CCDC58 is a potential biomarker for diagnosis, prognosis, immunity, and genomic heterogeneity in pan-cancer.

Coiled-coil domain-containing 58 (CCDC58) is a member of the CCDC protein family. Similar to other members, CCDC58 exhibits potential tumorigenic roles in a variety of malignancies. However, there is no systematic and comprehensive pan-cancer analysis to investigate the diagnosis, prognosis, immune infiltration, and other related functions of CCDC58. We used several online websites and databases, such as TCGA, GTEx, UALCAN, HPA, CancerSEA, BioGRID, GEPIA 2.0, TIMER 2.0, and TISIDB, to extract CCDC58 expression data and clinical data of patients in pan-cancer. Then, the relationship between CCDC58 expression and diagnosis, prognosis, genetic alterations, DNA methylation, genomic heterogeneity, and immune infiltration level were determined. In addition, the biological function of CCDC58 in liver hepatocellular carcinoma (LIHC) was investigated. Pan-cancer analysis results showed that CCDC58 was differentially expressed in most tumors and showed excellent performance in diagnosis and prediction of prognosis. The expression of CCDC58 was highly correlated with genetic alterations, DNA methylation, and genomic heterogeneity in some tumors. In addition, the correlation analysis of CCDC58 with the level of immune infiltration and immune checkpoint marker genes indicated that CCDC58 might affect the composition of the tumor immune microenvironment. Enrichment analysis showed that CCDC58-related genes were mainly linked to mitosis, chromosome, and cell cycle. Finally, biological function experiments demonstrated that CCDC58 plays an important role in tumor cell proliferation and migration. CCDC58 was first identified as a pan-cancer biomarker. It may be used as a potential therapeutic target to improve the prognosis of patients in the future.

Fibroblasts/three-dimensional scaffolds complexes promote wound healing in rats with skin defects.

We aim to construct a three-dimensional nano-skin scaffold material in vitro and study its promoting effect on wound healing in vivo. In this study, hybrid constructs of three-dimensional (3D) scaffolds were successfully fabricated by combination of type I collagen (COL-1) and polylactic-glycolic acid (PLGA). Fibroblasts and human umbilical cord mesenchymal stem cells (hUCMSCs) were used to implanted into 3D scaffolds and constructed into SD skin scaffolds in vitro. Finally, the fibroblasts/scaffolds complexes were inoculated on the surface of rat wound skin to study the promoting effect of the complex on wound healing. In our study, we successfully built a 3D scaffold, which had a certain porosity. Meanwhile, the content of COL-1 in the cell supernatant of fibroblast/scaffold complexes was increased. Furthermore, the expression of F-actin, CD105, integrin ß, VEGF, and COL-1 was up-regulated in hUCMSC/scaffold complexes compared with the control group. In vivo, fibroblast/scaffold complexes promoted wound healing in rats. Our data suggested that the collagen Ⅳ and vimentin were elevated and collagen fibers were neatly arranged in the fibroblast/scaffold complex group was significantly higher than that in the scaffold group. Taken together, fibroblast/scaffold complexes were expected to be novel materials for treating skin defects.

Cell response and bone ingrowth to 3D printed Ti6Al4V scaffolds with Mg-incorporating sol-gel Ta2O5 coating.

In recent years, additive manufacturing techniques have been used to fabricate 3D titanium (Ti)-based scaffolds for production of desirable complex shapes. However, insufficient osteointegration of porous Ti-based scaffolds can elicit long-term complications (e.g., aseptic loosening) and need further revision surgery. In this study, a magnesium (Mg)-incorporating tantalum (Ta) coating was deposited on a 3D Ti6Al4V scaffold using a sol-gel method for enhancing its osteogenic properties. To evaluate the biofunction of this surface, bone mesenchymal stem cells and rabbit femoral condyle were used to assess the cell response and bone ingrowth, respectively. Ta2O5 coatings and Mg-incorporating Ta2O5 coatings were both homogeneously deposited on porous scaffolds. In vitro studies revealed that both coatings exhibit enhanced cell proliferation, ALP activity, osteogenic gene expression and mineralization compared with the uncoated Ti6Al4V scaffold. Especially for Mg-incorporating Ta2O5 coatings, great improvements were observed. In vivo studies, including radiographic examination, fluorochrome labeling and histological evaluation also followed similar trends. Also, bone ingrowth to scaffolds with Mg-incorporating Ta2O5 coatings exhibited the most significant increase compared with uncoated and Ta2O5 coated scaffolds. All the above results indicate that Mg-doped Ta2O5 coatings are an effective tool for facilitating osteointegration of conventional porous Ti6Al4V scaffolds.

A ferroptosis-related ceRNA network in hepatocellular carcinoma for potential clinical applications.

OBJECTIVE: To explore the competing endogenous RNA (ceRNA) network related to ferroptosis in hepatocellular carcinoma (HCC) and its promise for clinical application. METHODS: We obtained RNA sequencing data for HCC and relevant clinical information from The Cancer Genome Atlas (TCGA) database. To assess the involvement of the autophagy, pyroptosis, and ferroptosis pathways in HCC, we used single-sample Gene Set Enrichment Analysis (ssGSEA) to compute scores for each sample based on pre-defined gene sets. We conducted Weighted Gene Co-Expression Network Analysis (WGCNA) to effectively modularize lncRNA, miRNA, and mRNA. Through extensive correlation analyses, we pinpointed the most crucial ferroptosis-associated modules. Moreover, we utilized online prediction tools to construct a corresponding ceRNA network. To establish the reliability of our results, we randomly chose a ceRNA axis consisting of DNAJC27-AS1/miR-23b-3p/PPIF for experimental validation. We performed luciferase reporter assays to validate the binding sites of DNAJC27-AS1, miR-23b-3p, and PPIF. RESULTS: We found a significant correlation between the level of ferroptosis and the overall survival of patients with HCC. Thus, we constructed a comprehensive ferroptosis-related ceRNA network. Our experimental findings revealed that DNAJC27-AS1 and PPIF act as direct sponges of miR-23b-3p, and thus are capable of downregulating ferroptosis in HCC cells. CONCLUSION: The ferroptosis-associated ceRNA network presented in this study represents a valuable resource for advancing our understanding of the role of ferroptosis in HCC.

Risk factors analysis of surgical complications of hepatic hemangioma: a modified Clavien-Dindo classification-based study.

PURPOSE: There are few studies on the risk factors of postoperative complications after surgical treatment of hepatic hemangioma (HH). This study aims to provide a more scientific reference for clinical treatment. METHODS: The clinical characteristics and operation data of HH patients undergoing surgical treatment in the First Affiliated Hospital of Air Force Medical University from January 2011 to December 2020 were retrospectively collected. All enrolled patients were divided into two groups based on the modified Clavien-Dindo classification: Major group (Grade II/III/IV/V) and Minor group (Grade I and no complications). Univariate and multivariate regression analysis was used to explore the risk factors for massive intraoperative blood loss (IBL) and postoperative Grade II and above complications. RESULTS: A total of 596 patients were enrolled, with a median age of 46.0 years (range, 22-75 years). Patients with Grade II/III/IV/V complications were included in the Major group (n = 119, 20%), and patients with Grade I and no complications were included in the Minor group (n = 477, 80%). The results of multivariate analysis of Grade II/III/IV/V complications showed that operative duration, IBL, and tumor size increased the risk of Grade II/III/IV/V complications. Conversely, serum creatinine (sCRE) decreased the risk. The results of multivariate analysis of IBL showed that tumor size, surgical method, and operative duration increased the risk of IBL. CONCLUSIONS: Operative duration, IBL, tumor size, and surgical method are independent risk factors that should be paid attention to in HH surgery. In addition, as an independent protective factor for HH surgery, sCRE should attract more attention from scholars.

Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome.

Diabetic nephropathy is a microvascular complication of diabetes mellitus, threatening the health of millions of people. Herein, we explored a blood glucose independent function of coptisine on diabetic nephropathy. A diabetic rat model was established by intraperitoneal administration of streptozotocin (65 mg/kg). Coptisine treatment (50 mg/kg/day) retarded body weight loss and reduced blood glucose. On the other hand, coptisine treatment also decreased kidney weight and the levels of urinary albumin, serum creatinine, and blood urea nitrogen, indicating an improvement of renal function. Treatment with coptisine also mitigated renal fibrosis, with alleviative collagen deposition. Likewise, in vitro study showed that coptisine treatment decreased apoptosis and fibrosis markers in HK-2 cells treated with high glucose. Furthermore, after coptisine treatment, the activation of NOD-like receptor pyrin domain containing protein 3 (NRLP3) inflammasome was repressed, with decreased levels of NLRP3, cleaved caspase-1, interleukin (IL)-1ß, and IL-18, indicating that the repression of NRLP3 inflammasome contributed to the effect of coptisine on diabetic nephropathy. In conclusion, this study revealed that coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome. It is indicated that coptisine may have the potential to be used in the diabetic nephropathy treatment.

Development and Validation of a Vascular Endothelial Growth Factor A-associated Prognostic Model for Unresectable Hepatocellular Carcinoma.

Purpose: High serum vascular endothelial growth factor (VEGF) levels have been identified as an independent risk factor for hepatocellular carcinoma (HCC). We aimed to construct a VEGF-included prognostic model to accurately perform individualized predictions of survival probability for patients with unresectable HCC. Patients and Methods: From October 2018 to March 2021, 182 consecutive newly diagnosed patients with unresectable HCC were retrospectively enrolled. Baseline serum VEGF-A and other characteristics were collected for all patients. Univariate Cox regression analysis and LASSO regression model were applied to develop the prognostic model, enhanced bootstrap method with 100 replicates was performed to validate its discrimination and calibration. We compared the final model with China Liver Cancer (CNLC) stage, American Joint Committee on Cancer (AJCC) stage, Barcelona Clinic Liver Cancer (BCLC) stage, and the model without the "VEGF". Finally, the established model was stratified by age. Results: The VEGF-associated prognostic model we established has high accuracy with an overall C-index of 0.7892 after correction for optimistic estimates. The area under the curve (AUC) of the time-dependent receiver operating characteristic (ROC) curves at 6-month, 1-year, and 2-year after correction were 0.843, 0.860, 0.833, respectively, and the calibration of the model was 0.1153, 0.1514, and 0.1711, respectively. The final model showed significant improvement in predicting OS when compared to the other models according to Harrell's C-index, The AUC of the time-dependent ROC, area under the decision curve analysis (AUDC), integrated discrimination improvement (IDI), and continuous net reclassification index (NRI). Conclusion: The VEGF-associated prognostic model may help to predict the survival probabilities of HCC patients with favorable performance and discrimination. However, further validation is required since we only verified this model using internal but not external data.

Comparative analysis of the prognosis of external beam radiation therapy (EBRT) and EBRT plus brachytherapy for glioblastoma multiforme: a SEER population-based study.

OBJECTIVE: Radiotherapy is one of the effective ways to treat glioblastoma multiforme (GBM). We aimed to explore the prognostic difference between external beam radiotherapy (EBRT) and EBRT combined with brachytherapy (EBRT + BT). METHODS: The GBM patients from the Surveillance, Epidemiology, and End Results (SEER) database were divided into two cohorts: the EBRT cohort and the EBRT + BT cohort. Kaplan-Meier (KM) analysis and Cox proportional hazards regression were used to determine the underlying risk factors for overall survival (OS) and disease-specific survival (DSS). And the competing risk model and propensity score matching (PSM) was adopted to eliminate potential biases. We also conducted subgroup analyses and interaction tests as well. RESULTS: There was a total of 41,010 eligible GBM patients. The median OS (15 months) and DSS (17 months) of the EBRT + BT cohort were significantly longer than that of the EBRT cohort (OS = 11 months, DSS = 12 months). After using the competing risk model and PSM, we found that only advanced age was the independent risk factor, while only EBRT + BT was the independent protective factor (HR = 0.84, 95%CI [0.74,0.96], p = 0.01). EBRT had universal effects in the treatment of GBM, and EBRT + BT had a more pronounced protective effect in the subgroups of males (HR = 0.81, 95%CI [0.68,0.97], p = 0.02) and local excision (HR = 0.82, 95%CI [0.34,0.95], p = 0.01). CONCLUSIONS: The therapeutical effect of EBRT + BT treatment is better than that of EBRT alone, especially in male patients or patients who have undergone local resection. Our findings may provide novel evidence to develop a better radiotherapy strategy for GBM patients.

A Novel Oxidative Phosphorylation-Associated Gene Signature for Prognosis Prediction in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common type of malignant tumor with high morbidity and mortality. The oxidative phosphorylation (OXPHOS) metabolic pathway produces adenosine triphosphate (ATP) by delivering electrons to transmembrane protein complexes in the mitochondria. This research was dedicated to identifying an OXPHOS-associated signature for the assessment of prognosis of HCC patients. A total of 371 HCC patients from the Cancer Genome Atlas (TCGA) and 231 HCC patients from the International Cancer Genome Consortium (ICGC) with RNA expression data and clinical data were employed as construction and validation cohorts, respectively. The least absolute shrinkage and selection operator (LASSO) Cox regression was applied to establish a multigene signature in the TCGA cohort, and the ICGC cohort was used for validation. The prognostic value of the risk signature was evaluated using univariate and multivariate Cox regression, Kaplan-Meier curves, and receiver operating characteristic (ROC) curves. The potential enrichment of biological functions was investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Meanwhile, we analyzed the correlation between the risk score and the tumor microenvironment (TME). A five-gene signature including ATP6V0B, ATP6V1C1, ATP6V1E1, TIMM9, and UQCRH was identified by LASSO Cox regression to classify patients into low- and high-risk groups. ROC curve analysis indicated that the five-gene signature is a prospective prognostic factor in HCC patients. Univariate and multivariate Cox regression analyses demonstrated that the risk score was an independent prognostic factor for overall survival (OS). Functional analysis showed that differentially expressed genes (DEGs) between the low- and high-risk groups were enriched in mitosis and the cell cycle pathway. In addition, the five-gene signature was associated with innate immune cell infiltration, immune subtypes, and tumor stemness. A novel OXPHOS-associated gene signature can be used for prognostic prediction for patients with HCC.

Tubulin-binding peptide RR-171 derived from human umbilical cord serum displays antitumor activity against hepatocellular carcinoma via inducing apoptosis and activating the NF-kappa B pathway.

OBJECTIVES: Hepatocellular carcinoma (HCC) still presents a high incidence of malignant tumours with poor prognosis. There is an urgent need for new therapeutic agents with high specificity, low toxicity and favourable solubility for the clinical treatment of HCC. MATERIALS AND METHODS: The bioactivity of human umbilical cord serum was investigated by proteomics biotechnology and a primitive peptide with certain biological activity was identified. The antitumour effect of RR-171 was detected by cell viability assay in vitro, and determined by subcutaneous xenograft models assay and miniPDX assay in vivo. Pull-down experiments were conducted to identify the potential targeting proteins of RR-171. Immunofluorescence assay and tubulin polymerization assay were conducted to explore the relationship between RR-171 and α-tubulin. Fluorescence imaging in xenograft models was used to explore the biodistribution of RR-171 in vivo. A phosphospecific protein microarray was performed to uncover the underlying signalling pathway by which RR-171 induces tumour cell death. RESULTS: The results indicated that RR-171 could be effective in the treatment of HCC in vivo and in vitro. RR-171 could aggregate significantly in solid tumours and had no obvious systemic toxicity in vivo. RR-171 could interact with α-tubulin and activate the NF-Kappa B pathway in HCC cells. CONCLUSIONS: Taken together, RR-171 exhibited significant antitumour activity against HCC in vivo and in vitro and could potentially be used in the clinical application of HCC.

AQP5 Is a Novel Prognostic Biomarker in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with a poor prognosis. The identification of effective molecular markers is of great significance for diagnosis and treatment. Aquaporins (AQPs) are a family of water channel proteins that exhibit several properties and play regulatory roles in human carcinogenesis. However, the association between Aquaporin-5 (AQP5) expression and prognosis and tumor-infiltrating lymphocytes in PAAD has not been reported. Methods: AQP5 mRNA expression, methylation, and protein expression data in PAAD were analyzed using GEPIA, UALCAN, HAP, METHSURV, and UCSC databases. AQP5 expression in PAAD patients and cell lines from our cohort was examined using immunohistochemistry and Western blotting. The LinkedOmics database was used to study signaling pathways related to AQP5 expression. TIMER and TISIDB were used to analyze correlations among AQP5, tumor-infiltrating immune cells, and immunomodulators. Survival was analyzed using TCGA and Kaplan-Meier Plotter databases. Results: In this study, we investigated AQP5 expression in PAAD and determined whether the expression of AQP5 is a strong prognostic biomarker for PAAD. We searched and analyzed public cancer databases (GEO, TCGA, HAP, UALCAN, GEPIA, etc.) to conclude that AQP5 expression levels were upregulated in PAAD. Kaplan-Meier curve analysis showed that high AQP5 expression positively correlated with poor prognosis. Using TIMER and TISIDB, we found that the expression of AQP5 was associated with different tumor-infiltrating immune cells, especially macrophages. We found that hypomethylation of the AQP5 promoter region was responsible for its high expression in PAAD. Conclusions: AQP5 can serve as a novel biomarker to predict prognosis and immune infiltration in PAAD.

Non-aqueous synthesis of high-quality Prussian blue analogues for Na-ion batteries.

A microwave-assisted solvothermal (MW-ST) method was developed to synthesize high-quality Prussian blue analogues. The tuned NaFeHCF exhibits low water content as well as good thermal stability. It delivers a high initial discharge capacity of 150 mA h g-1, good rate capability and cycling life over 500 cycles.

Identification of Potential Predictors of Prognosis and Sorafenib-Associated Survival Benefits in Patients with Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.

Some studies have shown that sorafenib could significantly prolong the overall survival of patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE). However, other studies revealed that patients had no access to sorafenib-related survival benefits after TACE. To identify the predictive biomarkers of therapeutic efficacy of sorafenib, we explored the potential predictive value of vascular endothelial growth factor (VEGF) and other clinical variables for survival benefits from sorafenib in patients treated with TACE previously. The results demonstrated that patients with tumor size > 7 cm or total bilirubin ≤ 17.3 µmol/L showed significant survival benefits from sorafenib after TACE treatment compared with those with tumor size ≤ 7 cm or total bilirubin > 17.3 µmol/L. Meanwhile, patients with VEGF > 131.09 pg/mL may obtain sorafenib-associated survival benefits after TACE when compared to those with VEGF ≤ 131.09 pg/mL, which needs further confirmation. The abovementioned results are helpful to confirm the specific population who are sensitive to targeted therapy. (1) Background: VEGF plays a crucial role in modulating proliferation and metastasis in HCC. We aimed to explore the relationship between VEGF and the prognosis, as well as the mortality risk of HCC patients who received TACE, and whether it and other variables could be considered as potential biomarkers for predicting the benefits from sorafenib. (2) Method: A total of 230 consecutive newly diagnosed patients with unresectable HCC treated with either TACE or TACE−sorafenib were collected retrospectively. Cox regression analyses were performed to evaluate the prognostic value of VEGF. Furthermore, restricted cubic splines were fitted to assess the nonlinear associations between VEGF and OS, and the threshold effect analysis was subsequently performed. Lastly, the potential factors for predicting the survival benefits from sorafenib after the TACE procedure were identified using the Cox proportional hazard model with an interaction term. (3) Results: VEGF was recognized as an independent prognostic factor for OS in the TACE alone cohort (HR = 3.237, p = 0.013). A nonlinear relationship was observed between VEGF and OS in HCC patients with TACE administration after adjustment for confounders (p for nonlinearity = 0.030); the mortality risk increased with increasing the baseline VEGF before the inflection point, and the HR for death was 1.008. There was no significant interaction between the VEGF levels and treatment modality (p for interaction = 0.233), and further studies are needed to identify its predictive value on the efficacy of sorafenib. Patients with tumor size > 7 cm or total bilirubin ≤ 17.3 µmol/L derived significant sorafenib-related benefits in OS when compared to those with tumor size ≤ 7 cm or total bilirubin > 17.3 µmol/L (p for interaction = 0.004 and 0.031, respectively). (4) Conclusions: Within a certain concentration range, elevated baseline VEGF meant an increased risk of death in HCC patients treated with TACE. Significant improvements in OS associated with sorafenib were observed in patients with higher tumor size and lower total bilirubin after TACE treatment.

Prognostic Signature of Hepatocellular Carcinoma and Analysis of Immune Infiltration Based on m6A-Related lncRNAs.

The relationship between m6A-related lncRNAs and prognosis in hepatocellular carcinoma (HCC) is not yet clear. We used Lasso regression to establish a prognostic signature based on m6A-related lncRNAs using a training set from TCGA, and then verified the signature efficacy in a test set. Fluorescence quantitative real-time PCR (qPCR), Survival analysis, clinical risk difference analysis, immune-related analysis, and drug-sensitivity analysis were conducted. The results revealed that 1,651 lncRNAs were differentially expressed in HCC tissues, among which, 163 were m6A-related. Univariate analysis showed that 87 lncRNAs were associated with the overall survival. Six differential m6A-related lncRNAs were validated and selected via Lasso regression to construct a prognostic signature which demonstrated a satisfactory predictive efficacy. In the clinically relevant pathologic stage, histologic grade, and T stage, the risk scores obtained based on this signature showed a statistically significant difference. The high- and low-risk groups exhibited a difference in the tumor immune infiltrating cells, immune checkpoint gene expression, and sensitivity to chemotherapy. In summary, the prognostic signature based on the m6A-related lncRNAs can effectively predict the prognosis of patients and might provide a new vista for the chemotherapy and immunotherapy of HCC.

Leaching kinetics and interface reaction of LiNi0.6Co0.2Mn0.2O2 materials from spent LIBs using GKB as reductant.

The application of green reductant is signification to recycling of cathode materials from spent lithium ions batteries. Here, ginkgo biloba was developed for enhancing leaching of spent LiNi0.6Co0.2Mn0.2O2 materials with systematically analysis of leaching kinetics and interface reaction. The leaching efficiencies of Ni, Mn, Co, and Li reach respectively 98.65 %, 98.25 %, 98.41 % and 99.99 % under optimal condition of 1.8 mol/L H2SO4 concentration, 9 g/L ginkgo biloba, 80 °C leaching temperature, 40 min time and 15 g/L pulp density. The apparent activation energies for leaching of Ni, Co, Mn and Li determined as 74.63, 79.33, 73.14 and 23.43 kJ/mol, respectively, indicates that the leaching process was controlled by the surface chemical reaction during the leaching process. Meanwhile, the regenerated material with better electrochemical performance was obtained by co-precipitation and calcination from leachate. Finally, the process is environmental friendly and economical feasible for recycling of spent lithium-ion batteries.

Comparing prognostic values of the 7th and 8th editions of the American Joint Committee on Cancer TNM staging system for gastric cancer.

BACKGROUND AND AIM: Our aim was to compare the prognostic value of the American Joint Committee on Cancer (AJCC) 7th and 8th editions staging systems for patients with gastric cancer in China. METHODS: A total of 1326 gastric cancer patients diagnosed between 2008 and 2012 were included. The discriminative ability of the AJCC 8th and 7th editions was compared using the Harrell's concordance index (C-index). RESULTS: There are two main modifications in the 8th edition. (i) pN3 staging was divided into pN3a and pN3b. The gastric cancer patients with pN3a experienced significantly better overall survival compared with those with pN3b (5-year overall survival: 34.5% vs. 15.6%, P < 0.001) (stratified by pT: pT3: 5-year overall survival: 33.9% vs. 13.2%, P < 0.001; pT4a: 32.8% vs. 16.9%, P = 0.056; pT4b: 17.0% vs. 11.1%, P = 0.048). (ii) Subgroup staging adjustments. The subgroup staging adjustments (T3N3bM0 (IIIB→IIIC), T4aN3aM0 (IIIC→IIIB), T4bN0M0 (IIIB→IIIA), and T4bN2M0 (IIIC→IIIB)) resulted in more gastric cancer patients being accurately staged. Furthermore, the C-index value of the 8th edition tumor node metastasis (TNM) staging system was significantly higher than that of the AJCC 7th TNM staging system to predict the survival of gastric cancer patients (0.701 vs. 0.685, P < 0.001). CONCLUSIONS: The 8th edition of the TNM staging system is superior to the 7th edition staging system for prediction of survival of gastric cancer patients in China.

Modified American Joint Committee on Cancer Tumor-Node-Metastasis Staging System Based on the Node Ratio Can Further Improve the Capacity of Prognosis Assessment for Gastric Cancer Patients.

Background and Objectives: Our aim was to investigate whether the modified American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system based on the node ratio can further improve the capacity of prognosis assessment for gastric cancer (GC) patients regardless of the number of lymph nodes examined (eLNs). Methods: A total of 17,187 GC patients in the Surveillance, Epidemiology, and End Results (SEER) database were included. On the basis of a training set of 7,660 GC patients, we built the tumor-node ratio-metastasis (TNrM) staging system, which was then externally validated with a validation set of 9,527 GC patients. Results: For the training set, the C-index value of the TNrM staging system was significantly higher than that of the AJCC 8th TNM staging system to predict survival for GC patients (C-index: 0.688 vs. 0.671, P < 0.001). Moreover, the C-index value of the TNrM staging system was significantly higher than that of the 8th TNM staging system to predict survival for GC patients with ≤15 eLNs (C-index: 0.682 vs. 0.673, P < 0.001), as well as for GC patients with >15 eLNs (C-index: 0.700 vs. 0.694, P < 0.001). Similar results were found in the validation set. Conclusions: The TNrM staging system predicted survival more accurately and discriminatively than the AJCC 8th TNM staging system for GC patients regardless of the number of eLNs.

GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway.

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis in vitro and in vivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib.

Sorafenib remains the standard care for patients with hepatocellular carcinoma (HCC) even though it has low antitumor efficacy. Protein neddylation is abnormally activated in many types of human cancer. However, whether dysregulation of neddylation is involved in HCC progression and whether targeting neddylation sensitizes HCC cells to sorafenib need to be ascertained. In the present study, it was demonstrated that high expression of neddylation components, neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and NEDD8­activating enzyme 1 (NAE1), were associated with poor survival of patients with HCC. Inhibition of neddylation by MLN4924, a small­molecule inhibitor of NAE1, significantly inhibited HCC growth, reduced clonogenic survival, increased apoptosis, and decreased migration capacity. Sorafenib alone exhibited minimal anticancer efficacy. However, a combination of sorafenib with MLN4924 at a low concentration significantly enhanced the inhibition of cell proliferation and migration as well as the induction of apoptosis induced by sorafenib. In vivo HCC xenograft mouse models also showed that MLN4924 increased the antitumor efficacy of sorafenib. Mechanistically, MLN4924 enhanced the antitumor activity of sorafenib in HCC cells via upregulation of cullin­RING E3 ubiquitin ligase (CRL)/Skp1­Cullin1­F box (SCF) E3 ubiquitin ligase substrates p21, p27, Deptor and IκBɑ. Taken together, these findings suggest that combination therapy of MLN4924 with sorafenib appears to present an additive effect with a maximal in the treatment of HCC.

Prognostic Value of the Number of Lymph Nodes Examined in Patients with Node-Negative Gastric Cancer.

BACKGROUND: Our aim was to evaluate the prognostic value of the number of lymph nodes examined (eLNs) in patients with node-negative gastric cancer (GC) and further to adjust the American Joint Committee on Cancer (AJCC) 8th staging system based on the number of eLNs. METHODS: Node-negative GC patients diagnosed during 1988-2015 from the Surveillance, Epidemiology, and End Results (SEER) database were included. On the basis of a primary cohort of 4159 node-negative GC patients, we built the adjusted AJCC 8th staging system, which was then internally validated by a bootstrap method, and externally validated with an independent cohort of 5565 node-negative GC patients. RESULTS: The median number of eLNs was 10. For the training set, the optimal eLNs thresholds were determined to be 9 for node-negative GC patients. The adjusted AJCC 8th staging system for node-negative GC patients based on the number of eLNs had a significantly higher Harrell's concordance index than the initial AJCC 8th staging system (C-index, 0.635 versus 0.616; P < 0.001). Thus, the adjusted AJCC 8th staging system had superior prognostic stratification. Similar results were found in the validation set. CONCLUSIONS: For node-negative GC patients in the United States, the adjusted AJCC 8th staging system based on the number of eLNs predicted survival more accurately and discriminatively.