Pyruvate kinase M2 (PKM2) is a key kinase of glycolysis and is characteristic of all proliferating cells. The role of PKM2 in gastric cancer (GC) is still ambiguous and yet to be determined. To ...better understand the role of PKM2 in both the migration and invasion of GC, we measured the expression of PKM2 in GC cell lines using qRT-PCR and western blot. The prognostic value of PKM2 was analyzed by Immunohistochemistry in a cohort containing 88 GC patients. PKM2 was knocked down by the short hairpin RNA plasmid vector in NCI-N87 and BGC-823 cells, and the biological behavior and downstream signaling pathways were also investigated in vitro. Subcutaneous xenografts and pulmonary metastases models were constructed in nude mice to compare the differences in tumorgenesis and metastasis after Knockdown of PKM2. Our results obtained from in vitro cell biological behavior, in vivo tumorigenicity studies, and primary GC samples revealed an oncogenic role for PKM2 in GC. Furthermore, for those GC patients who received radical resection, PKM2 might serve as a novel prognostic biomarker and target which would allow for a brand new treatment strategy for GC in the clinical settings.
Cancer-associated fibroblasts (CAFs) are important components of tumor stroma and play a key role in tumor progression. CAFs involve in crosstalk with tumor cells through various kinds of cytokines. ...In the present study, we screened hepatocyte growth factor (HGF) as a cytokine predominantly originating from CAFs. CAFs-derived HGF was found to promote MET-unamplified gastric cancer (GC) proliferation, migration, and invasion through the activation of HGF/c-Met/STAT3/twist1 pathway. It also activated interleukin (IL)-6/IL-6R/JAK2/STAT3/twist1 pathway by up-regulating IL-6R expression. As IL-6 was also found to upregulate c-Met expression, we identified the cooperation of HGF and IL-6 in enhancing the characteristics of CAFs. In vivo experiments revealed that CAFs-derived HGF promoted tumorigenesis and metastasis of MET-unamplified GC. Gene set enrichment analysis (GSEA) was performed to confirm our findings. Our study found that the increased expression of HGF in CAFs induced by MET-unamplified GC contributed to the malignant phenotype of both MET-unamplified GC and CAFs in tumor microenvironment.
B cell receptor associated protein 31 (BAP31) is closely associated with tumor progression, while the role and mechanism of BAP31 in gastric cancer (GC) remains unknown. This study explored that ...BAP31 was upregulated in GC tissues and high expression indicated poor survival of GC patients. BAP31 knockdown inhibited cell growth and induced G1/S arrest. Moreover, BAP31 attenuation increased the lipid peroxidation level of the membrane and facilitated cellular ferroptosis. Mechanistically, BAP31 regulated cell proliferation and ferroptosis by directly binding to VDAC1 and affected VDAC1 oligomerization and polyubiquitination. HNF4A was bound to BAP31 at the promoter and increased its transcription. Furthermore, knockdown of BAP31 inclined to make GC cells vulnerable to 5-FU and ferroptosis inducer, erastin, in vivo and in vitro. Our work suggests that BAP31 may serve as prognostic factor for gastric cancer and act as potential therapeutic strategy for gastric cancer.
Carbon sequestration is the primary function of biochar. Hence, it is necessary to design biochar with high carbon (C) retention and low C loss. In this study, three P compounds, including KH
PO
, ...Ca(H
PO
)
, and NH
H
PO
, were premixed with corn stalk (1:4,
/
), aiming to produce biochars (CSB+K, CSB+Ca, and CSB+N) with high C sequestration and slow release of P at three temperatures (300, 500, and 700 °C). The addition of all P sources obviously increased C retention, with the order of NH
H
PO
(65.6-83.5%) > Ca(H
PO
)
(60.4-78.2%) > KH
PO
(50.1-76.1%), compared with the pristine biochar (47.8-73.6%). The addition of Ca(H
PO
)
and KH
PO
led to an increase in aromaticity and graphitization, as evidenced by H/C, FTIR, Raman and XPS analysis, whereas an opposite result occurred on CSB+N. Furthermore, all three phosphates reduced C loss of biochars with H
O
oxidation, and CSB+Ca showed the best effect. Ca(H
PO
)
and KH
PO
pretreated biochars had higher resistance to K
Cr
O
oxidation and thermal treatment. In contrast, the C loss of NH
H
PO
-added biochar at 500 and 700 °C with K
Cr
O
oxidation was increased by 54% and 36%, respectively. During the pyrolysis process, Ca(H
PO
)
was transformed into insoluble Ca
P
O
, leading to the lowest P release rate of CSB+Ca. This study indicates that co-pyrolysis of corn stalk and Ca(H
PO
)
is optimal for increasing C retention, enhancing C stability and improving slow-release performance of P regardless of pyrolysis temperature.
Cancer‑associated fibroblasts (CAFs) are predominate cells in tumor stroma and play a key role in tumor progression. Hepatocyte growth factor (HGF) is a cytokine mainly derived from fibroblasts. In ...the present study, we reported that HGF significantly promoted angiogenesis of human umbilical vein endothelial cells (HUVECs) and vasculogenic mimicry (VM) formation of gastric cancer cells, respectively, by increasing cell proliferation and migration. In addition, mosaic vessels formed by HUVECs and gastric cancer cells were also increased with treatment of recombinant human HGF and conditioned medium from CAFs. The opposite results were achieved in HGF‑neutralized groups. In accordance with these observations, we determined that phosphorylation of AKT and ERK1/2 were upregulated in HUVECs and gastric cancer cells with HGF treatment and co‑culture with CAFs. Both AKT inhibitor LY294002 and ERK1/2 inhibitor U0126 reduced the ability of angiogenesis and VM formation, as well as mosaic vessel formation induced by HGF. Gene Set Enrichment Analysis and correlation analysis were performed to confirm our findings. In conclusion, CAF‑derived HGF promotes angiogenesis, VM and mosaic vessel formation via PI3K/AKT and ERK1/2 signaling in gastric cancer and HGF may serve as a potential therapeutic target for cancer anti‑vascular treatment.
The present study was designed to explore the prognostic value of preoperative inflammatory and nutritional biomarkers in stage III gastric cancer (GC) patients with adjuvant chemotherapy and to ...develop a novel scoring system called the inflammatory-nutritional prognostic score (INPS).
A total of 513 patients with pathological stage III GC undergoing radical gastrectomy followed by adjuvant chemotherapy from 2010 to 2017 were enrolled in the study. Clinicopathological characteristics and blood test parameters of individual patients were collected. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used for feature selection to construct INPS. Survival curves were generated using the Kaplan-Meier method with log-rank tests. The nomogram was generated based on the result of the multivariate analysis using Cox's proportional hazards model. The model was assessed by the concordance index (C-index) and was internally validated by bootstraps.
According to the results of Lasso Cox regression and K-M survival curves, INPS was determined as follows: a low body mass index (BMI) (<23 kg/m
), a low prealbumin (<180 mg/L), a high neutrophil-lymphocyte ratio (NLR) (≥2.7), a high platelet-lymphocyte ratio (PLR) (≥209.4), a low lymphocyte-monocyte ratio (LMR) (<2.8), and a low prognostic nutritional index (PNI) (<45.1); each were scored as 1, and the remaining values were scored as 0. The individual scores were then summed up to construct the INPS and further divided into 4 groups: Low Risk (INPS 0); Low-medium Risk (INPS 1); High-medium Risk (INPS 2-4); and High Risk (INPS 5-6). In multivariate analysis, INPS was an independent predictor of overall survival (OS) in stage III GC, with the 5-year OS rates of 70.8%, 57.4%, 41.5%, and 30.6%, respectively. The nomogram based on INPS and other independent predictors (gender, pT stage, pN stage, lymphovascular invasion, and CEA level) showed good predicting performance with a C-index of 0.707, which was superior to the TNM stage alone (C-index 0.645,
=0.008) and was internally validated with the corrected C-index of 0.693.
Preoperative INPS was an independent prognostic factor of stage III GC patients with radical surgery followed by adjuvant chemotherapy. The nomogram based on INPS may serve as a simple and potential model in risk stratification and guiding treatment strategies in clinical practice.
Abstract
Background
Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored.
...Methods
The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells.
Results
Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1β. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC.
Conclusions
GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.
The aim of the present study was to investigate the clinical significance, the biological function and the mechanisms of USP20 in gastric cancer. The expression of USP20 in 89 pairs of primary ...gastric cancer and peritumoral gastric tissues specimens were measured by immunohistochemistry. The correlation of USP20 expression with the survival and the clinicopathological characteristics of patients were analyzed. Moreover, the underlying mechanisms of ectopic USP20 expression and its impact on GC cells were also investigated. We found that the expression of USP20 is relatively low in GC tissues and negatively correlated with tumor size, tumor invasion and TNM staging. High expression of USP20 in GC predicted longer survival. Experimentally, small interfering RNA-mediated knockdown of USP20 expression significantly promoted cell proliferation, accelerated G1-S phase transition and attenuated the autophagy activity. Overexpression of USP20 led to the inhibition of proliferation, G1-S cell cycle transition delay and autophagy activation. Mechanistically, we confirmed that silencing the expression of USP20 in GC cells could reduce Claspin protein levels without altering Claspin mRNA levels, which is involved in the antitumor activity of USP20. Furthermore, the expression level of Claspin was relatively higher in peritumoral tissue than that of GC tissues and higher expression of Claspin in GC was also correlated with good prognosis of patients. Given its pivotal role in gastric tumorigenesis and progression, USP20 functioned as the tumor suppressor in GC and possessed promising value to be a therapeutic target for GC.
The detection of moving targets is to detect the change area in a sequence of images and extract the moving targets from the background image. It is the basis. Whether the moving targets can be ...correctly detected and segmented has a huge impact on the subsequent work. Aiming at the problem of high failure rate in the detection of sports targets under complex backgrounds, this paper proposes a research on the design of an intelligent background differential model for training target monitoring. This paper proposes a background difference method based on RGB colour separation. The colour image is separated into independent RGB three-channel images, and the corresponding channels are subjected to the background difference operation to obtain the foreground image of each channel. In order to retain the difference of each channel, the information of the foreground images of the three channels is fused to obtain a complete foreground image. The feature of the edge detection is not affected by light; the foreground image is corrected. From the experimental results, the ordinary background difference method uses grey value processing, and some parts of the target with different colours but similar grey levels to the background cannot be extracted. However, the method in this paper can better solve the defect of misdetection. At the same time, compared with traditional methods, it also has a higher detection efficiency.
Background:
Immune checkpoint inhibitor (ICI) therapies have revolutionized the treatment of metastatic cutaneous melanoma, but have only benefitted a subset of them. Gene mutations were reported to ...impact the ICI therapy outcomes in metastatic melanoma but have not been fully investigated. Hence, we systematically analyzed the impact of cancer-related gene mutations on the clinical outcome in metastatic melanoma patients who underwent ICI therapies.
Methods:
Publicly available discovery and validation cohorts (312 patients and 110 patients respectively, all the patients received ICI therapies) were included in this study. Cox proportional hazards regression analysis was used to assess the association of 468 cancer-related gene mutations with overall survival (OS) in the discovery cohort, and the polygenic hazard score (PHS) was constructed subsequently, and validated in the validation cohort. The Tumor Immune Estimation Resource (TIMER) online tools, which are based on The Cancer Genome Atlas database, were used to analyze the impact of gene mutations on tumor-infiltrated immune cells in melanoma samples.
Results:
We found eight gene mutations that were significantly associated with the overall survival (
BAP1, CARD11, IGF1R, KMT2D, PTPRD, PTPRT, ROS1, and TERT
,
p
< 0.05, mutation frequency >0.05). The PHS, which was based on these genes, was found to effectively discriminate the subset which benefited most from ICI therapies (HR = 1·54, 95%CI, 1.25–1.95;
p
< 0.001). After adjusting with age, sex, ICI regimes, and tumor mutation burden (TMB), we found that PHS was an independent predictor for the outcome of ICI therapies (adjusted HR = 1.84, 95%CI, 1.22–2.79;
p
= 0.004). The PHS was validated in the validation cohort (log-Rank
p
= 0.038). Further research found that
CARD11
and
PTPRD
mutations were significantly associated with more tumor-infiltrated immune cells in melanoma samples.
Conclusion:
For the first time, we have shown that PHS can independently and effectively predict the ICI therapy outcome in metastatic melanoma, which once validated by larger research, may help the decision-making process in melanoma.
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