[Retracted] MicroRNA­454 inhibits non­small cell lung cancer cells growth and metastasis via targeting signal transducer and activator of transcription­3.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration and invasion assay data shown in Figs. 2C and 4D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 3979­3986, 2018; DOI: 10.3892/mmr.2017.8350].

The Addition of Peripheral Blood Inflammatory Indexes to Nomogram Improves the Predictive Accuracy of Survival in Limited-Stage Small Cell Lung Cancer Patients.

BACKGROUND: Accumulated evidence for systemic inflammation response in several solid tumors prompts a possibility of prediction of patients' prognosis in a more accessible and valuable manner. However, the prognostic value of peripheral blood inflammatory markers in limited-stage small cell lung cancer (LS-SCLC) remains unclear. Therefore, we investigated the prognostic values of pretreatment inflammatory indexes in LS-SCLC patients. METHODS: We retrospectively identified 334 patients with LS-SCLC and collected their pretreatment serum levels of neutrophil, platelet, lymphocyte, leukocyte, hemoglobin, and albumin, then neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) were calculated. Patients were dichotomized as low-Risk or high-Risk group based on their corresponding cutoff values. Univariate and multivariate analyses were conducted with a Cox proportional hazards model. The least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to construct the inflammation-related prognostic scoring system named Risk for OS. Nomograms were established to provide prognostic information, allowing for more individualized prediction of survival. RESULTS: Higher pretreatment platelet, lymphocyte, and albumin were indicators of favorable overall survival (OS), whereas higher NLR and SII were accompanied by inferior OS. The prognosis of patients with high Risk was significantly worse than that with low Risk in both the training group and the validation group (both p < 0.001). Comparable area under the curve (AUC) values between the training group and the validation group were observed, yielding 1-, 3-, and 5-year OS rates of 67.3% vs. 69.2%, 66.8% vs. 69.5%, and 66.7% vs. 71.4%, respectively. Multivariate analyses revealed that Risk [hazard ratio (HR) = 0.551, p < 0.001] was an independent negative prognostic indicator for OS, which was further verified in the validation set. The addition of Risk to nomogram (C-index = 0.643) harbored improved predictive accuracy for OS when compared with that of clinical factors alone (C-index = 0.606); the AUC values of 1-, 3-, and 5-year OS rates were 71.7% vs. 66.4%, 73.5% vs. 66.6%, and 71.9% vs. 65.6%, respectively. CONCLUSIONS: Pretreatment peripheral blood inflammatory indexes may be a noninvasive serum biomarker for poor prognosis in LS-SCLC. The addition of Risk to the nomogram model could serve as a more powerful, economical, and practical method to predict survival for patients with LS-SCLC.

UBR5 inhibits the radiosensitivity of non-small cell lung cancer cells via the activation of the PI3K/AKT pathway.

Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) has been identified as an oncogene in diverse cancers; however, whether its expression was associated with radiosensitivities of non-small cell lung cancer (NSCLC) cells remains unclear. Expression levels of UBR5 in NSCLC tissues and cell lines were examined by immunohistochemical staining and western blotting. Colony formation assay, CCK-8 cell viability assay, flow cytometry, and caspase-3 activity assay were performed to evaluate the radiosensitization of UBR5 knockdown in NSCLC cells, and the underlying mechanism in vitro was also investigated. UBR5 was highly expressed in NSCLC tissues, and its high expression was associated with the poor prognosis in 50 patients with NSCLC. After X-ray irradiation, the protein expression levels of UBR5 were also increased in NSCLC cells. UBR5 inhibition enhanced the radiosensitivity of NSCLC cells by inhibiting the cell viability and inducing apoptosis. Further investigation indicated that UBR5 knockdown-mediated radiosensitization involved the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Knockdown of UBR5 radiosensitizes NSCLC cells via the inactivation of the PI3K/AKT signal, which provided a novel therapeutic target for NSCLC radiosensitization.

Knockdown of lncRNA PCAT1 Enhances Radiosensitivity of Cervical Cancer by Regulating miR-128/GOLM1 Axis.

PURPOSE: Cervical cancer (CC) is the fourth most common cancer with high death rate in females. The study aims to detect the mechanism of long non-coding RNA (LncRNA) PCAT1 on radiosensitivity of CC. METHODS: The expression of PCAT1, miR-128 and GOLM1 in CC tissues and cells was measured by qRT-PCR. Different doses of X-ray were used for radiation treatment of CC cells and 6 Gy was chosen to perform the following experiments. The proliferation, migration and invasion of CC cells were measured by MTT assay, wound healing assay and transwell assay, respectively. The target relationships among PCAT1, miR-128 and GOLM1 were predicted by StarBase and TargetScan and verified by luciferase reporter assay. The protein level of GOLM1 was determined by Western blot. The xenograft tumor model was constructed in nude mice to verify the effect of PCAT1 on radiosensitivity of CC in vivo. RESULTS: The PCAT1 expression was upregulated in CC tissues and cells. PCAT1 silencing enhances radiosensitivity of CC cells on proliferation, migration and invasion. MiR-128 was the target of PCAT1 and was negatively regulated by PCAT1. Upregulation of miR-128 enhances radiosensitivity of CC cells on proliferation, migration and invasion. GOLM1 was a target of miR-128 and was negatively regulated by miR-128. Upregulation of GOLM1 and downregulation of miR-128 both reversed the enhanced effect of PCAT1 knockdown on radiosensitivity of CC cells, which partly promoted the proliferation, migration and invasion of CC cells. CONCLUSION: Silencing of PCAT1 enhanced radiosensitivity of CC via targeting miR-128/GOLM1, which provided a new idea for treating CC.

Prognostic role of targeted therapy in patients with multiple-site metastases from non-small- cell lung cancer.

Aim: To evaluate the prognostic role of EGFR mutations in patients with multi-site metastases from non-small-cell lung cancer (NSCLC). Patients & methods: A total of 215 advanced NSCLC patients with multi-site metastases were included. The overall survival (OS) was the primary end point. Results: EGFR tyrosine kinase inhibitors (TKIs) significantly improved the OS in patients with brain metastases (p = 0.031) and bone metastases (p = 0.048). Meanwhile, it prolonged the OS in patients with lung or adrenal metastases, but not in patients with liver metastases. However, in patients without liver metastases, EGFR TKIs significantly improved the OS (p < 0.001). Conclusion: EGFR TKIs improved the prognosis in NSCLC patients with brain, bone, lung and adrenal metastases, but not in patients with liver metastases.

Efficacy of neoadjuvant chemotherapy combined with intraperitoneal hyperthermic chemotherapy in advanced ovarian cancer.

PURPOSE: To explore the efficacy and safety of neoadjuvant chemotherapy (NAC) combined with cytoreductive surgery (CRS) and postoperative intraperitoneal hyperthermic chemotherapy (IPHC) in the treatment of advanced ovarian cancer. METHODS: 132 patients with advanced ovarian cancer admitted to our hospital from May 2013 to May 2016 were enrolled and randomly divided into control group (n=44), IPHC group (n=44) and NAC+IPHC group (n=44). The patients in the control group underwent CRS and postoperative TP chemotherapy (iv. drip of paclitaxel + peritoneal perfusion of cisplatin), those in IPHC group underwent the CRS and postoperative IPHC+TP chemotherapy, and those in the NAC+IPHC group received two cycles of preoperative NAC and postoperative IPHC+TP chemotherapy. The surgery indexes (operation time, amount of intraoperative bleeding, diameter of tumor and number of metastatic foci) were recorded. The clinical effective rate, changes in levels of serum tumor markers and adverse reactions were evaluated. Moreover, the tumor recurrence and survival of patients after treatment were recorded. RESULTS: In NAC + IPHC group, the operation time, amount of intraoperative bleeding and of ascites, diameter of tumor and number of metastatic foci were all significantly reduced, and the optimal cytoreduction rate was increased compared with IPHC group and control group. The clinical effective rate was 43.2% (19/44), 61.4% (27/44) and 72.7% (32/44), respectively, in the three groups, with significant differences, and the clinical effective rate was obviously higher in NAC+IPHC group than in control group, while it had no significant difference in IPHC group compared with NAC+IPHC group or control group. After treatment, the levels of serum human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) were evidently higher in NAC + IPHC group than in IPHC group, while they were also evidently higher in IPHC group than in control group. According to the follow-up results, the 1-year recurrence rate in NAC+IPHC group was remarkably lower than in control group, and the median progression-free survival in NAC+IPHC group and IPHC group was remarkably longer than in control group, while it had no significant difference between NAC+IPHC group and IPHC group. The median overall survival had no statistically significant differences among the three groups. CONCLUSIONS: NAC combined with IPHC can significantly reduce the perioperative risk, increase the optimal cytoreduction rate and raise the clinical effective rate of CRS in the treatment of advanced ovarian cancer. Moreover, patients have good tolerance, and both tumor progression and survival of patients are significantly improved.

Radiomics signature extracted from diffusion-weighted magnetic resonance imaging predicts outcomes in osteosarcoma.

OBJECTIVE: Osteosarcoma often requires multidisciplinary treatment including surgery, chemotherapy and radiotherapy. However, tumor behavior can vary widely among patients and selection of appropriate therapies in any individual patient remains a critical challenge. Radiomics seeks to quantify complex aspects of tumor images under the assumption that this information is related to tumor biology. This study tested the hypothesis that a radiomic signature extracted from Diffusion-weighted magnetic resonance images (DWI-MRI) can improve prediction of overall survival (OS) compared with clinical factors alone in localised osteosarcoma. MATERIALS/METHODS: Pre-treatment DWI-MRI were collected from 112 patients (9-67 years of age) with histological-proven osteosarcoma that were treated with curative intent. The entire dataset was divided in two subsets: the training and validation cohorts containing 76 and 24% of the data respectively. Clinical data were extracted from our medical record. Two experienced radiotherapists evaluated DWI-MRIs for quality and segmented the tumor. A total of 103 radiomic features were calculated for each image. Least absolute shrinkage and selection operator (LASSO) regression was applied to select features. Association between the radiomics signature and OS was explored. Further validation of the radiomics signature as an independent biomarker was performed by using multivariate Cox regression. The Cox proportional-hazard regression model was also used to analyze the correlation between the prognostic factor and the survival for the clinical (C) model after the univariate analysis. Radiomics (R) model identified radiomics signature, which is the best predictor from the radiomic variable classes based on LASSO regression. Harrell's C-index was used to demonstrate the incremental value of the radiomics signature to the traditional clinical risk factors for the individualized prediction performance. RESULTS: Cox proportional-hazard regression model shows that: Tumor size, alkaline phosphatase (ALP) status before treatment and number of courses of chemotherapy were proven as the dependent clinical prognostic factors of osteosarcoma's overall survival time. The radiomics signature was significantly associated with OS, independent of clinical risk factors (radiomics signature: HR: 5.11, 95% CI: 2.85, 9.18, P < 0.001). Incorporating the radiomics signature into the coalition (C+R) model resulted in better performance (P < .001) for the estimation of OS (C-index: 0.813; 95% CI: 0.75, 0.89) than with the clinical (C) model (C-index: 0.764; 95% CI: 0.69, 0.85), or the single radiomics (R) model (C-index: 0.712; 95% CI: 0.65, 0.78). CONCLUSION: This study shows that the radiomics signature extracted from pre-treatment DWI-MRI improve prediction of OS over clinical features alone. Combination of the radiomics signature and the traditional clinical risk factors performed better for individualized OS estimation in patients with osteosarcoma, which might enable a step forward precise medicine. This method may help better select patients most likely to benefit from intensified multimodality diagnosis and therapies. Future studies will focus on multi-center validation of an optimized model.

Dihydroartemisinin alleviates oxidative stress in bleomycin-induced pulmonary fibrosis.

AIMS: Dihydroartemisinin has been shown to inhibit the development of pulmonary fibrosis in rats, but its mechanism has yet to be elucidated. This study aimed to determine the mechanisms of dihydroartemisinin in bleomycin-induced pulmonary fibrosis in a rat model. MAIN METHODS: Morphological changes and collagen deposition were analyzed via hematoxylin-eosin staining and Masson staining and the expression of biotic-factor-related oxidative stress in lung tissues was assayed with standard assay kits. The expressions of α-SMA, E-cadherin, and Nrf2/HO-1 were detected by Western blot and RT-PCR, and the cell morphology and proliferation of cultured type II alveolar epithelial cells (AECs) were assessed via microscopy and immunocytochemical assay. KEY FINDINGS: Dihydroartemisinin treatment significantly decreased the level of oxidative stress and collagen synthesis and inhibited AECs differentiation in bleomycin-induced pulmonary fibrosis compared to the control group (P < 0.001). SIGNIFICANCE: Our results indicated that dihydroartemisinin might decrease oxidative damage to attenuate lung injury and fibrosis.

Apatinib inhibits macrophage-mediated epithelial-mesenchymal transition in lung cancer.

Chemotherapy is one of the main treatment approaches for lung cancer. However, few drugs can be used in the post-first-line treatment of lung cancer. Apatinib is a small molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and is widely used in advanced gastric cancer. This study aimed to investigate the therapeutic effect of apatinib in the second-line treatment of lung cancer and explore its underlying mechanism from the aspect of macrophage-mediated epithelial-mesenchymal transition (EMT). The results showed that apatinib attenuated macrophage-induced EMT and migration of lung cancer cells but not normal lung cells, as demonstrated by the loss of epithelial properties and gain of mesenchymal characteristics. Moreover, apatinib selectively decreased hepatocyte growth factor (HGF) secretion in polarized macrophages. Furthermore, apatinib down-regulated the expression of the HGF-Met signaling pathway in polarized macrophage-stimulated lung cancer cells. Taken together, our study has identified a novel pathway through which apatinib exerts its anti-cancer functions, and provided a molecular basis for apatinib potential applications in the post-first line treatment of lung cancer.

MicroRNA-454 inhibits non­small cell lung cancer cells growth and metastasis via targeting signal transducer and activator of transcription-3.

Lung cancer is one of the most common type of cancers and the leading cause of cancer­related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases. Emerging studies have suggested that microRNAs are dysregulated in NSCLC and serve important roles in NSCLC initiation and development. However, to the best of our knowledge, the expression, roles and molecular mechanism of microRNA­454 (miR­454) have not been investigated in NSCLC. In the present study, miR­454 was demonstrated to be significantly downregulated in NSCLC tissues and cell lines, as assessed by western blot analysis and reverse transcription­quantitative polymerase chain reaction. Reduced miR­454 expression was significantly correlated with aggressive clinicopathological features in NSCLC. In addition, upregulation of miR­454 suppressed proliferation, migration and invasion NSCLC cells, as assessed by Cell Counting Kit­8 and in vitro migration and invasion assays, respectively. Furthermore, bioinformatics analysis identified STAT3 as a direct target gene of miR­454, and STAT3 knockdown was demonstrated to simulate the effects of miR­454 overexpression in NSCLC. In conclusion, the present study provided convincing evidence that miR­454 is downregulated in NSCLC, and regulates growth and metastasis by directly targeting STAT3, which suggests that miR­454 may be an efficient therapeutic target for NSCLC.

Drug resistance analysis of gefitinib-targeted therapy in non-small cell lung cancer.

The aim of the study was to examine the drug resistance analysis of gefitinib-targeted therapy in non-small cell lung cancer (NSCLC). In total, 156 NSCLC patients without surgical treatment were selected, including 117 cases of adenocarcinoma (75%), to receive single gefitinib 0.25 g/day or combined with platinum chemotherapy. Computed tomography was used to evaluate tumor growth for the response and non-response groups. The chemotherapy regimen was changed or combined with radiotherapy in the non-response group. Tumor progression or metastasis in the response group was considered as the generation of drug resistance. The chemotherapy regimen was altered in the response group. Eleven cases had tumor response in the non-response group after the chemotherapy regimen was adjusted (20%), 33 cases had complete response (CR) (32.7%), 44 cases had partial response (PR) (43.6%), and 24 cases had stable disease (SD) (23.8%) in the response group. The drug resistance rates of CR, PR, and SD showed no significant difference (P>0.05). However, the drug-resistant time of CR was significantly delayed and the difference was statistically significant (P<0.05). The response rates of CR, PR, and SD patients regaining the response rate showed no statistical significance after the chemotherapy regimen was adjusted, and the difference was not statistically significant (P>0.05). In conclusion, gefitinib-targeted therapy in NSCLC showed certain drug resistance, which may not be related to the response.