Oxidized-LDL Induces Metabolic Dysfunction in Retinal Pigment Epithelial Cells.

Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid ß-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.

Malignant triton tumor of the left thoracic cavity: a case report.

Malignant triton tumor (MTT) is a rare subtype of malignant peripheral nerve sheath tumors with rhabdomyoblastic differentiation. Although the condition may manifest sporadically, it typically affects adult patients with neurofibromatosis type 1. In this article, an extremely rare case of MTT with chest wall origin, which expanded into the left thoracic cavity, is reported. A 64-year-old male was admitted to the institution with sudden shortness of breath. Radiological examination revealed a large mass with massive pleural effusion occupying the patient's left hemithorax. A percutaneous needle biopsy was performed and the patient underwent subtotal tumor resection with left pleuropneumonectomy. Immunohistochemical study of postsurgical pathologic specimens confirmed the diagnosis of MTT. Despite extensive surgical removal, tumor recurrence was reported soon after resection, leading to patient's death 20 days after surgery due to acute respiratory failure. Investigation of rare MTT cases is necessary for understanding this condition.

The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer.

The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non-small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB-resistant (VR) lung cancer cells (NCI-H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP-binding Cassette Sub-family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins ß1 and ß3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB-resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.

A rare case of mediastinal functioning parathyroid adenoma removed successfully with thoracoscopy.

We report here a rare case of primary hyperparathyroidism that was associated with an ectopic parathyroid adenoma located in the mediastinum. A 66-year-old woman suffering from primary hyperparathyroidism had been followed-up on an outpatient basis for over 10 years. She suffered from persistent urolithiasis and osteopenia due to hypercalcemia. After technetium-99-sestamibi (99mTc-MIBI) scintigraphy revealed an ectopic adenoma in the superior mediastinum, thoracoscopic resection of the tumor was performed. Subsequently, her serum parathyroid hormone (PTH) level decreased dramatically and her serum calcium concentration was restored to normal. Two years following surgery, her serum PTH and Ca levels remain stable.

Ciliated muconodular papillary tumor of the lung: report of five cases.

We report five serial cases of ciliated muconodular papillary tumor (CMPT) of the lung. CMPT is characterized as a low-grade malignant tumor with ciliated columnar epithelial cells combined with goblet cells, typically presenting as peripheral lung tumor and often causing diagnostic or therapeutic problems. In the cases described here, all patients presented with abnormal chest shadow but no definitive symptoms. Although all tumors were peripheral, computed tomography (CT) revealed various radiographic findings including small lung nodules, ground-grass opacity or irregular-shaped consolidation. All patients underwent complete surgical resection, and no recurrence has been noted over follow-up. In all cases, pathological findings included columnar ciliated cells with mucus lakes, consistent with the immunohistochemical staining. As there are few reports on this tumor entity, which has not yet received a WHO classification, we believe our case series may be of interest.

Association between epithelial-mesenchymal transition and cancer stemness and their effect on the prognosis of lung adenocarcinoma.

The epithelial-mesenchymal transition (EMT) and cancer stemness (CS) are reported to be pivotal phenomena involved in metastasis, recurrence, and drug-resistance in lung cancer; however, their effects on tumor malignancy in clinical settings are not completely understood. The mutual association between these factors also remains elusive and are worthy of investigation. The purpose of this study was to elucidate the association between EMT and CS, and their effect on the prognosis of patients with lung adenocarcinoma. A total of 239 lung adenocarcinoma specimens were collected from patients who had undergone surgery at Kyoto University Hospital from January 2001 to December 2007. Both EMT (E-cadherin,vimentin) and CS (CD133, CD44, aldehyde dehydrogenase) markers were analyzed through immunostaining of tumor specimens. The association between EMT and CS as well as the patients' clinical information was integrated and statistically analyzed. The molecular expression of E-cadherin, vimentin, and CD133 were significantly correlated with prognosis (P = 0.003, P = 0.005, and P < 0.001). A negative correlation was found between E-cadherin and vimentin expression (P < 0.001), whereas, a positive correlation was found between vimentin and CD133 expression (P = 0.020). CD133 was a stronger prognostic factor than an EMT marker. Elevated CD133 expression is the signature marker of EMT and CS association in lung adenocarcinoma. EMT and CS are associated in lung adenocarcinoma. Importantly, CD133 is suggested to be the key factor that links EMT and CS, thereby exacerbating tumor progression.

Expression of the GLI family genes is associated with tumor progression in advanced lung adenocarcinoma.

BACKGROUND: The hedgehog (Hh) signaling pathway is aberrantly activated in various cancers. Expression of the GLI family of genes, which encode for transcriptional factors of the Hh pathway, has not been fully assessed in clinical samples of advanced lung adenocarcinoma. In this study, we retrospectively evaluated the expression of the GLI family of genes in advanced stage lung adenocarcinoma samples and determined their relation to patient survival. METHODS: The levels of GLI1, GLI2, and GLI3 mRNA expression were measured by quantitative real-time polymerase chain reaction in surgically obtained tissue samples from stage II-IV lung adenocarcinoma patients (n = 102). Pairwise comparisons between all three GLI mRNA expression were performed, and after dichotomizing the patients into low and high expression groups according to each GLI mRNA expression level, survival curves were calculated and multivariate analyses were conducted. RESULTS: Significant positive correlation was found between GLI1 and GLI3 mRNA expression (P <0.001). Tumors with higher expression (upper 15%) of GLI1 or GLI3 mRNA were associated with poor survival in stage II-IV (5-year overall survival rates: GLI1 mRNA low, 41.7% vs. high, 20.0%, P = 0.0074; GLI3 mRNA low, 43.1% vs. high, 13.3%, P = 0.0062) and stage III-IV (5-year overall survival rates: GLI1 mRNA low, 34.0% vs. high, 0%, P = 0.0012; GLI3 mRNA low, 33.4% vs. high, 7.7%, P = 0.057) lung adenocarcinoma patients. GLI2 mRNA expression did not appear to have great clinical significance. Multivariate analysis revealed higher GLI1 mRNA expression as an independent factor for unfavorable patient survival (P = 0.0030, hazard ratio = 3.1, 95% confidence interval = 1.5-6.2), as well as tumor differentiation and stage. CONCLUSIONS: Expression of GLI1 and GLI3 mRNA was strongly correlated, and their overexpression, especially that of GLI1, was found to be predictive of aggressive tumor behavior. This study indicates that the Hh pathway may be a key oncogenic signaling network in tumor pathogenesis and, thus, a potential therapeutic target in advanced lung adenocarcinoma.

Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas.

BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival. METHODS: One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index. RESULTS: The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p<0.0001 and p=0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors (p=0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors (p=0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors (p=0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (p=0.0016), especially in patients with nonepithelioid tumors (p=0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs (p=0.0142). CONCLUSIONS: The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs.

Higher expression of receptor tyrosine kinase Axl, and differential expression of its ligand, Gas6, predict poor survival in lung adenocarcinoma patients.

BACKGROUND: Downstream activation through receptor tyrosine kinases (RTKs) plays important roles in carcinogenesis. In this study, we assessed the clinical involvement of Axl, an RTK, and its ligand, Gas6, in surgically treated lung adenocarcinoma. METHODS: Axl and Gas6 mRNA and protein expression levels were quantified using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, in completely resected lung adenocarcinoma tissues (n = 88) and were evaluated for correlation with clinicopathologic features and patient survival. RESULTS: Higher expressions of Axl mRNA/protein and Gas6 protein were significantly related to worse clinicopathological features and prognosis (5-year overall survival rates: Axl mRNA low: 72.3 %, high: 49.7 %, P = 0.047; Axl protein low: 77.5 %, high: 38.6 %, P < 0.001; and Gas6 protein low: 70.5 %, high: 48 %, P = 0.042). On the contrary, higher Gas6 mRNA expression was related to better clinicopathological features and prognosis (5-year overall survival rates: Gas6 mRNA low: 59.2 %, high: 81.8 %, P = 0.054). Multivariate analysis suggests that high Axl mRNA expression may be an independent factor for poor patient prognosis (P = 0.04). CONCLUSIONS: In lung adenocarcinoma, Axl and Gas6 expression levels were associated with tumor advancement and patient survival, thus rendering them as reliable biomarkers and potential targets for treatment of lung adenocarcinoma.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma.

BACKGROUND: The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses. METHODS: The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed. RESULTS: Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results. CONCLUSIONS: Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Aortico-pulmonary paraganglioma: case report and Japanese review.

Aortico-pulmonary paraganglioma (APPG) is a rare middle mediastinal tumor. We experienced a case of APPG in a 52-year-old man. Chest computed tomography and magnetic resonance imaging revealed a multi-cystic mass in the subaortic area. A left thoracotomy was performed without definitive preoperative diagnosis. The tumor was strongly adherent to the pericardium and the surrounding large vessels, but a complete resection was undertaken. Histological and immunohistochemical examination revealed that it was a malignant paraganglioma with a microscopically positive surgical margin. After radiotherapy of 50 Gy for the mediastinum, the patient almost recovered from his hoarseness by thyroplasty. We also reviewed nine Japanese cases of APPG reported previously. Though APPG is rare, we must consider that a middle mediastinal tumor may be APPG, and preoperative examination and preoperative planning are necessary to prevent massive bleeding and microscopic residual tumor.