A ngiogenesis involves complex endothelial cell (EC) behaviors, such as proliferation, survival, migration, and tube formation. The most important stimulus promoting angiogenesis is tissue hypoxia. Hypoxia mediates several processes in ECs that are required for each step of angiogenesis.1 Hypoxia-induced angiogenesis is closely related to pathological situation. The dysregulation of these EC behaviors and thus abnormal angiogenesis are critically associated with hypoxia-induced pathological angiogenesis that occurs during the course of several diseases, such as cancer and vascular retinopathy.2,3 Therefore, identification of specific molecules involved in hypoxia-induced angiogenesis will facilitate studies to clarify the various molecular mechanisms involved in pathological angiogenesis and may aid the discovery of novel angiogenic drug targets.© 2014 American Heart Association, Inc. Objective-Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis that occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α and target genes are important for the angiogenic functions of ECs. Phospholipase D2 (PLD2) is a crucial signaling mediator that stimulates the production of the second messenger phosphatidic acid. PLD2 is involved in various cellular functions; however, its specific roles in ECs under hypoxia and in vivo angiogenesis remain unclear. In the present study, we investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Approach and Results-Pld2 knockout ECs exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of hypoxia-inducible factor-1α target genes, including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced hypoxia-inducible factor-1α expression at the translational level. The roles of PLD2 in hypoxia-induced in vivo pathological angiogenesis were assessed using oxygen-induced retinopathy and tumor implantation models in endothelial-specific Pld2 knockout mice. Pld2 endothelial-specific knockout retinae showed decreased neovascular tuft formation, despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 endothelial-specific knockout mice. Cellular responses to hypoxic stress are mediated by multiple mechanisms. Hypoxia-inducible factor-1 (HIF-1) is the most prominent factor that mediates cellular responses to hypoxia by inducing the expression of several target genes. Conclusions-Our 1Because HIF-1 activation is preferentially modulated by changes in the amount of the HIF-1α subunit, several factors and mechanisms have been suggested. Among these, the regulation of HIF-1α degradation through post-translat...
Background: There are limitations to current colorectal cancer (CRC)-specific diagnostic methods and therapies. Tumorigenesis proceeds because of interaction between cancer cells and various surrounding cells; discovering new molecular mediators through studies of the CRC secretome is a promising approach for the development of CRC diagnostics and therapies. Materials and Methods: A comparative secretomic analysis was performed using primary and metastatic human isogenic CRC cells. Proliferation was determined by MTT and thymidine incorporation assay, migration was determined by wound-healing assay (ELISA). The level of palmitoleoyl-protein carboxylesterase (NOTUM) in plasma from patients with CRC was determined by enzymelinked immunosorbent assay. Results: NOTUM expression was increased in metastatic cells. Proliferation was suppressed by inhibiting expression of NOTUM. Knockdown of NOTUM genes inhibited proliferation as well as migration, with possible involvement of p38 and c-JUN N-terminal kinase in this process. The result was verified in patients with CRC. Conclusion: NOTUM may be a new candidate for diagnostics and therapy of CRC. Colorectal cancer (CRC) is the fourth most common malignancy and a leading cause of cancer-related mortality worldwide (1). Recent estimates suggest that the burden of CRC is expected to increase by 60% by 2030, with more than 2.2 million new cases and 1.1 million deaths (2). A large proportion of this burden could be prevented either by the screening and detection of this cancer at early stages when chances of a cure are substantially higher than at later stages, or by the detection and removal of precancerous lesions (3, 4). Nevertheless, primary screening faces limitations in terms of invasiveness, available capacities, costs, inconvenience, and adherence (5, 6). Although blood-based protein biomarkers such as carcinoembryonic antigen and carbohydrate antigen 19-9 are already utilized in the clinical setting, they cannot be used alone to screen or diagnose cancer because levels of these markers can be abnormal for reasons other than cancer, such as hepatitis and inflammatory bowel disease (7). Thus, there is an urgent need for new biomarkers and molecular targets with relatively high sensitivity and specificity to CRC. Solid tumors such as CRC are composed of malignant cells along with other stromal cells such as neoplastic, mesenchymal, and inflammatory cells (8). Cancer cells interact with other cells through secreted factors, orchestrating complex signaling pathways (9). Cancer cells secrete various factors including soluble factors and proteases that alter adjacent stromal cells toward a permissive and supportive microenvironment for tumor progression (10). This cancer 'secretome' has been receiving increased interest for the discovery of diagnostic or prognostic cancer biomarkers, and can be a good tool for elucidating cancer biology (11, 12). Therefore, a comprehensive analysis of the cancer secretome can lead to discovery of potential biomarkers or therapeutic targets a...
Background and Objectives: Olfactory training is an alternative treatment based on modulation of the regeneration process of the olfactory system via repeated exposure to odors. Our study aimed to investigate the impact of olfactory training with intranasal corticosteroid in Korean patients with various causes of olfactory dysfunction. Subjects and Method: Our study population comprised 134 adults with olfactory dysfunction of different etiologies (postviral infection n=85; post-traumatic n=18; and idiopathic n=31). For training, patients exposed themselves to four different odors twice a day. All patients used fluticasone nasal spray (two sprays in each nostril once daily). Olfactory function was evaluated at baseline and again at three months, and results were quantified as patient TDI (threshold, discrimination, and identification) score. Results: Olfactory function improved in 74 of 134 patients (55.2%). Etiology of olfactory disorder, sex, and age had statistically significant influence on the improvement rate of olfactory function, among which etiology of olfactory loss was the most important. However, initial severity and duration of olfactory loss had no statistically significant influence on the improvement rate. The TDI score at three months of olfactory training showed remarkable improvement, primarily because of improvements in the discrimination and identification components. Conclusion: The present study showed that olfactory training with intranasal corticosteroid was beneficial to improve olfactory function in patients with olfactory dysfunction, particularly in postviral infection patients.
Background and Objectives: The etiologies of taste disorder are multiple. It is rarely considered vitamin deficiency can impact taste function. Vitamin B12 deficiency can be caused by total gastrectomy or malnutrition. The aim of this study was to investigate the characteristics of patients with taste disorders caused by vitamin B12 deficiency. Materials and Methods: We treated fourteen patients with vitamin B12 deficiency induced taste disorders. The symptoms of patients were decreased taste sensitivity, tongue pain, and abnormal tongue sensation. The patients' tongues were red, smooth, and no papillae. The laboratory test showed that decreased serum concentration of vitamin B12. Taste function test showed increased taste thresholds. Ten patients had total gastrectomyhistory and four patients were poor nutritional status. All patients were treated by administration of vitamin B12 intramuscularly. Results: The patients'symptoms were improved after treatment. The appearance of the tongue and the results of taste testing were also improved. Conclusions: The patients with taste disorder and tongue pain should be asked about operation history including gastrectomy, and vitamin B12 deficiency induced taste disorder should be considered in the differential diagnosis.
Objectives : To evaluate the clinical significance of abnormal bronchi originating from the trachea or main bronchi. Methods : 21 patients (male:female ratio, 13:8; mean age, 58.2 years, range 34-77), who were diagnosed with major tracheobronchial anomalies by bronchoscopy from January 2001 to March 2005, were enrolled in this study. The anomalous bronchi consisted of 13 tracheal bronchi and 8 cardiac accessory bronchus. The clinical features, bronchoscopic findings, and outcomes were analyzed retrospectively. Results : Common symptoms, including hemoptysis, cough and dyspnea, resulted from the underlying lung disease regardless of the bronchial anomalies. In this series of 13 tracheal bronchi, 7 cases originated from the trachea within 1cm of the carina (carinal type) and 6 cases originated at a higher level(tracheal type). Most patients had favorable outcome with conservative treatment for the underlying lung disease. Conclusion : Most tracheobronchial anomalies are found incidentally in the process of diagnosing lung disease. The clinical outcome of patients with a bronchial anomaly depends on the underlying lung disease.
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