Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) negatively regulates phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein levels through polyubiquitination and proteolysis, but its significance in lung cancer is still unclear. This study investigated the expression and the role of NEDD4-1 in tumor development and chemosensitivity of lung adenocarcinoma (ADC).</p><p><b>METHODS</b>We retrospectively investigated the expression and significance of NEDD4-1, PTEN, and p-Akt proteins in 135 paired ADC and adjacent noncancerous tissue specimens using immunohistochemistry. Furthermore, we evaluated the relationship between NEDD4-1 expression and clinicopathologic characteristics and prognosis. The effects of small interfering RNA against NEDD4-1 on proliferation and chemosensitivity were examined in A549 cells in vitro using 3- (4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)- 2H-tetrazolium method. The ability of migration and invasion of A549 cells was tested by transwell assay. Moreover, reverse-transcription quantitative polymerase chain reaction and Western blotting analyses were used to determine the expression of NEDD4-1, PTEN, phosphoinositide 3-kinase (PI3K)/Akt activity, and its downstream target proteins.</p><p><b>RESULTS</b>NEDD4-1 protein was significantly upregulated in lung ADC tissues, whereas it was weak or negative in normal lung epithelial cells. The expression of NEDD4-1 in ADC (78.5%, 106/135) was significantly much higher than that in adjacent normal lung tissue (13.3%, 29/135, P < 0.01), and it was associated with lymph node metastasis, tumor-node-metastasis (TNM) stage, and chemotherapy resistance. PTEN expression was downregulated in lung ADC (60.7% vs. 100.0% in noncancerous specimens, P = 0.007), and was negatively correlated with lymph node metastasis, histological variants, clinical stage, chemoresistance. In addition, expression of p-Akt in ADC tissues (71.1% 96/135) was much higher than that in adjacent lung epithelial cells (6.7%, 9/135, P < 0.01). Kaplan-Meier and multivariate analysis demonstrated that expressions of NEDD4-1 and PTEN were both independent risk factors for survival in patients with lung ADC. NEDD4-1 knockdown in vivo decreased proliferation, migration, and invasion and improved chemosensitivity to cisplatin and paclitaxel in A549 cells. NEDD4-1 knockdown also significantly enhanced PTEN expression and inhibited p-Akt activity and downstream target proteins.</p><p><b>CONCLUSIONS</b>NEDD4-1 upregulation may contribute to the progression of lung ADC. NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.</p>

Diagnostic accuracy of fiberoptic ductoscopy plus in vivo iodine staining for intraductal proliferative lesions / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Iodine staining during endoscopy has been successfully used to detect early carcinomatous and precancerous lesions in the esophagus, cervix, and oral cavity. The objective of this study was to determine the diagnostic accuracy of fiberoptic ductoscopy (FDS) plus in vivo iodine staining for intraductal proliferative lesions of the breast.</p><p><b>METHODS</b>We performed periodic acid-Schiff (PAS) and in vitro iodine staining on 52 and 64 specimens of benign mammary hyperplasia, respectively, and 57 and 53 specimens of ductal carcinoma in situ (DCIS), respectively. Next, FDS was performed on 177 recurrent nipple discharge patients who were randomly divided into two groups. One group was iodine-staining group in which 92 patients were randomly selected to undergo iodine staining during FDS, and the remaining 85 were assigned to the control group. Biopsy specimens of suspicious lesions were obtained and subjected to histopathological examination.</p><p><b>RESULTS</b>Following PAS staining, benign mammary hyperplasia lesions were positively stained, while negligible PAS positivity was observed in the DCIS lesions (P < 0.05). Following in vitro iodine staining, benign mammary hyperplasia specimens appeared dark brown, whereas DCIS samples appeared significantly lighter or unstained. Compared with the pathological examination results, FDS with iodine staining showed an agreement rate in the diagnosis of ductal intraepithelial neoplasia (DIN), sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and Youden index of 97.82%, 98.83%, 83.33%, 5.93, 0.014, and 0.8216, respectively; the corresponding values for FDS without iodine staining were 88.24%, 89.16%, 50.00%, 1.78, 0.217, and 0.3916, respectively.</p><p><b>CONCLUSION</b>FDS with iodine staining was superior to conventional FDS for the diagnosis of DIN and is valuable for breast cancer prevention.</p>

Upregulation of glucosylceramide synthase protein in papillary thyroid carcinoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Glucosylceramide synthase (GCS) can reduce ceramide levels and help cells escape ceramide-induced apoptosis, thus leading to multidrug resistance (MDR). However, its expression and clinical significance in thyroid neoplasms still remain unclear. We aimed to elucidate the expression of GCS and explore its correlation with the clinicopathological characteristics in papillary thyroid carcinomas (PTCs).</p><p><b>METHODS</b>We retrospectively investigated GCS protein expression level in tissue specimens obtained from 108 consecutive PTC patients by immunohistochemistry and Western blotting.</p><p><b>RESULTS</b>GCS was weakly positive or negative in normal follicular cells, but it was frequently overexpressed in PTC cells. GCS overexpression was associated with primary tumor size, local infiltration, lymph node metastasis, and local recurrence, but not associated with gender, age, pathological variants, tumor multifocality, tumor stage or distant metastasis. Western blotting also showed that GCS protein levels were much higher in PTCs' tissues than in normal thyroid tissues.</p><p><b>CONCLUSION</b>GCS was upregulated in PTCs and might be an independent factor affecting prognosis.</p>