BackgroundThe prognosis of gastric cancer is difficult to determine, although clinical indicators provide valuable evidence.MethodsIn this study, using screened biomarkers of gastric cancer in combination with random forest variable hunting and multivariable Cox regression, a risk score model was developed to predict the survival of gastric cancer. Survival difference between high/low-risk groups were compared. The relationship between risk score and other clinicopathological indicators was evaluated. Gene set enrichment analysis (GSEA) was used to identify pathways associated with risk scores.ResultsThe patients with high risk scores (median overall survival: 20.2 months, 95% CI [16.9–26.0] months) tend to exhibit early events compared with those with low risk scores (median survival: 70.0 months, 95% CI [46.9–101] months, p = 1.80e–5). Further validation was implemented in another three independent datasets (GSE15459, GSE26253, GSE62254). Correlation analyses between clinical observations and risk scores were performed, and the results indicated that the risk score was not significantly associated with gender, age and primary tumor size but was significantly associated with grade and tumor stage. In addition, the risk score was also not influenced by radiation therapy. Cox multivariate regression and three-year survival nomogram suggest that the risk score is an important indicator of gastric cancer prognosis. GSEA was used to identified KEGG pathways significantly associated with risk score, and signaling pathways involved in focal adhesion and the TGF-beta signaling pathway were identified.ConclusionThe risk score model successfully predicted the survival of 1,294 gastric cancer samples from four independent datasets and is among the most important indicators in clinical clinicopathological information for the prognosis of gastric cancer. To our knowledge, it is the first report to predict the survival of gastric cancer using optimized expression panel.

BackgroundGastric cancer (GC) is a heterogeneous disease that encompasses various molecular subtypes. The molecular mutation characteristics of circulating tumor DNA (ctDNA) in advanced gastric cancer (AGC), especially the clinical utility of TP53 mutation and MET amplification in ctDNA need to be further explored.ObjectivesThe aim of this study was mainly to assess the clinical utility of TP53 mutation and MET amplification in ctDNA as biomarkers for monitoring disease progression of AGC.Patients and MethodsWe used multigene NGS-panel technology to study the characteristics of ctDNA gene mutations and screen the key mutant genes in AGC patients. The Kaplan-Meier method was used to calculate the survival probability and log-rank test was used to compare the survival curves of TP53 mutation and MET amplification in ctDNA of AGC patients. The survival time was set from the blood test time to the follow-up time to observe the relationship between the monitoring index and tumor prognosis.ResultsWe performed mutation detection on ctDNA in 23 patients with AGC and identified the top 20 mutant genes. The five most frequently mutated genes were TP53 (55%), EGFR (20%), ERBB2 (20%), MET (15%) and APC (10%). TP53 was the most common mutated gene (55%) and MET had a higher frequency of mutations (15%) in our study. Kaplan-Meier analysis showed that patients with TP53 mutant in ctDNA had shorter overall survival (OS) than these with TP53 wild (P < 0.001). The Allele frequency (AF) of TP53 mutations in patient number 1 was higher in the second time (0.94%) than in the first time (0.36%); the AF of TP53 mutations in patient number 16 was from scratch (0∼0.26%). In addition, the AF of TP53 mutations in patients who survive was relatively low (P = 0.047). Simultaneously, Kaplan-Meier analysis showed that patients with MET amplification also had shorter OS than these with MET without amplification (P < 0.001).ConclusionTP53 and MET are the two common frequently mutant genes in ctDNA of AGC patients.TP53 mutation and MET amplification in ctDNA could predict disease progression of AGC patients.

Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD+/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.

BackgroundLabile carbon input could stimulate soil organic carbon (SOC) mineralization through priming effect, resulting in soil carbon (C) loss. Meanwhile, labile C could also be transformed by microorganisms in soil as the processes of new C sequestration and stabilization. Previous studies showed the magnitude of priming effect could be affected by soil depth and nitrogen (N). However, it remains unknown how the soil depth and N availability affect the amount and stability of the new sequestrated C, which complicates the prediction of C dynamics.MethodsA 20-day incubation experiment was conducted by adding 13C labeled glucose and NH4NO3 to study the effects of soil depth and nitrogen addition on the net C sequestration. SOC was fractioned into seven fractions and grouped into three functional C pools to assess the stabilization of the new sequestrated C.ResultsOur results showed that glucose addition caused positive priming in both soil depths, and N addition significantly reduced the priming effect. After 20 days of incubation, deep soil had a higher C sequestration potential (48% glucose-C) than surface soil (43% glucose-C). The C sequestration potential was not affected by N addition in both soil depths. Positive net C sequestration was observed with higher amount of retained glucose-C than that of stimulated mineralized SOC for both soil depths. The distribution of new sequestrated C in the seven fractions was significantly affected by soil depth, but not N addition. Compared to deep soil, the new C in surface soil was more distributed in the non-protected C pool (including water extracted organic C, light fraction and sand fraction) and less distributed in the clay fraction. These results suggested that the new C in deep soil was more stable than that in surface soil. Compared to the native SOC for both soil depths, the new sequestrated C was more distributed in non-protected C pool and less distributed in biochemically protected C pool (non-hydrolyzable silt and clay fractions). The higher carbon sequestration potential and stability in deep soil suggested that deep soil has a greater role on C sequestration in forest ecosystems.