Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer.

BACKGROUND: KRAS was reported to affect some metabolic genes and promote metabolic reprogramming in solid tumors. However, there was no comprehensive analysis to explore KRAS-associated metabolic signature or risk model for pancreatic cancer (PC). METHODS: In the current study, multiple bioinformatics analyses were used to identify differentially expressed metabolic genes based on KRAS mutation status in PC. Then, we developed and validated a prognostic risk model based on the selected KRAS-associated metabolic genes. Besides, we explored the association between the risk model and the metabolic characteristics as well as gemcitabine-associated chemoresistance in PC. RESULTS: 6 KRAS-associated metabolic genes (i.e., CYP2S1, GPX3, FTCD, ENPP2, UGT1A10, and XDH) were selected and enrolled to establish a prognostic risk model. The prognostic model had a high C-index of 0.733 for overall survival (OS) in TCGA pancreatic cancer database. The area under the curve (AUC) values of 1- and 3-year survival were both greater than 0.70. Then, the risk model was validated in two GEO datasets and also presented a satisfactory discrimination and calibration performance. Further, we found that the expression of some KRAS-driven glycolysis-associated genes (PKM, GLUT1, HK2, and LDHA) and gemcitabine-associated chemoresistance genes (i.e., CDA and RMM2) was significantly upregulated in high-risk PC patients evaluated by the risk model. CONCLUSIONS: We constructed a risk model based on 6 KRAS-associated metabolic genes, which predicted patients' survival with high accuracy and reflected tumor metabolic characteristics and gemcitabine-associated chemoresistance in PC.

SLC39A10 Upregulation Predicts Poor Prognosis, Promotes Proliferation and Migration, and Correlates with Immune Infiltration in Hepatocellular Carcinoma.

BACKGROUND: Recent evidence has shown that Solute Carrier Family 39 Member 10 (SLC39A10) promoted tumor progression in several cancer types. The study intended to explore the expression and function of SLC39A10 in hepatocellular carcinoma (HCC). METHODS: Multiple bioinformatics analyses were used to evaluate SLC39A10 expression and potential role in HCC. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to confirm SLC39A10 expression. Intro studies were performed to assess the effects of SLC39A10 on HCC cells proliferation and migration. Furthermore, flow cytometry was conducted to identify its specific function in apoptosis of HCC. RESULTS: SLC39A10 was significantly over-expressed in HCC samples from both bioinformatic databases and our cohort. Survival analyses suggested patients with high expression of SLC39A10 had poor overall survival and disease-free survival (P-value <0.01). Further, the expression of SLC39A10 was positively correlated with tumor-infiltrating lymphocytes and some immune checkpoints like CTLA4, TIM3 and TGFB1. In HCC cell lines, SLC39A10 knockdown inhibited cells proliferation and migration, but promoted apoptosis. CONCLUSION: An increased SLC39A10 expression was found and served as an unfavorable indicator of survival in HCC. Further studies suggested SLC39A10 promotes tumor aggressiveness and may provide a novel target for HCC therapy.

A Novel Prognostic Nomogram for Gallbladder Cancer after Surgical Resection: A Single-Center Experience.

BACKGROUND: Gallbladder cancer (GBC), which accounts for more than 80% of biliary tract malignancies, has a poor prognosis with an overall 5-year survival less than 10%. The study aimed to identify risk factors and develop a predictive model for GBC following surgical resection. METHODS: 98 GBC patients who underwent surgical resection from Guangdong Provincial People's Hospital were enrolled in the study. Cox-regression analysis was performed to identify significant prognostic factors. A nomogram was constructed and Harrell's concordance index, calibration plot, and decision cure analysis were used to evaluate the discrimination and calibration of the nomogram. RESULTS: Liver resection, tumor size, perineural invasion, surgical margin, and liver invasion were identified as independent risk factors for overall survival (OS) in GBC patients who underwent surgical resection. Based on the selected risk factors, a novel nomogram was constructed. The C-index of the nomogram was 0.777, which was higher than the American Joint Committee on Cancer (AJCC) staging system (0.724) and Nevin staging system (0.659). Decision cure analysis revealed that the nomogram had a better net benefit and the calibration curves for the 1-, 3-, and 5-year survival probabilities were also well matched with the actual survival rates. Lastly, high-risk GBC were stratified based on the scores of the nomogram and we found high-risk GBC were associated with both worse OS and disease-free survival (DFS). CONCLUSION: We developed a nomogram showing a better predictive capacity for patients' survival of resected GBC than the AJCC staging systems. The established model may help to stratify high-risk GBC and facilitate decision-making in the clinic.

Prognostic stratification based on a novel nomogram for left-sided pancreatic adenocarcinoma after surgical resection: a multi-center study.

Left-sided pancreatic adenocarcinoma (LPAC) has a poorer prognosis and has some distinct features compared to cancer of pancreatic head. A reliable model to predict the prognosis of LPAC following surgery is needed in clinical practice. Our study included 231 patients with resected LPAC from 3 Chinese pancreatic disease centers. Cox-regression analysis was conducted to identify independent risk factors of LAPC. Then we established a nomogram and performed C-index, receiver operating characteristic curve, calibration plot and decision curve analysis to assess its discrimination and calibration. As a result, CA19-9, surgical margin, tumor differentiation, lymph node metastasis, and postoperative adjuvant chemotherapy were identified as significant prognostic factors. Based on these predictors, a novel nomogram was constructed. The nomogram achieved high C-indexes in the training cohort (0.805) and validation cohort (0.719), which were superior than the AJCC-8 staging system and other nomograms. The area under curve of the nomogram for predicting patients survival at 1-, 2-, and 3-year in training cohort were more than 0.8. Kaplan-Meier survival curve for the subgroups stratified based on the nomogram showed a better separation than the AJCC-8 stage I, II, III, indicating a superior ability of risk stratification for our model. In summary, we constructed a nomogram which showed a better predictive ability for patients' survival with LPAC after surgical resection than the AJCC staging system and other predictive models. Our model would be helpful to discriminate high-risk LPAC and facilitate clinical decision making.

Cortical Excitability in Temporal Lobe Epilepsy with Bilateral Tonic-Clonic Seizures.

OBJECTIVE: We investigated motor cortical excitability (CE) in unilateral temporal lobe epilepsy (TLE) and its relationship to bilateral tonic-clonic seizure (BTCS) using paired-pulse transcranial magnetic stimulation (TMS). METHODS: In this cross-sectional study, we enrolled 46 unilateral TLE patients and 16 age-and sex-matched healthy controls. Resting motor thresholds (RMT); short-interval intracortical inhibition (SICI, GABAA receptor-mediated); facilitation (ICF, glutamatergic-mediated) with interstimulus intervals (ISIs) of 2, 5, 10, and 15 ms; and long-interval intracortical inhibition (LICI, GABAB receptor-mediated) with ISIs of 200-400 ms were measured via paired-pulse TMS. Comparisons were made between controls and patients with TLE, and then among the TLE subgroups (no BTCS, infrequent BTCS and frequent BTCS subgroup). RESULTS: Compared with controls, TLE patients had higher RMT, lower SICI and higher LICI in both hemispheres, and higher ICF in the ipsilateral hemisphere. In patients with frequent BTCS, cortical hyperexcitability in the ipsilateral hemisphere was found in a parameter-dependent manner (SICI decreased at a stimulation interval of 5 ms, and ICF increased at a stimulation interval of 15 ms) compared with patients with infrequent or no BTCS. CONCLUSIONS: Our results demonstrate that motor cortical hyper-excitability in the ipsilateral hemisphere underlies the epileptogenic network of patients with active BTCS, which is more extensive than those with infrequent or no BTCS.