Identification of molecular subtypes based on PANoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma

BackgroundPrevious studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC).MethodsBased on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments.ResultsThis study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration.ConclusionPANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment

Non-functional pancreatic neuroendocrine tumours: emerging trends in incidence and mortality

Abstract Background Our aim was to determine the epidemiology and recent changes in the trends of non-functional pancreatic neuroendocrine tumours (NF-pNETs) at the population level. In addition, we explored the risk factors that are associated with survival duration. Methods Cases were identified form the Surveillance, Epidemiology, and End Results (SEER) Programme database from 2000 to 2014. Data on incidence and incidence-based (IB) mortality for NF-pNET were obtained from this database. Secular trends in age-adjusted incidence and IB mortality were determined by using the Joinpoint Regression program. Data analyses were performed using chi-square tests, Kaplan-Meier curves and Cox proportional hazards regression. Results Overall, 4766 patients diagnosed with NF-pNET with a median age of 59 years were identified through our descriptive criteria. Caucasian patients accounted for the majority of the study population, and the proportion of patients with distant disease significantly decreased during our study period. Overall, there was an increase in incidence and IB mortality for NF-pNET; however, the rate of increase decreased during the recent years. In addition, the incidence trends of NF-pNET located in the pancreatic head significantly increased, and rates fo increase in IB mortality for NF-pNET in the pancreatic tail decreased in recent years. Additionally, the 1-, 5-, and 10-year survival rates were 79.0, 51.8, 38.1%, respectively. Furthermore, patient age, tumour grade, stage at diagnosis, tumour size, tumour site and resection were associated with mortality. Conclusion Despite increases in incidence and IB mortality, the rate of change in IB mortality for NF-pNET has decreased in recent years. Survival duration displayed a secular increase during the overall period, and the prognosis and survival duration of patients were closely related to the time of diagnosis, age of the patients and size and location of the tumour. Appropriate treatment adjustments based on tumour stage may thus facilitate improvements in patient outcomes

Forest plot of meta-analysis.

<p>Fixed-effect models of odds ratio for stone clearance (A), random-effects model of odds ratio for conversion to other procedures (B), random-effects model of odds ratio for total morbidity, (C) and fixed-effects model of odds ratio for biliary morbidity (D).</p

Laparoscopic Transcystic Common Bile Duct Exploration: Advantages over Laparoscopic Choledochotomy

<div><p>Purpose</p><p>The ideal treatment for choledocholithiasis should be simple, readily available, reliable, minimally invasive and cost-effective for patients. We performed this study to compare the benefits and drawbacks of different laparoscopic approaches (transcystic and choledochotomy) for removal of common bile duct stones.</p><p>Methods</p><p>A systematic search was implemented for relevant literature using Cochrane, PubMed, Ovid Medline, EMBASE and Wanfang databases. Both the fixed-effects and random-effects models were used to calculate the odds ratio (OR) or the mean difference (MD) with 95% confidence interval (CI) for this study.</p><p>Results</p><p>The meta-analysis included 18 trials involving 2,782 patients. There were no statistically significant differences between laparoscopic choledochotomy for common bile duct exploration (LCCBDE) (<i>n</i> = 1,222) and laparoscopic transcystic common bile duct exploration (LTCBDE) (<i>n</i> = 1,560) regarding stone clearance (OR 0.73, 95% CI 0.50–1.07; <i>P</i> = 0.11), conversion to other procedures (OR 0.62, 95% CI 0.21–1.79; <i>P</i> = 0.38), total morbidity (OR 1.65, 95% CI 0.92–2.96; <i>P</i> = 0.09), operative time (MD 12.34, 95% CI −0.10–24.78; <i>P</i> = 0.05), and blood loss (MD 1.95, 95% CI −9.56–13.46; <i>P</i> = 0.74). However, the LTCBDE group showed significantly better results for biliary morbidity (OR 4.25, 95% CI 2.30–7.85; <i>P</i><0.001), hospital stay (MD 2.52, 95% CI 1.29–3.75; <i>P</i><0.001), and hospital expenses (MD 0.30, 95% CI 0.23–0.37; <i>P</i><0.001) than the LCCBDE group.</p><p>Conclusions</p><p>LTCBDE is safer than LCCBDE, and is the ideal treatment for common bile duct stones.</p></div

Flow diagram of study selection.

<p>Flow diagram of study selection.</p

DataSheet_1_Identification of molecular subtypes based on PANoptosis-related genes and construction of a signature for predicting the prognosis and response to immunotherapy response in hepatocellular carcinoma.docx

BackgroundPrevious studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC).MethodsBased on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments.ResultsThis study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration.ConclusionPANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment.</p

Funnel plots for meta-analysis.

<p>A, Nine articles in the meta-analysis of biliary morbidity; B, 14 articles in the meta-analysis of length of hospital stay. C, Three articles in the meta-analysis of hospital expenses.</p

Description of included trials.

<p>Description of included trials.</p

Image_5_Signature construction and molecular subtype identification based on cuproptosis-related genes to predict the prognosis and immune activity of patients with hepatocellular carcinoma.tif

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies in the world, with high incidence, high malignancy, and low survival rate. Cuproptosis is a novel form of cell death mediated by lipoylated TCA cycle proteins-mediated novel cell death pathway and is highly associated with mitochondrial metabolism. However, the relationship between the expression level of cuproptosis-related genes (CRGs) and the prognosis of HCC is still unclear.MethodsCombining the HCC transcriptomic data from The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus (GEO) databases, we identified the differentially expressed cuproptosis-related genes (DECRGs) and obtained the prognosis-related DECRGs through univariate regression analysis.LASSO and multivariate COX regression analyses of these DECRGs yielded four genes that were used to construct the signature. Next, we use ROC curves to evaluate the performance of signatures. The tumor microenvironment, immune infiltration, tumor mutation load, half-maximum suppression concentration, and immunotherapy effects were also compared between the low-risk and high-risk groups. Finally, we analyzed the expression level, prognosis, and immune infiltration correlation on the four genes that constructed the model.ResultsFour DECRGs s were used to construct the signature. The ROC curves indicated that signature can better assess the prognosis of HCC patients. Patients were grouped according to the signature risk score. Patients in the low-risk group had a significantly longer survival time than those in the high-risk group. Furthermore, the tumor mutation burden (TMB) values were associated with the risk score and the higher-risk group had a higher proportion of TP53 mutations than the low-risk group.ESTIMATE analysis showed significant differences in stromal scores between the two groups.N6-methyladenosine (m6A) and multiple immune checkpoints were expressed at higher levels in the high-risk group. Then, we found that signature score correlated with chemotherapeutic drug sensitivity and immunotherapy efficacy in HCC patients. Finally, we further confirmed that the four DECRGs genes were associated with the prognosis of HCC through external validation.ConclusionsWe studied from the cuproptosis perspective and developed a new prognostic feature to predict the prognosis of HCC patients. This signature with good performance will help physicians to evaluate the overall prognosis of patients and may provide new ideas for clinical decision-making and treatment strategies.</p