon-Hee Oh 4 , Kwon-Ha Yoon 5 , Eun-Taik Jeong 1 , Hak-Ryul Kim 1 1 Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 2 Department of Laboratory Medicine, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Korea 3 Department of Thoracic and Cardiovascular Surgery, Chonbuk National University Medical School, Jeonju, Jeonbuk, Korea 4 Department of Natural Medical Sciences, College of Health Science, Chosun University, Seosuk-dong, Gwangju, Korea 5 Department of Radiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, Korea * These authors have contributed equally to this work Correspondence to: Hak-Ryul Kim, e-mail: kshryj@wku.ac.kr Keywords: autophagy, apoptosis, pemetrexed, simvastatin Received: March 30, 2015 Accepted: August 10, 2015 Published: August 20, 2015 ABSTRACT Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.

Trichostatin A (TSA), originally developed as an antifungal agent, is one of potent histone deacetylase (HDAC) inhibitors, which are known to cause growth arrest and apoptosis induction of transformed cells, including urinary bladder, breast, prostate, ovary, and colon cancers. However, the effect of HDAC inhibitors on human non-small cell lung cancer cells is not clearly known yet. Herein, we demonstrated that treatment of TSA resulted in a significant decrease of the viability of H157 cells in a dose-dependent manner, which was revealed as apoptosis accompanying with nuclear fragmentation and an increase in sub-G0/G1 fraction. In addition, it induced the expression of Fas/FasL, which further triggered the activation of caspase-8. Catalytic activation of caspase-9 and decreased expression of anti-apoptotic Bcl-2 and Bcl-XL proteins were observed in TSA-treated cells. Catalytic activation of caspase-3 by TSA was further confirmed by cleavage of pro-caspase-3 and intracellular substrates, including poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, a characteristic phenomenon of mitochondrial dysfunction, including mitochondrial membrane potential transition and release of mitochondrial cytochrome c into the cytosol was apparent in TSA-treated cells. Taken together, our data indicate that inhibition of HDAC by TSA induces the apoptosis of H157 cells through signaling cascade of Fas/FasL-mediated extrinsic and mitochondria-mediated intrinsic caspases pathway.

The cysteine proteinases of Paragonimus westermani are known to play important roles in invasion and pathogenesis to hosts and in immune modulation and nutrient uptake. In this study, we have cloned a new cysteine proteinase of P. westermani, PwCP2, from adult worms and tested its diagnostic usefulness. The PwCP2 gene had an open reading frame of 816 base pairs and a conserved catalytic triad of cysteine, histidine, and asparagine residues. The mature form of recombinant PwCP2 (rPwCP2) lacking a proregion was overexpressed in Escherichia coli and used to produce antiserum. Western blot and immunohistochemical analyses using this antiserum showed that PwCP2 was expressed as a mature form, 24-kD product in a crude extract and in the excretory-secretory product of P. westermani, and was localized mainly in the intestinal epithelium of the adult worm. Western blot analysis using the rPwCP2 showed not only high sensitivity (90%) and specificity (100%) to sera from patients with paragonimiasis westermani, but also no cross-reactivity with sera from patients with clonorchiasis, sparganosis, or cysticercosis. Furthermore, an enzyme-linked immunosorbent assay using rPwCP2 exhibited a sensitivity of 93% and a specificity of 93% with sera of rats infected with P. westermani metacercariae. These results suggest that the excretory-secretory PwCP2 can be used for the diagnosis of paragonimiasis.

A 72-year-old man was referred to our hospital with an endobronchial mass spotted on chest computed tomography (CT). On examination, he was afebrile, but complained of cough and sputum. Laboratory test results were normal. His chest CT showed an ovoid fat attenuation nodule in the left upper lobe bronchus (Fig. 1A). Flexible bronchoscopy was performed to investigate the endobronchial lesion, and a polypoid tumor was found in the left upper lobe bronchus that was leading to total obstruction (Fig. 1B). Because left upper bronchus obstruction could lead to recurrent postobstructive pneumonia, cryotherapy was performed. The tip of the cryoprobe was placed in direct contact with the tumor and was pulled and withdrawn with the frozen tissue using a bronchoscope (Fig. 2A-​-2C).2C). The mass was successfully removed after repeated procedures. Histopathological examination showed mature cartilage and adipose tissue in the deeper layer, and the patient was diagnosed with an endobronchial hamartoma (Fig. 2D). At 1-month follow-up, a bronchoscopic examination showed no remnants of the mass and no tumor recurrence. Figure 1. (A) A chest computed tomography (CT) shows a 1.1-cm ovoid fat attenuated nodule in the left upper lobe bronchus (arrow). (B) Bronchoscopic examination shows an intrabronchial tumor in the left upper lobe bronchus. Figure 2. (A-C) Tumor resection using cryotherapy. (D) Histopathology of the tumor shows mature cartilage and adipose tissue (H&E, ×40). Hamartomas can occur in any region of the lung, but are rarely identified as endobronchial. A majority of patients with parenchymal hamartoma are asymptomatic; the possibility of endobronchial hamartomas as a cause of postobstructive pneumonia should be considered. In a Korean study that reviewed 24 cases of endobronchial hamartoma, 10 (42%) showed obstructive pneumonia. Thus, treatment should also be administered to asymptomatic cases. Because hamartomas rarely recur or become malignant, minimally invasive procedures should be chosen. Bronchoscopy is a modality currently used for diagnosis and treatment. Various bronchoscopic techniques, such as those using YAG laser or argon, electrocautery, cryotherapy, argon, and plasma coagulation are used for benign endobronchial tumors. We herein reported a successfully-treated endobronchial hamartoma using cryotherapy. In conclusion, endobronchial hamartomas are benign tumors of the tracheobronchial tree that potentially can cause morbidity due to bronchial obstruction and recurrent pneumonia. Endoscopic treatment with a flexible bronchoscope and cryotherapy provide excellent outcomes for these patients.

Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.

Background: This study was conducted in order to elucidate the effects of docetaxel on the growth of peroxiredoxin 1 (Prx1) knockdown A549 xenograft tumors and further tested the role of Prx1 as a predictor for how a patient would respond to docetaxel treatment. Methods: Effects of docetaxel on the growth of scrambled- and shPrx1-infected A549 xenograft tumors in nude mice were measured. Moreover, immunohistochemical expression of Prx1 was evaluated in paraffin-embedded tissues from 24 non-small cell lung cancer patients who had received docetaxel-cisplatin regimens as a first-line treatment. Results: Docetaxel treatment in Prx1 knockdown xenograft tumor resulted in reduced tumors growth compared with other groups. Prx1 knockdown increased the production of cleaved caspases-8 and -9 in the control itself compared to scramble tumors. Moreover, docetaxel treatment in Prx1 knockdown tissue led to an increased protein band. Phosphorylated Akt was found in Prx1 scramble tissues. Phosphorylated FOXO1 was detected in the docetaxel treatment group. On the other hand, Prx1 knockdown completely suppressed the Akt-FOXO1 axis. The median progression-free survival (PFS) of patients with low Prx1 expression was 7 months (95% confidence interval [CI], 6.0−7.7), whereas the median progression-free survival of patients with high Prx1 expression was 4 months (95% CI, 4.0−5.0). However, high Prx1 expression was not associated with decreased PFS (p=0.114). Conclusion: Our findings suggest that elevated Prx1 provides resistance to docetaxel treatment through suppression of FOXO1-induced apoptosis in A549 xenograft tumors, but may not be related with the predictive significance for response to docetaxel treatment.

Prevention of lung cancer is more feasible and holds greater promise when different agents are used in combination to target multiple processes during carcinogenesis. The mechanisms by which non-steroidal anti-inflammatory drugs and statins inhibit cancer cell growth and induce apoptosis are not fully understood. This study was designed to investigate lung cancer chemoprevention through a mechanism-based approach using sulindac at low doses in combination with simvastatin. We found that sulindac-induced cytotoxicity was significantly enhanced in the presence of simvastatin. The combination of sulindac and simvastatin induced more extensive caspase-dependent apoptosis in A549 cells compared to that induced with either drug alone. The combination of sulindac and simvastatin also increased the loss of mitochondrial transmembrane potential (∆Ψm) and the cytosolic release of cytochrome c. In addition, ROS generation in cells treated with both sulindac and simvastatin was markedly increased compared to cells treated with either sulindac or simvastatin alone. The enhancement of ROS generation by sulindac and simvastatin was abrogated by pretreatment with NAC, which also prevented apoptosis and mitochondrial dysfunction induced by sulindac and simvastatin. These results suggest that sulindac and simvastatin-induced ROS generation in A549 lung cancer cells causes their accumulation in mitochondria, triggering the release of apoptogenic molecules from the mitochondria to the cytosol, and thus leading to caspase activation and cell death.

The expression levels of Prx1 are frequently elevated in several human cancers, including lung cancer and may confer increased resistance to treatment. In this study, we investigated the role of Prx1 in docetaxel-induced apoptosis in A549 lung cancer cells. To test whether Prx1 knockdown affected the sensitivity of A549 cells to docetaxel treatment, we generated short hairpin RNA (shRNA) constructs targeting Prx1 and analyzed the effect of Prx1 knockdown on growth and apoptosis. Tumor growth was evaluated in scrambled shRNA- or shPrx1-infected A549 cell tumors receiving docetaxel treatment. In addition, mechanistic information was gathered by western blot analysis from cell lysates of scrambled- and shPrx1-infected A549 cells pretreated with or without LY294002 and subsequently treated with docetaxel. We found that Prx1 knockdown resulted in enhanced docetaxel-induced cytotoxicity in a dose-dependent manner. In vivo, the growth rate of shPrx1-infected A549 tumors was significantly reduced compared to that of scrambled shRNA-infected A549 tumors. Prx1 knockdown also augmented the inhibitory effects of docetaxel on tumor growth. Prx1 knockdown increased the apoptotic potential through activation of the caspase cascade and suppressed docetaxel-induced phosphorylation of Akt and its substrate forkhead box O1 (FOXO1). Moreover, treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 reduced the phosphorylation of FOXO1 and increased the cytotoxicity of docetaxel in A549 cells. Our findings suggest that Prx1 may modulate the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis.

Purpose C-reactive protein (CRP) has been implicated in various inflammatory and advanced malignant states. Increased serum CRP (s-CRP) levels have been shown to be associated with independent prognostic factors for survival in patients with advanced lung cancer. However, only few studies have focused on the role of CRP in pleural effusions. This study aimed to evaluate the diagnostic and prognostic value of pleural CRP (p-CRP) in lung cancer patients with malignant pleural effusion (MPE). Materials and Methods Pleural effusion (PE) samples were collected from patients with MPE (68 lung cancers; 12 extrathoracic tumors), and from 68 patients with various benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of p- and s-CRP were measured by enzyme-linked immunosorbent assay. CRP level in pleural fluid and its association with survival were examined. Results p-CRP levels correlated with s-CRP levels (r=0.82, p

Malignant fibrous histiocytoma, a type of sarcoma, is a malignant neoplasm with uncertain origin that arises in both the soft tissues and the bone. The occurrence of primary malignant fibrous histiocytoma of the pleura is extremely rare. We report a case of a 65-year-old Korean man who is being diagnosed with primary malignant fibrous histiocytoma of the pleura.

Survivin has been shown to inhibit apoptosis, enhance proliferation and promote angiogenesis. This study aimed to identify diagnostic value of survivin protein in malignant pleural effusion (MPE) and to investigate the prediction of response to chemotherapy and the prognostic role on pleural survivin in lung cancer patients with MPE. Pleural effusion samples were collected from 67 patients with MPE (58 lung cancers; 9 extrathoracic tumors), and from 68 patients with benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of pleural fluid survivin, Cyfra 21-1, and carcinoembryonic antigen (CEA) were measured by enzyme-linked immunosorbent assay. The expression profile of survivin in pleural fluid, and its association with survival, were investigated. Survivin levels were significantly elevated in patients with MPE, especially primary lung cancer than in those of benign origin. Survivin, Cyfra 21-1, and CEA varied in diagnostic accuracy for differentiating MPE from benign pleural effusion by 67.5, 68.3, and 93.4%, respectively. Lung cancer patients with MPE who were positive for survivin expression were more refractory to chemotherapy (P = 0.003). Positive for survivin expression was correlated with a reduced overall survival in univariate (P = 0.0001) and multivariate (P = 0.004) analyses. Using the appropriate cut-off points, CEA in pleural fluid has a higher accuracy than other tumor markers, and that survivin has a low diagnostic accuracy for differentiating MPE from benign pleural effusion. Our findings suggest that positive survivin expression may be used as a predictor of a poor response to chemotherapy and shorter survival in lung cancer patients with MPE.

Statins, HMG-CoA reductase inhibitors have been studied for their antiproliferative and proapototic effects. Recently, statin-induced apoptosis has been associated with down-regulation of survivin expression in cancer cells. However, the mechanism of deregulated survivin by simvastatin on lung cancer is still unclear. Herein, we demonstrated that simvastatin induced caspase-dependent apoptosis in A549 lung cancer cells. Simvastatin also resulted in a decrease in the expression of phosphorylated Akt. In addition, simvastatin effectively down-regulated survivin mRNA and protein, but not cIAP-1 and cIAP-2. The combination of simvastatin and 10 μM LY294002 (non-toxic dose) augmented apoptosis significantly, as evidenced by cleavage of PARP. The immunoreactive band of survivin was markedly decreased in cells treated with 50 μM LY294002 (toxic dose) as well as by the combination of simvastatin and 10 μM LY294002. Moreover, survivin down-regulation by RNA interference induced apoptosis accompanied by an increase in hypodiploid DNA content. Taken together, these data suggest that the anti-cancer effect of simvastatin via induction of apoptosis is related to Akt signaling dependent down-regulation of survivin in lung cancer A549 cells.

Background and Methods: To study the effects of corticosteroid (CS) on the parquat (PQ) induced lung injury, serial cellular analyses of bronchoalveolar lavage (BAL) fluid were done with simultaneous histopathologic examination after intraperitoneal injection of PQ on the rats. The sacrificed animals were divided into three groups; control group, PQ group received intraperitoneal injection of 20 mg/kg of PQ, and CS group received daily injection of Methylprednisolone sodium succinate (20 mg/kg) in addition to PQ. Results: 1) Cellular analyses of BAL fluid: The total cell count in the BAL fluid were increased gradually from 6 hours after PQ administration (p

Pseudoaneurysm due to cancer is uncommon generally and is extremely rare in lung cancer. We report two cases of false aneurysms due to lung cancer that spontaneously regressed upon chemotherapy without intervention. Both patients had squamous cell carcinoma of the lung and the diagnosis of a pseudoaneurysm was made using computed tomography. There was no evidence of severe bronchial hemorrhage and the psuedoaneurysms were small and well-encased. Chemotherapy was performed and the pseudoaneurysms resolved.

Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.

Heme oxygenase-1 (HO-1) is highly expressed in various tumor tissues and plays an important role in tumor cell growth through anti-oxidative and anti-apoptotic effects. Herein, we demonstrate that A549 cells express high levels of HO-1, Nrf2, and NF-kappaB compared to other lung cancer cell lines, including H23, H157, and H460. Ectopic expression of HO-1 small interfering RNA (siRNA) increased both apoptosis and degradation of procaspase-3. Transfection studies with siRNA specific for Nrf2 and NF-kappaB revealed that HO-1 expression in A549 cells is mediated by transcriptional activation of Nrf2, but not NF-kappaB. A549 cells are less susceptible to cisplatin cytotoxicity than other lung cancer cell lines, concomitant with increases in HO-1 expression and MAPK phosphorylation in a time-dependent fashion. Furthermore, inhibition of HO-1 by siRNA and a specific HO-1 inhibitor ZnPP augments cisplatin cytotoxicity toward A549 cells. Pharmacologic suppression of HO-1 activity resulted in a marked increase in the ROS generation in cisplatin-treated cells. In addition, pharmacologic inhibitors of MAPK suppressed the induction of HO-1 and Nrf2 expression by cisplatin. These findings suggest that HO-1 may modulate the chemosensitivity of lung cancer A549 cells to cisplatin through the MAPK-Nrf2 pathway.

A 44-year-old Korean male died of rapidly progressive respiratory failure and refractory hypoxemia in 8 days after being admitted with a fever and dyspnea. The patient was diagnosed with pseudomembranous necrotizing tracheobronchial aspergillosis by fibroptic bronchoscopy and it was not related to an invasion of the pulmonary parenchyma. To the best of our knowledge, this case represents a patient with pseudomembranous necrotizing tracheobronchial aspergillosis that developed in an immunocompetent host, rapidly resulting in airway obstruction with acute respiratory failure and refractory hypoxemia without an invasion of the pulmonary parenchyma.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to enhance the responsiveness of tumor cells toward chemotherapeutic drugs and radiation. However, the precise mechanism of synergistic enhancement in tumoricidal activity is not clearly known. Herein, we demonstrate that the combination treatment of arsenic trioxide (As 2 O 3 ) and sulindac resulted in a synergistic augmentation of cytotoxicity toward NCI-H157 lung cancer cells, which was revealed as apoptosis accompanied by chromatin fragmentation and an increase in sub-G 0 /G 1 fraction. In addition, combination treatment with As 2 O 3 and sulindac increased the catalytic activity of caspase-3, -8, and -9 along with induction of Fas/FasL expression and cytosolic release of cytochrome c. Pharmacologic scavenging study of reactive oxygen species (ROS) revealed that synergistic augmentation of cytotoxicity was achieved by generation of ROS, which might modulate the expression of Bcl-2 family proteins, the activity of caspase-3, and mitochondrial membrane potential transition.

Purpose: Most of lung cancer patients had received the systemic chemotherapy because they had diagnosed the advanced stage at presentation. Cislplatin-based chemotherapy is main regimen for advanced lung cancer. But serious adverse reaction (SAE) had occurred after chemotherapy. This is main reason for chemotherapy withdrawal. If we will use the reduced dose of cispaltin, cisplatin-based the chemotheray will be continued. To figure out whether the effect of low dose of cisplatin will be synergistically enhance by autophagy inhibiton, even though the reduced dose of cisplatin less effect for treatment response, We investigated that role of autophagy by 3-methyladenine, class III PI3kinase inhibitor in cisplatin-treated lung cancer cells. Methods: Lung cancer cells were incubated with normal media and treated the 5uM (LD20) and 20uM(LD50) of cislpaltin according to time dependent. We examined the sensitivity to low or high doses of cisplatin treatment using the MTT cell viability assay and compared apoptosis and autophagy by nuclear stianing, apoptotic or autophagic related proteins or autophagic vacuoles. autophagy is also displayed the development of acidic vascular organelles by acridine orange and the fluorescent expression of GFP-LC3 protein in the GFP-LC3 transfected cells. Result: Low dose of cisplatin-treated lung cancer cells is relatively less sensitive to cell death rather than high dose treated cells in a time-dependent manners. We didnot find out the nuclear fragmentation in lower dose even though detected its in high dose. PARP cleavages also were not detected in low dose of cisplatin exception 24H. We observed that massive vacuolization in the cytoplasm were seen at lower dose treated cells. Acridine orange stain-positive cells also were increased according to time dependent. We figured out that the autophagosome-incorporated LC3 II protein expression more increased in low dose treated cells (24H to 48H) in spite of no detection of LC3 II in high dose treated cells. The expression of GFP-LC3 were increased in 5uM treated cells by time-dependent manner. When 3-methyladenine, class III PI3kinase inhibitor, was pretreated in 5uM cisplatin-treated lung cancer cells, cell survival significantly were decreased. Conclusion: Autophagy induces cytoprotection in lower dose of cisplatin-treated lung cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1043.

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.