Purpose
Risk stratification based on somatic mutations in
TERT
promoter and
BRAF
/
RAS
has been well established for papillary thyroid cancer (PTC), and there is emerging evidence showed that
TERT
...promoter methylation was frequently observed in thyroid cancer patients with adverse features. This study was aimed to comprehensive explore the prognostic value of
BRAF
/
RAS
mutations,
TERT
promoter mutations, and
TERT
promoter methylation in PTC.
Methods
The relationships of
BRAF
/
RAS
mutations,
TERT
promoter mutations, and
TERT
promoter methylation with clinical characteristics and outcomes of PTC were analyzed in 382 patients with PTC.
Results
TERT
promoter mutation and hypermethylation were collectively observed in 52 (13.6%) samples and associated with
BRAF
/
RAS
mutation, aggressive clinical characteristics, and poor clinical outcomes of PTC. Coexistence of
BRAF
/
RAS
and
TERT
alterations was found in 45 of 382 (11.8%) PTC patients and strongly associated with old patient age, extrathyroidal extension, advanced pathologic T stage and metastasis. Importantly, patients with both
BRAF
/
RAS
and
TERT
alterations had higher rates of tumor recurrence (13.6% vs 1.5%,
P
= 0.042) and disease progression (24.4% vs 3.3%,
P
< 0.001) than patients without any alterations, and cox regression analysis revealed that the coexistence of
BRAF
/
RAS
and
TERT
alterations, but not
BRAF
/
RAS
or
TERT
alterations alone, increased the risk of progression-free interval with an adjusted HR of 10.35 (95% CI: 1.79–59.81,
P
= 0.009).
Conclusions
This study suggested that comprehensively analysis of
BRAF
/
RAS
mutations,
TERT
promoter mutation and methylation is an effective strategy to identify high-risk patients with PTC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The telomerase reverse transcriptase (TERT) is overexpressed and associated with poor prognosis in papillary thyroid cancer (PTC), the most common subtype of thyroid cancer. The overexpression of ...TERT in PTC was partially attributed to transcriptional activation by two hotspot mutations in the core promoter region of this gene. As one of the major epigenetic mechanisms of gene expression regulation, DNA methylation has been proved to regulate several tumor-related genes in PTC. However, the association of
promoter DNA methylation with TERT expression and PTC progression is still unclear. By treating PTC cell lines with demethylating agent decitabine, we found that the
promoter methylation and the genes' expression were remarkably decreased. Consistently, PTC patients with
hypermethylation had significantly higher TERT expression than patients with
hypomethylation. Moreover,
hypermethylated patients showed significant higher rates of poor clinical outcomes than patients with
hypomethylation. Results from the cox regression analysis showed that the hazard ratios (HRs) of
hypermethylation for overall survival, disease-specific survival, disease-free interval (DFI) and progression-free interval (PFI) were 4.81 (95% CI, 1.61-14.41), 8.28 (95% CI, 2.14-32.13), 3.56 (95% CI, 1.24-10.17) and 3.32 (95% CI, 1.64-6.71), respectively. The HRs for DFI and PFI remained significant after adjustment for clinical risk factors. These data suggest that promoter DNA methylation upregulates TERT expression and associates with poor clinical outcomes of PTC, thus holds the potential to be a valuable prognostic marker for PTC risk stratification.
Thyroid cancer is the most frequent malignancy of the endocrine system, of which papillary thyroid cancer (PTC) is the predominant form with a rapid increasing incidence worldwide. Rearranged during ...transfection (RET) fusions are common genetic drivers of PTC and the potent RET inhibitor selpercatinib has been recently approved for treating advanced or metastatic RET fusion-positive thyroid cancer. In this study we aimed to develop a droplet digital PCR (ddPCR) system to accurately detect RET fusion in PTC samples.
The frequency and distribution of RET fusions in PTC were analyzed using genomic data of 402 PTC patients in The Cancer Genome Atlas (TCGA) database. To establish the ddPCR system for detecting CCDC6::RET fusion, a plasmid containing CCDC6::RET infusion fragment was constructed as standard template, the annealing temperature and concentrations of primers and probe were optimized. The analytical performance of ddPCR and quantitative reverse transcription PCR (qRT-PCR) were assessed in standard templates and tissue samples from 112 PTC patients. Sanger sequencing was performed in all the RET fusion-positive samples identified by ddPCR.
RET fusions were observed in 25 (6.2%) of the 402 TCGA samples, and 15 (60%) of the RET fusion-positive patients had the CCDC6::RET fusion. Compared with qRT-PCR, the ddPCR method showed a lower limit of detection (128.0 and 430.7 copies/reaction for ddPCR and qRT-PCR, respectively). When applying the two methods to 112 tissue samples of PTC, eleven (9.8%) CCDC6::RET fusion-positive samples were detected by qRT-PCR, while ddPCR identified 4 additional positive samples (15/112, 13.4%). All the CCDC6::RET fusion-positive cases identified by ddPCR were confirmed by Sanger sequencing except for one case with 0.14 copies/uL of the fusion.
The accurate and sensitive ddPCR method reported here is powerful to detection CCDC6::RET fusion in PTC samples, application of this method would benefit more RET fusion-positive patients in the clinic.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•GDC-0994 inhibits the growth of BRAF mutant cancer cells in vitro and in vivo.•GDC-0994 induces cell cycle arrest in BRAF mutation positive cancer cells.•GDC-0994 treatment affects the expressions ...of cell cycle-related genes.•BRAF mutation confers sensitivity to multiple ERK1/2 inhibitors.
BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Utilization and exploitation of marine resources by humans have contributed to the growth of marine research. As technology progresses, artificial intelligence (AI) approaches are progressively being ...applied to maritime research, complementing traditional marine forecasting models and observation techniques to some degree. This article takes the artificial intelligence algorithmic model as its starting point, references several application trials, and methodically elaborates on the emerging research trend of mixing machine learning and physical modeling concepts. This article discusses the evolution of methodologies for the building of ocean observations, the application of artificial intelligence to remote sensing satellites, smart sensors, and intelligent underwater robots, and the construction of ocean big data. We also cover the method of identifying internal waves (IW), heatwaves, El Niño-Southern Oscillation (ENSO), and sea ice using artificial intelligence algorithms. In addition, we analyze the applications of artificial intelligence models in the prediction of ocean components, including physics-driven numerical models, model-driven statistical models, traditional machine learning models, data-driven deep learning models, and physical models combined with artificial intelligence models. This review shows the growth routes of the application of artificial intelligence in ocean observation, ocean phenomena identification, and ocean elements forecasting, with examples and forecasts of their future development trends from several angles and points of view, by categorizing the various uses of artificial intelligence in the ocean sector.
Hotspot mutations in the core promoter region of the
telomerase reverse transcriptase
(
TERT
) gene have been well established to associate with aggressive clinical characteristics, radioiodine ...refractory, tumor recurrence, and mortality in thyroid cancer. Several E-twenty-six (ETS) transcription factors were reported to selectively bound to the mutant
TERT
promoter and activated TERT expression. In this study we aimed to investigate whether
TERT
promoter mutations confer sensitivity to ETS inhibitor YK-4-279 in thyroid cancer cells and whether this inhibitor could be served as a potential therapeutic agent for thyroid cancer.
In vitro
assays showed that YK-4-279 treatment sharply suppressed cell viability, colony formation, migration, and invasion, as well as induced cell cycle arrest and apoptosis in a panel of thyroid cancer cells. The cell viability after YK-4-279 treatment was similar between cell lines harboring mutant and wild-type
TERT
promoters. Furthermore, YK-4-279 treatment reduced both luciferase activity and mRNA expression of TERT independent of
TERT
promoter mutation status. Data from RNA-seq further revealed that YK-4-279 significantly affected biological processes including DNA replication and cell cycle. Reduced DNA helicase activity and decreased expression of several helicase genes were observed after YK-4-279 treatment. Moreover, YK-4-279 significantly inhibited tumor growth and induced apoptosis in a xenograft mice model. Thus, ETS inhibitor YK-4-279 suppressed TERT expression and conferred anti-tumor activity in a
TERT
promoter mutation-independent manner, and it could be a potential agent for the treatment of advanced thyroid cancers.
Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its ...role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The
in vitro
findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.
Idiopathic pulmonary fibrosis (IPF) is caused by persistent micro-injuries and aberrant repair processes. Myofibroblast differentiation in lung is a key event for abnormal repair. ...Dihydroartemisinin(DHA), a well-known anti-malarial drug, have been shown to alleviate pulmonary fibrosis, but its mechanism is not clear. Ferroptosis is involved in the pathgenesis of many diseases, including IPF. Ferritinophagy is a form of cellular autophagy which regulates intracellular iron homeostasis. The function of DHA on myofibroblasts differentiation of pulmonary and whether related with ferroptosis and ferritinophagy are unknown now. Using human fetal lung fibroblast 1(HFL1) cell line and the qRT-PCR, immunofluorescent and Western blotting techniques, we found that after TGF-β1 treatment, the levels of ɑ-SMA expression and ROS increased; the mRNA and protein levels of FTH1 and NCOA4, the content of Fe2+ and 4-HNE increased significantly at 6h, then gradually reduced with time. After DHA treatment, FHL1 cells appeared ferroptosis; the levels of α-SMA mRNA and protein reduced and the levels of ROS and 4-HNE increased; the Fe2+ levels decreased sharply at 6h, then increased with time, and were higher than normal since 24h; the mRNA and protein levels of FTH1 and NCOA4 decreased, exhibited a downward trend. These results show that Fe2+, ROS and lipid peroxidation are involved in and ferritinophagy is inhibited during fibroblast-to-myofibroblast differentiation; The depletion of Fe2+ at early stage induced by DHA treatment triggers the ferritinophagy in HFL1 cells, leading to degradation of FTH1 and NCOA4 and following increase of Fe2+ levels. DHA may inhibit the fibroblast-to-myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
There are existing semantic segmentation methods that incorporate the idea of edge detection by using multi-branch networks to focus on edges and subjects separately, but there are a large ...number of unfocused aspects and limited improvement. In this paper, we suggest the Fast-DecoupledNet, a semantic segmentation network. We design Edge Feature Extractor to extract the target’s edge features more accurately, and the global features obtained by joint downsampling are computed to obtain the subject features and the final features. In addition, we employ a shallower ResNet as the backbone network to reduce computational complexity while ensuring computational accuracy. Our proposed methods achieve the state-of-the-art 72.59 F-score and 77.64% mIoU on the
Deepglobe Land Cover Classification
dataset.
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Laser-metal inert gas (MIG) hybrid welding-brazing was adopted to achieve a dissimilar metal butt joint of 6061-T6 aluminum alloy and 304 stainless steel. The effect that laser power ...and welding speed had upon the wettability, intermetallic compound (IMC) layer microstructure and tensile strength of the joint with and without reinforcement was investigated. The results show that the spreading width of the molten metals on both sides of the steel increased with welding heat input, where the maximum spreading width on both sides of the steel was 5.7 and 4.8mm respectively for a welding speed of 5mm/s and a laser power of 1000W. The total thickness of the IMC layer increased and its morphology varied with increasing heat input. The maximum tensile strength of the joint without reinforcement was improved to 180MPa with a welding speed of 5mm/s and a laser power of 1000W, which was attributed to the fact that the transformation of Fe4Al13 morphology reduced the stress concentration in this layer. The tensile strength of the joint with reinforcement was up to 200MPa (70% of the 6061-T6 tensile strength). The fracture occurred at the heat-affected zone of the 6061-T6 aluminum alloy.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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