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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.

Background Patients with locally advanced rectal cancer generally have different response rates to preoperative neoadjuvant chemo-radiotherapy. This study investigated the value of the apparent diffusion coefficient (ADC) as a predictor to forecast the response to neoadjuvant chemo-radiotherapy in patients with locally advanced rectal cancer. Methods Ninety-one locally advanced rectal cancer patients who underwent neoadjuvant chemo-radiotherapy between 2015 and 2018 were enrolled. Diffusion-weighted magnetic resonance imaging was performed before treatment and within 4 weeks after the completion of neoadjuvant chemo-radiotherapy. Mean ADC values of regions of interest were evaluated by two radiologists. The tumor response was evaluated according to RESCIST 1.1. The cut-off value for the mean ADC and increasing percentage (ΔADC%) after neoadjuvant chemo-radiotherapy was calculated using the receiver operating characteristic curve. The response rate of pre-ADC and ΔADC% above/below the cut-off values was determined using the chi-square test, respectively. Primary tumor progression-free survival (PFS) was analyzed using the Kaplan–Meier method, based on the pre-ADC and ΔADC% cut-off values. Results The cut-off value of mean pre-ADC and ΔADC% was 0.94 × 10 –3 mm 2 /s (80.36% sensitivity, 74.29% specificity) and 26.0% (73.21% sensitivity, 77.14% specificity), respectively. Lower mean pre-ADC values were related to a better response rate (83.3% vs 29.7%, P  < 0.001) and PFS (26.12 vs 17.70 months, P  = 0.004). ΔADC% above the cut-off value was also related to a better response rate (83.7% vs 35.7%, P  < 0.001) and PFS (26.93 vs 15.65 months, P  = 0.034). Conclusions The mean ADC pre-treatment value and ΔADC% were potential predictors for the tumor response in locally advanced rectal cancer patients treated with neoadjuvant chemo-radiotherapy.

Objectives This study aims to develop and validate a novel radiomics model utilizing magnetic resonance imaging (MRI) to predict progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) who are receiving a combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents. This is an area that has not been previously explored using MRI-based radiomics. Methods 111 patients with uHCC were enrolled in this study. After performing univariate cox regression and the least absolute shrinkage and selection operator (LASSO) algorithms to extract radiological features, the Rad-score was calculated through a Cox proportional hazards regression model and a random survival forest (RSF) model. The optimal calculation method was selected by comparing the Harrell’s concordance index (C-index) values. The Rad-score was then combined with independent clinical risk factors to create a nomogram. C-index, time-dependent receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis were employed to assess the forecast ability of the risk models. Results The combined nomogram incorporated independent clinical factors and Rad-score calculated by RSF demonstrated better prognosis prediction for PFS, with C-index of 0.846, 0.845, separately in the training and the validation cohorts. This indicates that our model performs well and has the potential to enable more precise patient stratification and personalized treatment strategies. Based on the risk level, the participants were classified into two distinct groups: the high-risk signature (HRS) group and the low-risk signature (LRS) group, with a significant difference between the groups ( P  < 0.01). Conclusion The effective clinical-radiomics nomogram based on MRI imaging is a promising tool in predicting the prognosis in uHCC patients receiving ICIs combined with anti-angiogenic agents, potentially leading to more effective clinical outcomes.

Objectives This study aimed to access the performance of apparent diffusion coefficient (ADC) as a predictor for treatment response to whole-brain radiotherapy (WBRT) in patients with brain metastases (BMs) from non-small-cell lung cancer (NSCLC). Methods A retrospective analysis was conducted of 102 NSCLC patients with BMs who underwent WBRT between 2012 and 2016. Diffusion-weighted MRI were performed pre-WBRT and within 12 weeks after WBRT started. Mean single-plane ADC value of ROIs was evaluated by two radiologists blinded to results of each other. The treatment response rate, intracranial progression-free survival (PFS), and overall survival (OS) were analyzed based on the ADC value and ΔADC respectively. At last, we used COX and logistic regression to do the multivariate analysis. Results There was good inter-observer agreement of mean ADC value pre-WBRT, post-WBRT, and ΔADC between the 2 radiologists (Pearson correlation 0.915 [pre-WBRT], 0.950 [post-WBRT], 0.937 [ΔADC], p < 0.001, for each one). High mean ADC value were related with better response rate (72.2% vs 37.5%, p = 0.001) and iPFS (7.6 vs 6.4 months, p = 0.031). High ΔADC were related with better response rate (73.6% vs 36.7%, p < 0.001). Multivariate analysis shows that histopathology, BMs number, high ADC value pre-WBRT, and high ΔADC post-WBRT were related to better treatment response of WBRT, and KPS, BMs number, and low ADC value pre-WBRT increased the risk of developing intracranial relapse. Conclusions The mean single-plane ADC value pre-WBRT and ΔADC post-WBRT were potential predictor for intracranial tumor response to WBRT in NSCLC patients with brain metastases. Key Points • ADC value is a potential predictor of intracranial treatment response to WBRT in NSCLC patients with brain metastases. • Higher mean ADC value pre-WBRT and ΔADC post-WBRT of brain metastases were related to better intracranial tumor response. • Prediction of response before WBRT using ADC value can help oncologists to make better therapy plans and avoid missing opportunities for rescue therapy.

Background. Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes and molecular signaling underlie the sensitization of nociceptive pathways. We previously found that the activation of microglial glucagon-like peptide 1 receptor (GLP-1R) could potently relieve formalin-, bone cancer-, peripheral nerve injury-, and diabetes-induced pain hypersensitivity. So far, little is known about how the gene profile changes upon the activation of GLP-1R signaling in the pathophysiology of neuropathic pain. Methods. Spinal nerve ligation (SNL) was performed to induce neuropathic pain in rats. Mechanical allodynia was assessed using von Frey filaments. The expression of IL-10, β-endorphin, and μ-opioid receptor (MOR) was examined by real-time quantitative polymerase chain reaction (qPCR) and whole-cell recording. Measurements of cellular excitability of the substantia gelatinosa (SG) neurons by whole-cell recording were carried out. R packages of differential gene expression analysis based on the negative binomial distribution (DESeq2) and weighted correlation network analysis (WGCNA) were used to analyze differential gene expression and the correlated modules among GLP-1R clusters in neuropathic pain. Results. The GLP-1R agonist, exenatide, has an antiallodynic effect on neuropathic pain, which could be reversed by intrathecal injections of the microglial inhibitor minocycline. Furthermore, differential gene expression analysis (WGCNA) indicated that intrathecal injections of exenatide could reverse the abnormal expression of 591 genes in the spinal dorsal horn induced by nerve injury. WGCNA revealed 58 modules with a close relationship between the microglial GLP-1R pathway and features of nerve injuries, including pain, ligation, paw withdrawal latency (PWL), and anxiety. The brown module was identified as the highest correlated module, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that inflammatory responses were most correlated with PWL. To further unravel the changes of hyperalgesia-related neuronal electrophysiological activity mediated by microglia GLP-1 receptors, whole-cell recording identified that MOR agonism stimulated a robust outward current in the sham groups compared with the spinal nerve ligation (SNL) groups. This inhibitory effect on the SNL group was more sensitive than that of the sham group after bath application of β-endorphin. Conclusions. Our results further confirmed that the GLP-1R pathway is involved in alleviating pain hypersensitivity mediated by spinal microglia activation, and inflammatory responses were the most correlated pathway associated with PWL changes in response to exenatide treatment. We found that the identification of gene regulation in response to GLP-1R activation is an effective strategy for identifying new therapeutic targets for neuropathic pain. Investigation for the activation of spinal microglial GLP-1R which might ameliorate inflammatory responses through gene expression and structural changes is providing a potential biomarker in pain management.

Long noncoding RNAs (lncRNAs) can promote hepatocellular carcinoma (HCC) initiation and progression. In this report, we examined the role of lncRNA LINC02476 in HCC. The expression levels of different lncRNAs in HCC were explored using the TCGA database and lncRNA LINC02476 was selected for further study. The expression of LINC02476 in HCC tissues was determined by real-time PCR. The clinicopathological characteristics of HCC patients were analyzed relative to the expression of LINC02476. The expression of LINC02476 was downregulated in HCC cells using a lentiviral vector and different assays were performed to study cell growth, proliferation, invasion, apoptosis and the cell cycle. MiR-497 was selected as a miRNA that could interact with LINC02476 which was further tested by RNA immunoprecipitation. HMGA2 was selected as a possible target of miR-497, and their interaction was examined by a luciferase reporter assay. LINC02476 expression was elevated in HCC cell lines and HCC tissues. When LINC02476 was downregulated, the growth and the invasion of HCC cells decreased in vitro and in vivo. LINC02476 negatively regulated the expression of miR-497 by acting as a ceRNA. HMGA2 was directly targeted and inhibited by miR-497. The results indicate that LINC02476 functions through the miR-497/HMGA2 axis and that it has a role in the growth and metastasis of HCC cells. Therefore, LINC02476 could be an interesting new molecular target in HCC therapies.

An innovative approach involving chemical modification of the surface of MgO nanoparticles (NPs) for steelmaking and application of NPs to carbon structural steel has been investigated. The results show that the inclusions in the test steels were completely converted to MgAl 2 O 4 spinel or MnS complex inclusions. The mean inclusion size decreased with increasing NP content from 0.01% to 0.03%, but increased at 0.05% because of NP aggregation. Addition of NPs increased the amount of intragranular ferrite and prevented polygonal ferrite formation, thereby enhancing the impact toughness. Impact tests showed that the dimple fractures in steel with 0.05% NP content were deeper than those in the other samples because the MgAl 2 O 4 inclusions were larger. The surface-modified MgO NPs had a major effect on the inclusion characteristics and microstructure of carbon structural steel.

Steel products have experienced long-standing problems such as unstable product quality and low product homogeneity. In the continuous casting process, realizing constant-temperature pouring is an effective way to improve product homogeneity. Plasma heating can compensate for the temperature drop during casting with a tundish and maintain a stable degree of superheating of the molten steel in the tundish. Plasma heating has a certain impact on the cleanliness of the molten steel and on the tundish covering flux in the tundish while compensating for the temperature drop. This paper uses SEM-EDS, XRD and FactSage to analyze the cleanliness of molten steel and the characteristics of the tundish covering flux before and after plasma heating. The results show that the number density of inclusions in the tundish is significantly lower after heating, improving the floating removal of small-sized inclusions; after heating, the surface morphology of the tundish covering flux sample appears transparent and glassy, with uniform morphology. XRD results show that the tundish covering flux after plasma heating exhibits no crystal precipitation and is amorphous and that there is a certain regularity before and after heating; there are no obvious changes in the composition of the tundish covering flux in the liquid phase area.

Tundish plasma heating is an effective method for achieving steady casting with low superheat and constant temperature. In order to study the flow field, temperature field in tundish heated by plasma, a three-dimensional transient mathematical model was established in the present work. A four-strand T-type tundish in a steelmaking plant was used to explore the changes in the flow field and temperature field of molten steel in the tundish under different plasma heating powers. The results showed that plasma heating affected the flow state of molten steel. It could eliminate the short-circuit flow at outlet. When the plasma heating was 500 kW, the molten steel had an obvious upward flow. The turbulence intensity was improved and distributed evenly with an increase in plasma heating power. In the prototype tundish, the temperature of the outlet was dropped by nearly 2–3 K within 300 s. With the increase of plasma heating power, the low temperature area in the tundish gradually was decreased. When the heating power was 1000 kW, the temperature difference of two outlets was 0.5 K and the overall temperature distribution was more uniform. The research results have a certain guiding significance for the selection of the actual plasma heating power on site.

Duan Y, Zhao M, Jiang M, Li Z, Ni C. Onco Targets Ther. 2020;13:2701-2710. At the authors request, the Editor and Publisher of OncoTargets and Therapy wish to retract the published article. The authors have informed the journal that they have concerns with the reliability of the published results. It was also found that several western blot images in Figures 2E, 2G and 2H appear to have been duplicated. The authors were unable to provide a satisfactory explanation for this and were unable to provide any original data relating to their study. The Editor has agreed with the request to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as \"Retracted\". This retraction relates to this paper