Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi+MEKi) therapies have significantly improved clinical outcomes in patients with metastatic melanoma. Unfortunately, the efficacy is beset by the acquisition of drug resistance1–6. Here we investigated molecular mechanisms underlying acquired resistance to BRAFi (BRAFi resistance, “BR”) and BRAFi+MEKi (combination therapy resistance, “CR”). Consistent with previous studies, BR is mediated by ERK pathway re-activation. CR is, however, mediated by mechanisms independent of re-activation of ERK in many therapy-resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in acquired drug resistant cells and play a pivotal role in mediating both BR and CR. Our screening using reverse phase protein array (RPPA) revealed distinct mechanisms by which PAKs mediate BR and CR. In BR, PAKs phosphorylate CRAF and MEK to reactivate ERK. In CR, PAKs regulate JNK and β-catenin phosphorylation, mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide new insights into molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.
SUMMARY Melanoma patients with oncogenic BRAFV600E mutation have poor prognoses. While the role of BRAFV600E in tumorigenesis is well established, its involvement in invasion that is clinically observed in melanoma patients, remains a topic of debate. Here we show that BRAFV600E melanoma cells have extensive invasion activity as assayed by degradation of extracellular matrix, and generation of F-actin and cortactin foci that mediate membrane protrusion. Inhibition of BRAFV600E blocks melanoma cell invasion. In a BRAFV600E-driven murine melanoma model or in patients’ tumor biopsies, cortactin foci decrease upon inhibitor treatment. In addition, genome-wide expression analysis shows that a number of invadopodia-related genes are down-regulated after BRAFV600E inhibition. Mechanistically, BRAFV600E induces phosphorylation of cortactin and the exocyst subunit Exo70 through ERK, which regulates actin dynamics and matrix metalloprotease secretion, respectively. Our results provide support for the role of BRAFV600E in metastasis, and suggest that inhibiting invasion is a potential therapeutic strategy against melanoma.
Background Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent malignant tumors of the head and neck and presents high risks of recurrence and poor prognosis postoperatively. The aim of this study was to establish a predictive model based on fatty acid metabolism (FAM) genes to forecast the prognosis of HNSCC patients and the subsequent treatment strategies. Methods We accessed the TCGA and GEO databases for HNSCC genes and clinical data. The FAM risk score model was created and validated using a combination of univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression analysis. Combining risk scores and clinical characteristics, a nomogram was established and assessed. Subsequently, the function, gene mutation, immune difference, and chemotherapeutic drug sensitivity of the groups with high‐ and low‐risk scores were analyzed. Consequently, the mode's validity was evaluated comprehensively by combining single gene analysis. Results The FAM risk score model for predicting HNSCC prognosis had certain validity. Patients in the high‐ and low‐risk groups had genetic mutations, and the prognosis was the poorest for the high‐risk groups with high genetic mutations. The patients with low‐risk scores were suitable for immunotherapy since they had increased infiltration of immune cells. In contrast, the patients in the other groups were more suitable for chemotherapy. Conclusion The results of this study demonstrated that the FAM risk score model may predict the prognosis of HSNCC and has a certain therapeutic guidance value.
In this paper, the thermal performance of an AntMiner mining machine containing 189 chips on three printed circuit board (PCBs) is experimentally studied. The numerical method is applied to analyze the local airflow and thermal distribution alongside the flow direction and shows a good agreement with the experimental results. Some hot-spot regions are identified where chips might suffer under high-temperature operating condition. Meanwhile, the highly compact arrangement may result in pronounced bypass and jeopardize the thermal performance of the mining machine rapidly; thereby, the airflow management strategy for such confined compartment is implemented. The result shows that the flowrate distribution can be notably improved. Although the total flowrate is slightly reduced by 4.4%, the maximum chip temperature on three PCBs can be reduced by 3.2 °C, 3.5 °C, and 3.0 °C, and the corresponding improvement on thermal performance reaches 13.3%, 15.6%, and 13.0%, respectively. Furthermore, the maximum temperature of the downstream chips will be reduced by 2.5 °C when incorporating the “partial bypass” design by the removal of 12 backside heat sinks. The corresponding heat transfer performance is improved by 8.9–13.9%.
Objective This study aims to explore the predictive value of SLC25A17 in the prognosis and tumor microenvironment (TME) of patients with head and neck squamous cell carcinoma (HNSCC) and to provide ideas for individual clinical treatment. Methods A pancancer analysis of the differential expression of SLC25A17 among different tumors was first conducted via the TIMER 2.0 database. Subsequently, the expression of SLC25A17 and related clinical information of HNSCC patients were obtained from the TCGA database, and patients were divided into two groups according to the median value of SLC25A17 expression. K‒M survival analysis was conducted to compare the overall survival (OS) and progression-free survival (PFS) between the groups. The Wilcoxon test was used to compare the distribution of SLC25A17 in different clinical characteristics, and univariate Cox and multivariate Cox analyses were performed to analyze independent prognostic factors to establish a predictive nomogram. Calibration curves were generated to verify the reliability of predicting 1-year, 3-year and 5-year survival rates and another cohort (GSE65858) was used for external validation. Gene set enrichment analysis was conducted to compare the enriched pathways, and the immune microenvironment was assessed using the CIBERSORT and estimate packages. Furthermore, the expression levels of SLC25A17 in immune cells were also analyzed with single-cell RNA-seq via the TISCH. Moreover, the immunotherapeutic response and chemotherapy drug sensitivity were compared between the two groups to guide precise treatment. The TIDE database was applied to predict the possibility of immune escape in the TCGA-HNSC cohort. Results Compared with normal samples, the expression of SLC25A17 was much higher in HNSCC tumor samples. For patients with high SLC25A17 expression, the OS and PFS were shorter than those with low SLC25A17 expression, indicating a worse prognosis. The expression of SLC25A17 varied in different clinical features. Univariate Cox and multivariate COX analyses showed that SLC25A17, age, and lymph node metastasis are independent prognostic risk factors for HNSCC, and the survival prediction model based on these factors had reliable predictive value. Patients in the low-expression group exhibited more immune cell infiltration, higher TME scores, higher IPS scores and lower TIDE scores than those in the high-expression groups, suggesting better immunotherapeutic response with lower SLC25A17 expression. Moreover, patients in the high-expression group were more sensitive to chemotherapy. Conclusions SLC25A17 can effectively predict the prognosis of HNSCC patients and could be a precise individual-targeted indicator for the treatment of HNSCC patients.
X rudder is particularly important for submarine maneuverability, but its influence on wake flow field remains largely unknown. In this study, the X rudder was scaled down three-dimensionally to 80%, 85%, 90%, 95% and 100% of the original rudder area with unchanged aspect ratio and installation position of rudder shaft. Next, the effects of X rudder area on the horizontal mechanical properties and wake flow field of the submarine with a tail control plane were analyzed using the CFD method. The results showed that when the X rudder area was reduced by 20%, the resistance was not significantly affected, and the yaw torque was still larger than that of cross-shaped rudder submarine. At the rudder angles of 0°, 2° and 5°, the velocity non-uniformity coefficients of S1 were reduced by about 9%, 25% and 71%, respectively, when compared to those of S5.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.