SDC1 and ITGA2 as novel prognostic biomarkers for PDAC related to IPMN.

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1high was enriched in interferon alpha (IFN-α) response and ITGA2high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.

Research progress and value of albumin-related inflammatory markers in the prognosis of non-small cell lung cancer: a review of clinical evidence.

Inflammatory markers have a wide range of predictive values in the prognosis of non-small lung cancer (NSCLC). Poor nutritional status usually means a poor prognosis in patients with NSCLC, which is widely recognized by oncologists and nutritionists. Serum albumin has a certain value in evaluating the prognosis of patients. Several inflammatory albumin-related markers have been proposed, but they have not been widely used in predicting the prognosis of NSCLC in clinical practice. We aim to systematically review the published clinical evidence of albumin-related inflammatory markers in predicting the prognosis of NSCLC and to describe their progress and value. The results showed that the markers included in the review could be prognostic indicators in patients with NSCLC. However, we found that the cut-off value of albumin-related inflammatory markers with quantitative nature was very chaotic and needed to be defined by recognized standards. We summarized and compared the advantages and disadvantages of these markers, but a prospective cohort study with long-term follow-up after adjustment for important confounders is still necessary. Whether the results and conclusions could be directly applied in clinical practice needs to be identified and evaluated. There is an urgent need to classify and standardize the albumin-related inflammatory markers that play an important role in the prognosis of NSCLC, which is the key to ensuring the transformation from clinical study to clinical application.

Albumin-related inflammatory markers could be prognostic indicators in non-small cell lung cancer.The classification and standardization of albumin-related inflammatory markers guarantee the transformation from clinical study to clinical application.Future prospective studies of albumin-related inflammatory markers excluding confounding factors are very necessary.

Independent predictive value of blood inflammatory composite markers in ovarian cancer: recent clinical evidence and perspective focusing on NLR and PLR.

Ovarian cancer (OC) is one of the deadliest malignant tumors affecting women worldwide. The predictive value of some blood inflammatory composite markers in OC has been extensively reported. They can be used for early detection and differential diagnosis of OC and can be used for predicting survival, treatment response, and recurrence in the affected patients. Here, we reviewed the predictive values of composite inflammatory markers based on complete blood count, namely neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, and systemic inflammation index and markers based on blood protein, namely C-reactive protein-to-albumin ratio and prognostic nutritional index in OC, with a focus on NLR and PLR. We referred to the clinical studies on these six markers, reviewed the patient population, and summarized the marker cut-off values, significance, and limitations of these studies. All these studies were retrospective and most of them were single-center clinical studies with small sample sizes. We found that the cut-off values of these markers have not been unified, and methods used to determine these values varied among studies. The predictive value of these markers on survival was mainly reflected in the postoperative patients of multiple subtypes of ovarian cancer including epithelial OC, high-grade serous ovarian carcinoma, and ovarian clear cell carcinoma. We focused on NLR and PLR and calculated their pooled hazard ratios. NLR and PLR were reliable in predicting overall and progression-free survivals in patients with OC. Therefore, it is necessary to adjust important confounding factors and conduct a long-term follow-up prospective cohort study to further clarify the cut-off values of NLR and PLR and their clinical applications.

Analysis of the correlation between Zeste enhancer homolog 2 (EZH2) mRNA expression and the prognosis of mesothelioma patients and immune infiltration.

Mesothelioma lies one of the most malignant tumors, in which the identification of the corresponding biomarkers is extremely critical. This study aims to investigate the prognostic value of enhancer homolog 2 (EZH2) mRNA expression in mesothelioma patients accompanied with its immune infiltration analysis. Gene expression, clinical information and enrichment analysis were obtained based on the Cancer Genome Atlas (TCGA), the immune infiltration analysis and bioinformatics analysis were performed. Clinical information and gene expression were obtained from 86 patients with mesothelioma based on TCGA database. Survival analysis, GSEA enrichment analysis, and immune infiltration analysis of EZH2 expression were carried out using R (version 3.6.3) (statistical analysis and visualization). The correlation of EZH2 expression with immune cell infiltration in mesothelioma was analyzed according to the TIMER database (Fig. https://cistrome.shinyapps.io/timer/ ). A univariate and multivariate analysis of general data obtained from the TCGA database was performed, involving age, gender, stage, pathological type, and whether they had received radiotherapy, the results indicated the association of high expression of EZH2 with poor prognosis in mesothelioma patients, with the worse prognosis in the High group (HR = 2.75, 95% CI 1.68-4.52, P < 0.010). Moreover, ROC curves showed that EZH2 expression predicted 1-year survival with an AUC of 0.740, 2-year survival with an AUC of 0.756, and 3-year survival with an AUC of 0.692, suggesting a robust predictive effect of EZH2 expression on prognosis. KEGG pathway analysis indicated five pathways showing the strongest positive correlation with EZH2 expression: cell cycle, DNA replication, Cell adhesion molecules cams, Primary immuno deficiency, Tsate transduction, and five pathways showing the strongest negative correlation with EZH2 expression: Glycolysis gluconeogenesis, Drug metabolism, cytochrome P450, retinol metabolism, fatty acid metabolism ribosome. We investigated the correlation between EZH2 expression and the level of immune infiltration in mesothelioma tissues. The results indicated that EZH2 expression played a critical role in immune infiltration, of which the high expression was correlated with the reduced number of NK cells, Mast cells, and Th17 cells. Moreover, mesothelioma patients with high EZH2 expression differ from those with low EZH2 expression in their tumor immune microenvironment. EZH2, as a new prognostic biomarker for mesothelioma, contributes to elucidating how changes in the immune environment promote the development of mesothelioma. Further analysis, EZH2 may serve as a biological test to predict the prognosis of mesothelioma.

Does Dexmedetomidine Reduce the Risk of Atrial Fibrillation and Stroke After Adult Cardiac Surgery? A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Postoperative atrial fibrillation is a common consequence of cardiac sur-gery with increased stroke complications and mortality. Although dexmedetomidine is thought to prevent postoperative atrial fibrillation and stroke because of its sympa-tholytic and anti-inflammatory properties, data from different studies show the effect of dexmedetomidine on postoperative atrial fibrillation and stroke uncertain in adult patients with cardiac surgery. METHODS: A database including EMBASE, PubMed, and Cochrane CENTRAL was searched for randomized controlled trials comparing dexmedetomidine with placebo or other anesthetic drugs in adult cardiac surgery. The primary outcome was the incidence of postoperative atrial fibrillation. The secondary outcomes were the incidence of postop-erative stroke, mechanical ventilation duration, intensive care unit length of stay, hospi-tal length of stay, and mortality. RESULTS: Eighteen trials with a total of 2933 patients were enrolled in the meta-analyses. Compared with controls, dexmedetomidine significantly reduced the incidence of post-operative atrial fibrillation [odds ratio, 0.82; 95% CI, 0.69-0.98; P = .03]. There was no sig-nificant difference between groups in stroke (odds ratio, 1.36; 95% CI, 0.59-3.16; P = .47), mechanical ventilation duration [weighted mean difference, -0.17; 95% CI, -0.35 to 0.14;P=.39], intensive care unit length of stay (weighted mean difference, -0.03; 95% CI,-0.93 to 0.87; P = .95), hospital length of stay (weighted mean difference, -0.04; 95% CI,-0.40 to 0.32; P = .83) and mortality (odds ratio, 0.72; 95% CI, 0.32-1.60; P = .42). CONCLUSION: Perioperative dexmedetomidine reduced the incidence of postoperative atrial fibrillation in adult patients undergoing cardiac surgery. But there was no signifi-cant difference in the incidence of stroke, mechanical ventilation duration, intensive care unit length of stay, hospital length of stay, and mortality.

Prognostic Value of Glasgow Prognostic Score in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Background: Systemic inflammation is a key factor in tumor growth. The Glasgow Prognostic Score (GPS) has a certain value in predicting the prognosis of lung cancer. However, these results still do not have a unified direction. Methods: A systematic review and meta-analysis were performed to investigate the relationship between GPS and the prognosis of patients with non-small cell lung cancer (NSCLC). We set patients as follows: GPS = 0 vs. GPS = 1 or 2, GPS = 0 vs. GPS = 1, GPS = 0 vs. GPS = 2. We collected the hazard ratio (HR) and the 95% confidence interval (CI). Results: A total of 21 studies were included, involving 7333 patients. We observed a significant correlation with GPS and poor OS in NSCLC patients (HRGPS=0 vs. GPS=1 or 2 = 1.62, 95% CI: 1.27-2.07, p ≤ .001; HRGPS=0 vs GPS=1 = 2.14, 95% CI:1.31-3.49, p ≤ .001; HRGPS=0 vs. GPS=2 = 2.64, 95% CI: 1.45-4.82, p ≤ .001). Moreover, we made a subgroup analysis of surgery and stage. The results showed that when divided into GPS = 0 group and GPS = 1 or 2 group, the effect of high GPS on OS was more obvious in surgery (HR = 1.79, 95% CI: 1.08-2.97, p = .024). When GPS was divided into two groups (GPS = 0 and GPS = 1 or 2), the III-IV stage, higher GPS is associated with poor OS (HR = 1.73, 95% CI: 1.43-2.09, p ≤ .001). In the comparison of GPS = 0 and GPS = 1 group (HR = 1.56, 95% CI: 1.05-2.31, p = .026) and the grouping of GPS = 0 and GPS = 2(HR = 2.23, 95% CI: 1.17-4.26, p = .015), we came to the same conclusion. Conclusion: For patients with NSCLC, higher GPS is associated with poor prognosis, and GPS may be a reliable prognostic indicator. The decrease of GPS after pretreatment may be an effective way to improve the prognosis of NSCLC.

Discovery of Pyrazine-Carboxamide-Diphenyl-Ethers as Novel Succinate Dehydrogenase Inhibitors via Fragment Recombination.

The discovery of novel succinate dehydrogenase inhibitors (SDHIs) has attracted great attention worldwide. Herein, a fragment recombination strategy was proposed to design new SDHIs by understanding the ligand-receptor interaction mechanism of SDHIs. Three fragments, pyrazine from pyraziflumid, diphenyl-ether from flubeneteram, and a prolonged amide linker from pydiflumetofen and fluopyram, were identified and recombined to produce a pyrazine-carboxamide-diphenyl-ether scaffold as a new SDHI. After substituent optimization, compound 6y was successfully identified with good inhibitory activity against porcine SDH, which was about 2-fold more potent than pyraziflumid. Furthermore, compound 6y exhibited 95% and 80% inhibitory rates against soybean gray mold and wheat powdery mildew at a dosage of 100 mg/L in vivo assay, respectively. The results of the present work showed that the pyrazine-carboxamide-diphenyl-ether scaffold could be used as a new starting point for the discovery of new SDHIs.

Design, synthesis, and fungicidal evaluation of novel oxysterol binding protein inhibitors for combatting resistance associated with oxathiapiprolin.

Oxathiapiprolin, the first successful oxysterol binding protein (OSBP) inhibitor for oomycete control, is regarded as an important milestone in the history of fungicide discovery. However, its interaction with OSBP remain unclear. Moreover, some plant pathogenic oomycetes have developed medium to high resistance to oxathiapiprolin. In this paper, the three-dimensional (3D) structure of OSBP from Phytophthora capsici (pcOSBP) was built, and its interaction with oxathiapiprolin was systematically investigated by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The computational results showed that oxathiapiprolin bound to pcOSBP forms H-bonds with Leu73, Lys74, Ser69, and water molecules. Then, based on its interaction with pcOSBP, oxathiapiprolin was structurally modified to discover new analogs with high fungicidal activity and a low risk of resistance. Fortunately, compound 1e was successfully designed and synthesized as the most potent candidate, and it showed a much lower resistance risk (RF < 1) against LP3-M and LP3-H in P. capsici. The present work indicated that the piperidinyl-thiazole-isoxazoline moiety is useful for further optimization. Furthermore, compound 1e could be used as a lead compound for the discovery of new OSBP inhibitors.