The radiomics nomogram predicts the prognosis of pancreatic cancer patients with hepatic metastasis after chemoimmunotherapy.

OBJECTIVE: To construct a prognostic model based on MR features and clinical data to evaluate the progression free survival (PFS), overall survival (OS) and objective response rate (ORR) of pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy. METHODS: 105 pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy were assigned to the training set (n = 52), validation set (n = 22), and testing set (n = 31). Multi-lesion volume of interest were delineated, multi-sequence radiomics features were extracted, and the radiomics models for predicting PFS, OS and ORR were constructed, respectively. Clinical variables were extracted, and the clinical models for predicting PFS, OS and ORR were constructed, respectively. The nomogram was jointly constructed by radiomics model and clinical model. RESULT: The ORR exhibits no significant correlation with either PFS or OS. The area under the curve (AUC) of nomogram for predicting 6-month PFS reached 0.847 (0.737-0.957), 0.786 (0.566-1.000) and 0.864 (0.735-0.994) in the training set, validation set and testing set, respectively. The AUC of nomogram for predicting 1-year OS reached 0.770 (0.635-0.906), 0.743 (0.479-1.000) and 0.818 (0.630-1.000), respectively. The AUC of nomogram for predicting ORR reached 0.914 (0.828-1.00), 0.938 (0.840-1.00) and 0.846 (0.689-1.00), respectively. CONCLUSION: The prognostic models based on MR imaging features and clinical data are effective in predicting the PFS, OS and ORR of chemoimmunotherapy in pancreatic cancer patients with hepatic metastasis, and can be used to evaluate the prognosis of patients.

HDACs/mTOR inhibitor synergizes with pyrotinib in HER2-positive pancreatic cancer through degradation of mutant P53.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), as a highly lethal malignancy with high mortality, lacks of effective treatment. Canonical therapeutic targets in PDAC demand further verification among which HER2 receptor tyrosine kinase inhibitor pyrotinib as treatment targets has not be decided. METHODS: Anti-PDAC efficacy of pyrotinib was evaluated both in vitro and in vivo using both cell lines and patient-derived xenografts. By screening a large-scale library of 1453 compounds, we identified HDACs/mTOR inhibitor 1 as a promising candidate to synergize with pyrotinib. The combination therapy was evaluated in vitro and in vivo in multiple cell lines and animal models. Furthermore, RNA-seq analysis was performed to reveal the latent molecular mechanism of combination therapy. RESULTS: In our study, pyrotinib monotherapy was found to be inefficient to anti-PDAC which exhibited limited anti-proliferation effect in vitro and in vivo. Through therapy combined with HDACs/mTOR inhibitor 1, pyrotinib triggered intense apoptosis in PDAC both in cell lines and animal models. Mechanistic analyses revealed that mutant P53 degradation mediated by HDAC inhibition synergized with HER2 and mTOR inhibition. CONCLUSIONS: In conclusion, identification of HDACs/mTOR inhibitor as a synergistic inhibitor, provides a potent therapeutic strategy that targets HER2-positive pancreatic cancer.

A Novel Molecular Signature of Cancer-Associated Fibroblasts Predicts Prognosis and Immunotherapy Response in Pancreatic Cancer.

Cancer-associated fibroblasts (CAFs), a prominent population of stromal cells, play a crucial role in tumor progression, prognosis, and treatment response. However, the relationship among CAF-based molecular signatures, clinical outcomes, and tumor microenvironment infiltration remains largely elusive in pancreatic cancer (PC). Here, we collected multicenter PC data and performed integrated analysis to investigate the role of CAF-related genes (CRGs) in PC. Firstly, we demonstrated that α-SMA+ CAFs were the most prominent stromal components and correlated with the poor survival rates of PC patients in our tissue microarrays. Then, we discriminated two diverse molecular subtypes (CAF clusters A and B) and revealed the significant differences in the tumor immune microenvironment (TME), four reported CAF subpopulations, clinical characteristics, and prognosis in PC samples. Furthermore, we analyzed their association with the immunotherapy response of PC patients. Lastly, a CRG score was constructed to predict prognosis, immunotherapy responses, and chemosensitivity in pancreatic cancer patients. In summary, these findings provide insights into further research targeting CAFs and their TME, and they pave a new road for the prognosis evaluation and individualized treatment of PC patients.

Comparison of thermal ablation and routine surgery for the treatment of papillary thyroid microcarcinoma: a systematic review and Meta-analysis.

BACKGROUND: Thermal ablation (TA), as an alternative to surgery, has shown some benefits in the treatment of papillary thyroid microcarcinoma (PTMC) patients, especially for those who are at high risk for surgery or refuse surgery. We performed a systematic review and meta-analysis to evaluate the efficiency, safety, and economy of TA, compared with those of routine surgery (RS), for the treatment of PTMC. METHODS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were retrieved from inception to 10 January 2020 to identify relevant original studies on comparison of TA and RS for treatment of PTMC. The recurrence rate, recurrence-free survival (RFS), complication rate, operation time, postoperative length of stay, and cost during the perioperative period were extracted as main indices. The pooled standardized mean difference (SMD) or odds ratio (OR) with 95% confidence intervals (CI) were calculated and analyzed. Chi-square test and I2 statistic were applied to determine the heterogeneity among studies. The sensitivity analysis was applied to explore the origin of heterogeneity, and the publication bias was evaluated by Egger's test. RESULTS: Seven retrospective studies with a total of 867 patients met the eligibility criteria and were included in the final meta-analysis. Our study demonstrated that TA showed significant reduction in complication with a pooled OR 0.24 (95% CI 0.13 to 0.43), postoperative length of stay with a pooled SMD -3.14 (95% CI -4.77 to -1.51) and cost during the perioperative period with a pooled SMD of -1.69 (95% CI -3.18 to -0.20). It also demonstrated that both TA and RS had similar pooled proportion of recurrence of OR 0.93 (95% CI 0.38 to 2.30) and recurrence-free survive (RFS). The sensitivity analysis showed that each included study had no significant effect on the results and the results were stable and reliable. The Egger's test demonstrated publication bias was acceptable. CONCLUSIONS: TA may not be oncologically inferior to RS, and it is a relatively safe and economical alternative for the treatment of PTMC.

The Role of Bile Acids in Pancreatic Cancer.

Bile acids are well known to promote the digestion and absorption of fat, and at the same time, they play an important role in lipid and glucose metabolism. More studies have found that bile acids such as ursodeoxycholic acid also have anti-inflammatory and immune-regulating effects. Bile acids have been extensively studied in biliary and intestinal tumors but less in pancreatic cancer. Patients with pancreatic cancer, especially pancreatic head cancer, are often accompanied by biliary obstruction and elevated bile acids caused by tumors. Elevated total bile acid levels in pancreatic cancer patients usually have a poor prognosis. There has been controversy over whether elevated bile acids are harmful or beneficial to pancreatic cancer. Still, there is no doubt that bile acids are important for the occurrence and development of pancreatic cancer. This article summarizes the research on bile acid as a biomarker and regulation of the occurrence, development and chemoresistance of pancreatic cancer, hoping to provide some inspiration for future research.

Cuproptosis-related lncRNAs are correlated with tumour metabolism and immune microenvironment and predict prognosis in pancreatic cancer patients.

Cuproptosis is a novel cell death pathway, and the regulatory mechanism in pancreatic cancer (PC) is unclear. The authors aimed to figure out whether cuproptosis-related lncRNAs (CRLs) could predict prognosis in PC and the underlying mechanism. First, the prognostic model based on seven CRLs screened by the least absolute shrinkage and selection operator Cox analysis was constructed. Following this, the risk score was calculated for pancreatic cancer patients and divided patients into high and low-risk groups. In our prognostic model, PC patients with higher risk scores had poorer outcomes. Based on several prognostic features, a predictive nomogram was established. Furthermore, the functional enrichment analysis of differentially expressed genes between risk groups was performed, indicating that endocrine and metabolic pathways were potential regulatory pathways between risk groups. TP53, KRAS, CDKN2A, and SMAD4 were dominant mutated genes in the high-risk group and tumour mutational burden was positively correlated with the risk score. Finally, the tumour immune landscape indicated patients in the high-risk group were more immunosuppressive than that in the low-risk group, with lower infiltration of CD8+ T cells and higher M2 macrophages. Above all, CRLs can be applied to predict PC prognosis, which is closely correlated with the tumour metabolism and immune microenvironment.

Chemotherapeutic drugs-induced pyroptosis mediated by gasdermin E promotes the progression and chemoresistance of pancreatic cancer.

Pyroptosis is closely associated with cancer development; however, the role of pyroptosis in pancreatic ductal adenocarcinoma (PDAC), a fatal malignant tumour with a poor overall survival rate, remains elusive. Here, we explored the mechanism of chemotherapy-induced pyroptosis and elucidated the role of pyroptosis in mediating PDAC progression and chemoresistance. The results demonstrated first- and second-line chemotherapeutic drugs against PDAC, including gemcitabine, irinotecan, 5-fluorouracil, paclitaxel, and cisplatin, induced concurrent pyroptosis and apoptosis. During this process, gasdermin E (GSDME) was cleaved by activated caspase-3, which was accompanied by pro-apoptotic caspase-7/8 activation. GSDME knockdown switched pyroptosis to apoptosis, decreased invasion and migration, and enhanced the sensitivity of PDAC cells to chemotherapy in vitro and in vivo. GSDME was highly expressed in PDAC tissues and positively correlated with histological differentiation and vascular invasion. Furthermore, cells that survived pyroptosis promoted proliferation and invasion and impaired the chemosensitivity of PDAC cells, which was attenuated by the GSDME knockdown. Our findings demonstrated that chemotherapeutics against PDAC induce GSDME-dependent pyroptosis, and GSDME expression positively correlated with PDAC progression and chemoresistance. Targeting GSDME may be a novel approach to overcoming chemoresistance in PDAC.

PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells.

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.

Genome-wide screening and immune landscape suggest a potential-m6A-related lncRNA risk signature for predicting prognosis of melanoma.

Background: Melanoma is the most dangerous form of skin cancer because of its high metastatic potential. Potential-N6-methyladenosine (m6A)-related long noncoding RNAs (pMRlncRNAs) play a vital role in malignancy. The identification of prognostic-related pMRlncRNAs and development of risk signatures could improve the prognosis and promote the precise treatment of melanoma. Methods: Gene expression and relevant clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic-related pMRlncRNAs were selected using univariate Cox regression analysis. Patients with melanoma were classified into different subtypes using the "ConsensusClusterPlus" package, and the ESTIMATE algorithm was applied to depict their immune landscape. A pMRlncRNA risk signature was developed using least absolute shrinkage and selection operator regression analysis and verified using survival analysis and receiver operating characteristic curves. Gene set enrichment analysis (GSEA) was used to investigate the underlying biological pathways. The relationships between risk score and clinicopathological characteristics, as well as programmed cell death-ligand 1 (PD-L1) expression level, were investigated. A nomogram with calibration curves was established to comprehensively predict the outcome of melanoma. Results: Fifteen pMRlncRNAs were significantly associated with overall survival (OS). Two cluster subtypes were identified by consensus clustering. Patients in cluster 2 were associated with better OS, higher PD-L1 expression level, lower T stage, and higher ESTIMATEScore, ImmuneScore, and StromalScore than those in cluster 1. There were differences in immune cell infiltration between the 2 clusters. Ten pMRlncRNAs with prognostic value were selected to develop a risk signature, that functioned as an independent prognostic factor for melanoma. Patients with low-risk scores had a better prognosis in general. The area under the curve (AUC) value (0.720), as well as 1-, 3-, and 5-year calibration curves, revealed that the risk signature has suitable predictive power for prognosis. GSEA revealed 10 pathways that might play important roles in melanoma. Moreover, patients with high-risk scores were associated with advanced T stage, cluster 1, lower ImmuneScore, and higher PD-L1 expression level. Conclusions: We developed a novel 10-pMRlncRNA risk signature that could elucidate the crucial role of pMRlncRNAs in the immune landscape of melanoma and predict prognosis.

A novel angiogenesis-based molecular signature related to prognosis and tumor immune interactions of pancreatic cancer.

Angiogenesis, a hallmark of cancer, is related to prognosis, tumor progression, and treatment response. Nevertheless, the correlation of angiogenesis-based molecular signature with clinical outcome and immune cell infiltration has not been thoroughly studied in pancreatic cancer. In this study, multiple bioinformatics methods were combined to evaluate prognosis, immune cell infiltration, and the alterations of angiogenesis-related genes (ARGs) in PC samples, and further establish a novel angiogenesis-related gene signature. Moreover, the protein and mRNA expression levels of four angiogenesis risk genes were determined by Human Protein Atlas (HPA) database and qPCR analysis, respectively. Here, we recognized two distinct angiogenesis subtypes and two gene subtypes, and revealed the critical roles of ARGs in the tumor immune microenvironment (TIME), clinical features, and prognosis. Consequently, we established an ARGs score to predict prognosis and therapeutic response of PC patients, and validated its robust predictive ability. Additionally, the ARGs score was markedly associated with clinical outcomes, tumor mutation burden (TMB), and chemotherapeutic drug sensitivity. In brief, our findings imply that the ARGs score is a robust prognostic indicator and may contribute to the development of effective individualized therapies for PC.

Association of aging-related genes with prognosis and immune infiltration in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies. Aging is described as the degeneration of physiological function, which is complexly correlated with cancer. It is significant to explore the influences of aging-related genes (ARGs) on PAAD. Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets, we used univariate Cox regression analysis and acquired eight differentially expressed ARGs with prognostic values. Two molecular subtypes were identified based on these ARGs to depict PAAD patients' overall survival (OS) and immune microenvironments preliminarily. Cluster 1 had a poor OS as well as a worse immune microenvironment. Through least absolute shrinkage and selection operator (LASSO) regression analysis, we constructed a seven-ARG risk signature based on the TCGA dataset and verified it in Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) to predict the prognoses, immune microenvironments, signal pathways, tumor mutations, and drug sensitivity of PAAD patients. The high-risk group possessed an unfavorable OS compared with that of the low-risk group. We also verified the independence and clinical availability of the risk signature by Cox regression analyses and the establishment of a nomogram, respectively. The higher risk score was associated with several clinical factors such as higher grade and advanced tumor stage as well as lower immunoscore and cluster 1. The negative associations of risk scores with immune, stroma, and estimate scores proved the terrible immune microenvironment in the high-risk group. Relationships between risk score and immune checkpoint gene expression as well as signal pathways provided several therapeutic targets. PAAD patients in the low-risk group possessed lower tumor mutations as well as a higher susceptibility to axitinib and vorinostat. The high-risk group bore a higher TMB and cisplatin and dasatinib may be better options. We used immunohistochemistry and qPCR to confirm the expression of key ARGs with their influences on OS. In conclusion, we identified two ARG-mediated molecular subtypes and a novel seven-ARG risk signature to predict prognoses, immune microenvironments, signal pathways, tumor mutations, and drug sensitivity of PAAD patients.

Prediction of Survival and Tumor Microenvironment Infiltration Based on Pyroptosis-Related lncRNAs in Pancreatic Cancer.

Pancreatic cancer (PC) is a fatal tumor with high mortality. Pyroptosis plays a tumor suppressor role as a novel cell death. However, the influences of the pyroptosis-related lncRNAs (PRlncRNAs) on the prognosis and tumor microenvironment (TME) infiltration have not been fully studied in PC. Using coexpression analysis and univariate Cox regression analysis, we identified seventeen prognostic PRlncRNAs from The Cancer Genome Atlas (TCGA) dataset, which were all expressed differently in normal and tumor samples. A seven-PRlncRNA risk signature was constructed and validated using the least absolute shrinkage and selection operator (LASSO) regression. Furthermore, we verified its independence and created a nomogram to validate the clinical viability of the risk signature. We then identified its relationship with clinical factors and evaluated its values in TME infiltration, functional enrichment, tumor mutation, and therapeutic responses in PC. Lower ImmuneScore, ESTIMATEScore, and advanced tumor stage were connected with high-risk score. The low-risk group was characterized by better OS, elevated immune activation, and higher susceptibility of pazopanib and sunitinib. The high-risk group possessed a worse immune infiltration and poor survival, with higher tumor mutations and lapatinib and paclitaxel that may be better choices in this group. In conclusion, we developed an original seven-PRlncRNA risk signature to predict prognosis, TME infiltration, tumor mutation, and therapeutic options for PC patients.

Prediction of Ubiquitin Ligase Nrdp1-Associated Proteins in Glioma Database.

The ubiquitin proteasome pathway is conserved from yeast to mammals and is necessary for the targeted degradation of most short-lived proteins in eukaryotic cells. Its protein substrates include cell cycle regulatory proteins and proteins that are not properly folded in the endoplasmic reticulum. Owing to the ubiquity of its protein substrates, ubiquitination regulates a variety of cellular activities, including cell proliferation, apoptosis, autophagy, endocytosis, DNA damage repair, and immune response. With new genomic data continuously being obtained, ubiquitination through genomic data analysis will be an effective method. We obtained 83 overlapping genes from four glioma databases, which differed from ubiquitin ligase Nrdp1 expression, including 36 downregulated and 47 upregulated genes. The KEGG pathways, molecular functions, cellular components, and biological processes potentially associated with Nrdp1 were obtained using GSEA and Cytoscape. In human gliomas, differences in the expression of Nrdp1 were identified between nontumor brain tissue and different glioma tissues, but no difference in expression was found between low­grade glioma (LGG) and anaplastic glioma (AG). In survival analysis, we found no significant association between Nrdp1 expression level and patient prognosis.

PART1 and hsa-miR-429-Mediated SHCBP1 Expression Is an Independent Predictor of Poor Prognosis in Glioma Patients.

Gliomas are the most common primary brain tumors. Because of their high degree of malignancy, patient survival rates are unsatisfactory. Therefore, exploring glioma biomarkers will play a key role in early diagnosis, guiding treatment, and monitoring the prognosis of gliomas. We found two lncRNAs, six miRNAs, and nine mRNAs that were differentially expressed by analyzing genomic data of glioma patients. The diagnostic value of mRNA expression levels in gliomas was determined by receiver operating characteristic (ROC) curve analysis. Among the nine mRNAs, the area under the ROC curve values of only CEP55 and SHCBP1 were >0.7, specifically 0.834 and 0.816, respectively. Additionally, CEP55 and SHCBP1 were highly expressed in glioma specimens and showed increased expression according to the glioma grade, and outcomes of high expression patients were poor. CEP55 was enriched in the cell cycle, DNA replication, mismatch repair, and P53 signaling pathway. SHCBP1 was enriched in the cell cycle, DNA replication, ECM receptor interaction, and P53 signaling pathway. Age, grade, IDH status, chromosome 19/20 cogain, and SHCBP1 were independent factors for prognosis. Our findings suggest the PART1-hsa-miR-429-SHCBP1 regulatory network plays an important role in gliomas.