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RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

Extra-coarse-grained WC-Co cemented carbides are focused by researchers due to the high wear resistance and toughness, whereas the densification and WC grain tailoring are key factors for obtaining excellent performance. Extra-coarse-grained WC-10Co cemented carbides with an average grain size of 8.3-8.8 μm were prepared by a mild-ball-milling and vacuum sintering processes with ultra-fine WC powder obtained by mild-ball-milling method.The effects of sintering time on density, WC grain and mechanical properties were studied. The results show that the relative density first increases and then decreases with sintering time increasing from 30 min to 120 min.Ultra-fine pores also increase by the oxidation and accumulation of Co on the surface, and abnormal grains are formed by the aggregation of some WC grains.Therefore, the elimination of pores is hindered.Furthermore, the average grain size of WC firstly increases and then decreases due to orderly dissolution-precipitation of ultra-fine WC and fragmented fine WC, and finally WC grains are formed with wide distribution.As sintering holding time increases to 60 min, the partial spherical WC grain with curved surface is transformed into performance friendly hexagonal prism grain with rounded edge through faceted steps growth mechanism. Here, the bending strength and impact toughness reach the maximum of 1733 MPa and 28 kJ·m-2, respectively.Furthermore, the primary defects are difficult to be completely eliminated in some grains during sintering.With longer sintering holding time, the increased multiple defects result in the deterioration of properties.

Diabetic retinopathy (DR) is increasingly becoming a main complication of diabetes, and is difficult to cure. In our research, network pharmacology analysis suggested that both compound Danshen dripping pills (CDDP) and bezafibrate (BZF) have potential protective effects against DR and the two drugs may act synergistically. The pharmacological effects of the coadministration of CDDP and BZF were elucidated in db/db mice, which simulate DR. Fluorescein fundus angiography showed that coadministration attenuated vascular leakage. Optical coherence tomography and hematoxylin and eosin staining showed that coadministration improved retinal thickness better than CDDP monotherapy. In addition, cell fluorescence images of reactive oxygen species revealed that coadministration of CDDP and BZF had more potent effects against oxidative stress than CDDP monotherapy. Metabolomics analysis showed that coadministration reduced the ratio of oxidized glutathione to reduced glutathione further than CDDP monotherapy. Coadministration of CDDP and BZF may provide additional protective effects by resisting vascular leakage, increasing retinal thickness, and inhibiting inflammation and oxidative stress in DR.

Objective: Accumulating literatures suggested that long non-coding RNAs (lncRNAs) were involved in tumorigenesis and cancer progression in lung adenocarcinoma (LUAD). However, the precise regulatory mechanism of lncRNA Lung cancer-associated transcript 1 (LUCAT1) in LUAD is not well defined. In this study, we aimed to investigate the biological function and mechanism of lncRNA LUCAT1 in regulating tumor migration and glycolysis of LUAD.Methods: High throughput sequencing was performed to identify differentially expressed lncRNAs between LUAD patients and healthy controls. The expression levels of LUCAT1 in LUAD clinical specimens or cell lines were evaluated by In situ hybridization (ISH) and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Functional experiments, including wound-healing, transwell invasion assays, glucose absorption, lactate metabolism and tumor xenograft experiments were conducted to identify the biological functions of LUCAT1 in LUAD. Silencing of LUCAT1, over-expression of LUCAT1 and miR-4316 were generated in LUAD cell lines to verify the regulatory mode of LUCAT1-mir-4316-VEGFA axis.Results: Our findings revealed that lncRNA LUCAT1 was significantly up-regulated in LUAD serum exosomes, tumor tissues, and LUAD cells in comparison with corresponding controls. Receiver operating characteristic curve (ROC) analysis indicated that the area under the curve (AUC) value of serum exosomal LUCAT1 reached 0.852 in distinguishing LUAD patients from healthy individuals. High expression of LUCAT1 in LUAD patient tissues was associated with enhanced Lymph Node Metastasis (LNM), advanced Tumor Node Metastasis (TNM) stage and poorer clinical outcome in LUAD patients. Knockdown of LUCAT1 inhibited LUAD cell metastasis and glycolysis in vitro as well as tumor metastasis in vivo, while overexpression of LUCAT1 induced a promoted LUAD metastasis and glycolysis. Furthermore, mechanistic investigations revealed that LUCAT1 elevated LUAD cell metastasis and glycolysis by sponging miR-4316, which further led to the upregulation of VEGFA. Finally, the regulatory axis LUCAT1-miR-4316-VEGFA was verified in LUAD.Conclusion: Our present research suggested that LUCAT1 facilitate LUAD cell metastasis and glycolysis via serving as a competing endogenous RNA to regulate miR-4316/VEGFA axis, which provided a novel diagnostic marker and therapeutic target for LUAD patients.

Melanoma is a disease characterized by lesions that activate ERK. Although 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF-mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS, resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition, leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation, resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.

The atmospheric river (AR) is a long, narrow, and transient corridor of strong horizontal water vapor transport. Various AR detection methods have been proposed, which have introduced significant uncertainty to the identified AR characteristics. This study has designed a data fusion algorithm to merge 12 data sets of different global and regional AR identification algorithms published by the Atmospheric River Tracking Method Intercomparison Project (ARTMIP) covering the period from 1980 to 2016. It aims to conduct frequency statistics to further research the global distribution, interannual variation, the trends in poleward shifting, and the impacted factors of AR occurrence. The quantitative results indicate an overall increasing trend in interannual variation, with a more pronounced growth trend observed in the oceanic region between 40 and 60ºS. Additionally, the study identifies a poleward shift in the peak latitude of AR occurrence frequency, with speeds of 0.589° and 0.769° per decade in the Northern and Southern Hemispheres, respectively. This shift may be associated with the tropical poleward expansion. Upon examining the relationship between AR frequency and sea surface temperature (SST) as well as zonal wind, the study finds that distinct dominant factors influence AR in different regions. AR events near the 30°N/S ocean are influenced more significantly by zonal wind than by SST. These findings shed light on the global characteristics of AR occurrences and provide insights into the factors governing their variability across different areas. Plain Language Summary: Researchers employ an array of tools to detect a weather phenomenon event known as the atmospheric river (AR), which is a long, narrow corridor in the atmosphere that transports water vapor originating from the tropics. Each tool employs a distinct methodology for identifying these atmospheric rivers, which can lead to varying results. This diversity makes it challenging for us to select a single methodology to study AR on a global scale and over long periods. To address this problem, we have developed an innovative algorithm. This algorithm merges the results from different tools to create a more consistent and comprehensive data set of atmospheric rivers. Utilizing this novel data set, we investigated how atmospheric rivers have evolved over time and across different locations. Our research indicates a poleward shift of AR positions throughout the research period. Moreover, we also examined the sea surface temperature and wind patterns, and their connections to the frequency of atmospheric rivers. These insights could provide insightful implications for how climate changes might influence these important weather phenomena in the future. Key Points: Proposed a data fusion algorithm merging 12 Atmospheric River Detection Tools data sets based on their identification results conflictsThe poleward shifts of the AR frequency peak and tropical expansion have a moderate correlation during the research periodAR events near the 30° N/S ocean are influenced more significantly by zonal wind than by sea surface temperature [ABSTRACT FROM AUTHOR]

Abstract Recently, expression signatures of exosomal long non-coding RNAs (lncRNAs) have been proposed as potential non-invasive biomarkers for cancer detection. In this study, we aimed to develop a urinary exosome (UE)-derived lncRNA panel for diagnosis and recurrence prediction of bladder cancer (BC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to screen and evaluate the expressions of eight candidate lncRNAs in a training set (208 urine samples) and a validation set (160 urine samples). A panel consisting of three differently expressed lncRNAs (MALAT1, PCAT-1 and SPRY4-IT1) was established for BC diagnosis in the training set, showing an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.854. Subsequently, the performance of the panel was further verified with an AUC of 0.813 in the validation set, which was significantly higher than that of urine cytology (0.619). In addition, Kaplan-Meier analysis suggested that the up-regulation of PCAT-1 and MALAT1 was associated with poor recurrence-free survival (RFS) of non-muscle-invasive BC (NMIBC) (p

Lung cancer is the first leading cause of cancer deaths worldwide. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence shows that long noncoding RNA (lncRNA) are capable of modulating tumor initiation, proliferation and metastasis. In the present study, we aimed to evaluate whether circulating lncRNA could be used as biomarkers for diagnosis and prognosis of NSCLC. Expression profiles of 14 lncRNA selected from other studies were validated in 20 pairs of tissues by quantitative real‐time PCR, and the dysregulated lncRNA thus identified were further validated in serum samples from two independent cohorts along with three tumor makers (CEA, CYFRA21‐1, and SCCA). Receiver‐operating characteristic analysis was utilized to estimate the diagnostic efficiency of the candidate lncRNA and tumor markers. Importantly, we observed an association between lncRNA expression and overall survival (OS) rate of NSCLC. The expressions of SOX2 overlapping transcript (SOX2OT) and ANRIL were obviously upregulated in NSCLC tissues and serum samples compared with normal controls (P