Prognostic-Related Biomarkers in Pancreatic Ductal Adenocarcinoma Correlating with Immune Infiltrates Based on Proteomics.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) accounts for 85% of pancreatic carcinoma cases. Patients with PDAC have a poor prognosis. The lack of reliable prognostic biomarkers makes treatment challenging for patients with PDAC. Using a bioinformatics database, we sought to identify prognostic biomarkers for PDAC. MATERIAL AND METHODS Using proteomic analysis of the Clinical Proteomics Tumor Analysis Consortium (CPTAC) database, we were able to identify core differential proteins between early and advanced pancreatic ductal adenocarcinoma tissue, and then we used survival analysis, Cox regression analysis, and area under the ROC curves to screen for more significant differential proteins. Additionally, the Kaplan-Meier plotter database was utilized to determine the relationship between prognosis and immune infiltration in PDAC. RESULTS We identified 378 differential proteins in early (n=78) and advanced stages (n=47) of PDAC (P<0.05). PLG, COPS5, FYN, ITGB3, IRF3, and SPTA1 served as independent prognostic factors of patients with PDAC. Patients with higher COPS5 expression had shorter overall survival (OS) and recurrence-free survival, and those with higher PLG, ITGB3, and SPTA1, and lower FYN and IRF3 expression had shorter OS. More importantly, COPS5, IRF3 were negatively associated with macrophages and NK cells, but PLG, FYN, ITGB3, and SPTA1 were positively related to the expression of CD8+ T cells and B cells. COPS5 affected the prognosis of PDAC patients by acting on B cells, CD8+ T cells, macrophages, and NK cells immune infiltration, while PLG, FYN, ITGB3, IRF3, and SPTA1 affected PDAC patient prognosis through some immune cells. CONCLUSIONS PLG, COPS5, FYN, IRF3, ITGB3 and SPTA1 could be potential immunotherapeutic targets and valuable prognostic biomarkers of PDAC.

Pd(II)-Catalyzed Synthesis of Alicyclic[b]-Fused Pyridines via C(sp2)-H Activation of α,ß-Unsaturated N-Acetyl Hydrazones with Vinyl Azides.

A new synthetic protocol for alicyclic[b]-fused pyridines with complete regioselectivity from α,ß-unsaturated N-acetyl hydrazones and vinyl azides via Pd(II)-catalyzed C-H activation/cyclization/aromatization strategy has been described. A series of five- to eight-membered alicyclic[b]-fused pyridines were prepared in a one-step manner with wide substrate scope and good functional group tolerance.

Cytotoxic withanolides from the aerial parts of Tubocapsicum anomalum.

Ten new withanolides (1-10) and three artificial withanolides (11-13) were isolated from the aerial parts of Tubocapsicum anomalum, together with five known analogues (14-18). Their structures were determined on the basis of extensive spectroscopic and chemical methods. They include seven acnistin-type (1-4, 11, 14 and 15), three withajardin-type (5-7), and eight normal-type (8-10, 12, 13 and 16-18) withanolides. Of normal-type withanolides, a chemical conversion from the 16α,17α-epoxywithanolide (16) to Δ13,14-16α-hydroxywithanolide (18) was achieved by Wagner-Meerwein rearrangement. All isolates were evaluated for their cytotoxicity against four human tumor cell lines (HCT-116, HepG2, MCF-7 and A375). Among them, compounds 1-3, 6-8, 14, 16-18 showed cytotoxic activity with IC50 values of 0.24-8.71 µM.

STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype-phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one-third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI-related cancers is currently unknown but our results highlight a novel STK11 genotype-phenotype association as the basis for future genetic counseling and basic research studies.

Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells.

BACKGROUND: The Epstein-Barr virus (EBV)-encoded EB nuclear antigen 1 (EBNA1) protein is required for maintenance and transmission of the viral episome in EBV-infected cells. The objective of this study was to investigate the role of EBNA1 protein in nasopharyngeal carcinoma (NPC). METHODS: Tissue samples from 48 patients with NPC and 12 patients with chronic nasopharyngitis were subjected to immunohistochemical analysis of EBNA1 expression. EBNA1 combinational DNA was used to overexpress EBNA1 protein in NPC cell lines to assess tumor cell epithelial-mesenchymal transition (EMT), colony formation, migration and invasion, and gene expression. RESULTS: EBNA1 protein was highly expressed in NPC tissue specimens, and its expression was associated with NPC lymph node metastasis. EBNA1 expression affected NPC cell morphology and the expression of EMT markers in vitro. Furthermore, overexpression of EBNA1 inhibited the expression of microRNA 200a (miR-200a) and miR-200b and, in turn, up-regulated expression of their target genes, zinc finger E-box binding homeobox 1 ( ZEB1) and ZEB2, which are well known mediators of EMT. In addition, EBNA1-regulated miR-200a and miR-200b expression was mediated by transforming growth factor-ß1. CONCLUSIONS: The current findings provided novel insight into the vital role of EBNA1 in manipulating a molecular switch of EMT in EBV-positive NPC cells.

Ligand-controlled regiodivergent Ni-catalyzed trans-hydroboration/carboboration of internal alkynes with B2pin2.

Unprecedented regioselective trans-hydroboration and carboboration of unbiased electronically internal alkynes were realized via a nickel catalysis system with the aid of the directing group strategy. Furthermore, the excellent α- and ß-regioselectivity could be accurately switched by the nitrogen ligand (terpy) and phosphine ligand (Xantphos). Mechanistic studies provided an insight into the rational reaction process, that underwent the cis-to-trans isomerization of alkenyl nickel species. This transformation not only expands the scope of transition-metal-catalyzed boration of internal alkynes but also, more particularly, portrays the vast prospects of the directing group strategy in the selective functionalization of unactivated alkynes.

Inhibition of ACOX1 enhances the therapeutic efficacy of obeticholic acid in treating non-alcoholic fatty liver disease and mitigates its lipotoxicity.

Background and aims: High-dose Obeticholic acid exhibits promise for non-alcoholic fatty liver disease (NAFLD) treatment but can induce lipotoxicity. Our study sought to understand this mechanism and propose a solution. Approach and Results: In a non-alcoholic fatty liver disease (NAFLD) model induced by a high-fat diet in FXR-/- mice, we pinpointed that FXR regulated the expression of ACOX1 through RNA-Seq analysis. In the livers of FXR-/- mice, both ACOX1 mRNA and protein expression notably decreased. In both HL-7702 and HEP-G2 cells, the silencing of FXR through shRNA plasmids decreased ACOX1 expression, while FXR activation with GW4064 increased it. These effects were reversible with the ACOX1-specific inhibitor, 10,12-Tricosadiynoic acid. In the NAFLD model of FXR-/- mice, The activation of ACOX1 is correlated with elevated serum LDL, triglycerides, and aggravated hepatic steatosis. However, the combination of 10,12-Tricosadiynoic acid with low-dose obeticholic acid effectively treated hepatic steatosis, reducing LDL levels in the NAFLD model of wild-type mice. This combination therapy demonstrated efficacy comparable to high-dose obeticholic acid alone. Notably, the combined drug regimen treats hepatic steatosis by inhibiting the IL-1ß and α-SMA pathways in NAFLD. Conclusion: Combining ACOX1-specific inhibitors with low-dose obeticholic acid effectively treats high-fat diet-induced hepatic steatosis and reduces serum LDL. This approach enhances the therapeutic effects of obeticholic acid and mitigates its lipotoxicity by inhibiting the IL-1ß and α-SMA pathways.

AgNOx as Nitrogen Source for [1+1+3] Cycloaddition of Isocyanides with Isocyanates: Selective Synthesis of 1,2,4-Triazoles.

A novel [1+1+3] annulation of AgNOx, isocyanides, and isocyanates for the selective synthesis of 1,2,4-triazoles is presented herein. In this transformation, AgNOx and isocyanates are used as nitrogen sources instead of the traditional hydrazine or diazonium reagents. This process also involves N-O/C-H/C═N bond cleavage and the construction of new N-N/C-N bonds with a good substrate scope and functional group tolerance.

Serum Anion Gap at Admission Predicts All-Cause Mortality in Critically Ill Patients With Cirrhosis: A Retrospective Cohort Study.

INTRODUCTION: The primary objective of this study was to evaluate admission serum anion gap (AG) as a predictor of all-cause mortality in critically ill patients with cirrhosis. METHODS: A total of 3,084 cirrhotic patients were included and randomly divided into training and validation cohorts (n = 2,159 and 925, respectively). Patients were categorized into high and normal AG groups based on their AG values. Cox regression and Kaplan-Meier survival analysis were used to assess the relationships between AG levels and outcomes. RESULTS: Both cohorts showed strong parameter similarity ( P > 0.05). High AG was associated with significantly lower survival probabilities. Cox models confirmed elevated AG as a risk factor, even after adjusting for covariates (hazard ratio: 1.920, 1.793, and 1.764 for 30-day, 60-day, and hospital mortality, respectively). Subgroup analyses, especially regarding chronic kidney disease, revealed complex interactions. Serum AG displayed predictive power comparable with established scoring systems. DISCUSSION: Elevated AG at admission is a valuable predictor of poor outcomes and increased mortality risk in critically ill cirrhotic patients. Serum AG can serve as an easily accessible tool for risk assessment and prognosis evaluation in this population.

Monolayer graphene film on ZnO nanorod array for high-performance Schottky junction ultraviolet photodetectors.

A new Schottky junction ultraviolet photodetector (UVPD) is fabricated by coating a free-standing ZnO nanorod (ZnONR) array with a layer of transparent monolayer graphene (MLG) film. The single-crystalline [0001]-oriented ZnONR array has a length of about 8-11 µm, and a diameter of 100∼600 nm. Finite element method (FEM) simulation results show that this novel nanostructure array/MLG heterojunction can trap UV photons effectively within the ZnONRs. By studying the I-V characteristics in the temperature range of 80-300 K, the barrier heights of the MLG film/ZnONR array Schottky barrier are estimated at different temperatures. Interestingly, the heterojunction diode with typical rectifying characteristics exhibits a high sensitivity to UV light illumination and a quick response of millisecond rise time/fall times with excellent reproducibility, whereas it is weakly sensitive to visible light irradiation. It is also observed that this UV photodetector (PD) is capable of monitoring a fast switching light with a frequency as high as 2250 Hz. The generality of the above results suggest that this MLG film/ZnONR array Schottky junction UVPD will have potential application in future optoelectronic devices.

Specific bile acids inhibit hepatic fatty acid uptake in mice.

UNLABELLED: Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%. CONCLUSION: The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease.

Flexible CuS nanotubes-ITO film Schottky junction solar cells with enhanced light harvesting by using an Ag mirror.

Here we report the fabrication of a novel photovoltaic device based on CuS nanotubes (CuSNTs) and indium tin oxide (ITO) Schottky junctions. Large-quantity synthesis of CuSNTs was accomplished via a solution-based sacrificial template method under moderate conditions, while ITO Schottky contacts were fabricated via micro-fabrication and pulsed laser deposition (PLD). Upon light illumination, CuSNTs-ITO Schottky junctions exhibited pronounced photovoltaic behavior, giving rise to a power conversion efficiency of 1.17% on a conventional SiO(2)/Si substrate. Furthermore, by utilizing PET as the substrate, transparent and flexible CuSNTs-ITO solar cells were constructed and showed performance close to their device counterparts on a rigid substrate. Notably, it was found that the flexible devices were robust against tensile strain and could stand a bending angle up to ∼95°. To enhance the light absorption of the devices, an Ag mirror layer was deposited on the rear side of the PET substrate so as to allow multiple reflection and absorption of the incident light. As a result, the flexible devices showed a substantial performance improvement, yielding an efficiency of ∼2%. Our results demonstrate that low-cost and environmentally friendly CuSNTs-ITO solar cells are promising candidates for new-generation photovoltaic devices.

High-performance nonvolatile Al/AlO(x)/CdTe:Sb nanowire memory device.

Here we demonstrate a room temperature processed nonvolatile memory device based on an Al/AlO(x)/CdTe:Sb nanowire (NW) heterojunction. Electrical analysis shows an echelon hysteresis composed of a high-resistance state (HRS) and a low-resistance state (LRS), which can allow it to write and erase data from the device. The conductance ratio is as high as 106, with a retention time of 3 × 104 s. Moreover, the SET voltages ranged from +6 to +8 V, whilst the RESET voltage ∼0 V. In addition, flexible memory nano-devices on PET substrate with comparable switching performance at bending condition were fabricated. XPS analysis of the Al/AlO(x)/CdTe:Sb NW heterojunction after controlled Ar⁺ bombardment reveals that this memory behavior is associated with the presence of ultra-thin AlO(x) film. This Al/AlO(x)/CdTe:Sb NW heterojunction will open up opportunities for new memory devices with different configurations.

Fabrication of p-type ZnSe:Sb nanowires for high-performance ultraviolet light photodetector application.

p-type ZnSe nanowires (NWs) with tunable electrical conductivity were fabricated on a large scale by evaporating a mixed powder composed of ZnSe and Sb in different ratios. According to the structural characterization, the Sb-doped ZnSe NWs are of single crystalline form and grow along the [001] direction. The presence of Sb in the ZnSe NWs was confirmed by XPS spectra. Electrical measurement of a single ZnSe:Sb NW based back-gate metal-oxide field-effect-transistor reveals that all the doped NWs exhibit typical p-type conduction characteristics, and the conductivity can be tuned over eight orders of magnitude, from 6.36 × 10(-7) S cm(-1) for the undoped sample to ∼37.33 S cm(-1) for the heavily doped sample. A crossed p-n nano-heterojunction photodetector made from the as-doped nanostructures displays pronounced rectification behavior, with a rectification ratio as high as 10(3) at ±5 V. Remarkably, it exhibits high sensitivity to ultraviolet light illumination with good reproducibility and quick photoresponse. Finally, the work mechanism of such a p-n junction based photodetector was elucidated. The generality of the above result suggests that the as-doped p-type ZnSe NWs will find wide application in future optoelectronics devices.

Identification of potential feature genes in non-alcoholic fatty liver disease using bioinformatics analysis and machine learning strategies.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and NAFLD-associated hepatocellular carcinoma (HCC) has continuously increased in recent years. Machine learning is an effective method for screening the feature genes of a disease for prediction, prevention and personalized treatment. Here, we used the "limma" package and weighted gene co-expression network analysis (WGCNA) to screen 219 NAFLD-related genes and found that they were mainly enriched in inflammation-related pathways. Four feature genes (AXUD1, FOSB, GADD45B, and SOCS2) were screened by LASSO regression and support vector machine-recursive feature elimination (SVM-RFE) machine learning algorithms. Therefore, a clinical diagnostic model with an area under the curve (AUC) value of 0.994 was constructed, which was superior to other indicators of NAFLD. Significant correlations existed between feature genes expression and steatohepatitis histology or clinical variables. These findings were also validated in external datasets and a mouse model. Finally, we found that feature genes expression was significantly decreased in NAFLD-associated HCC and that SOCS2 may be a prognostic biomarker. Our findings may provide new insights into the diagnosis, prevention and treatment targets of NAFLD and NAFLD-associated HCC.

Perivascular epithelioid cell tumors of the liver misdiagnosed as hepatocellular carcinoma: Three case reports.

BACKGROUND: Hepatic perivascular epithelioid cell neoplasms (PEComas) are rare. Diagnostic and treatment experience with hepatic PEComa remains insufficient. CASE SUMMARY: Three hepatic PEComa cases are reported in this paper: One case of primary malignant hepatic PEComa, one case of benign hepatic PEComa, and one case of hepatic PEComa with an ovarian mature cystic teratoma. During preoperative imaging and pathological assessment of intraoperative frozen samples, patients were diagnosed with hepatocellular carcinoma (HCC), while postoperative pathology and immunohistochemistry subsequently revealed hepatic PEComa. Patients with hepatic PEComa which is misdiagnosed as HCC often require a wider surgical resection. It is easy to mistake them for distant metastases of hepatic PEComa and misdiagnosed as HCC, especially when it's combined with tumors in other organs. Three patients eventually underwent partial hepatectomy. After 1-4 years of follow-up, none of the patients experienced recurrence or metastases. CONCLUSION: A clear preoperative diagnosis of hepatic PEComa can reduce the scope of resection and prevent unnecessary injuries during surgery.

Risk factors for the development of sepsis in patients with cirrhosis in intensive care units.

Sepsis is a serious complication of liver cirrhosis. This study aimed to develop a risk prediction model for sepsis among patients with liver cirrhosis. A total of 3130 patients with liver cirrhosis were enrolled from the Medical Information Mart for Intensive Care IV database, and randomly assigned into training and validation cohorts in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) regression was used to filter variables and select predictor variables. Multivariate logistic regression was used to establish the prediction model. Based on LASSO and multivariate logistic regression, gender, base excess, bicarbonate, white blood cells, potassium, fibrinogen, systolic blood pressure, mechanical ventilation, and vasopressor use were identified as independent risk variables, and then a nomogram was constructed and validated. The consistency index (C-index), receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA) were used to measure the predictive performance of the nomogram. As a result of the nomogram, good discrimination was achieved, with C-indexes of 0.814 and 0.828 for the training and validation cohorts, respectively, and an area under the curve of 0.849 in the training cohort and 0.821 in the validation cohort. The calibration curves demonstrated good agreement between the predictions and observations. The DCA curves showed the nomogram had significant clinical value. We developed and validated a risk-prediction model for sepsis in patients with liver cirrhosis. This model can assist clinicians in the early detection and prevention of sepsis in patients with liver cirrhosis.

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter.

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose. Thus, it is an excellent model to probe the relationship between substructures and bioavailability. Here, we proposed the concept of "nonbioavailable substructures", referring to substructures that are unfavorable to bioavailability. A machine learning model was developed to identify nonbioavailable substructures based on their molecular properties and shows the accuracy of 83.5%. A more potent SERT inhibitor DH4 was discovered with a bioavailability of 83.28% in rats by replacing the nonbioavailable substructure of approved drug vilazodone. DH4 exhibits promising anti-depression efficacy in animal experiments. The concept of nonbioavailable substructures may open up a new venue for the improvement of drug bioavailability.

Decaprenyl Diphosphate Synthase Subunit 1 (PDSS1): A Potential Prognostic Biomarker and Immunotherapy-Target for Hepatocellular Carcinoma.

Purpose: PDSS1 (decaprenyl diphosphate synthase subunit 1) plays an important role in the progression of several types of tumor. However, the biological functions of PDSS1 remain unclear in patients with hepatocellular carcinoma (HCC). In this study, We attempted to determine the role of PDSS1 in predicting the survival and efficacy of immunotherapy for HCC patients. Methods: We analyzed the expression of PDSS1 in pan-cancer by Tumor Immune Estimation Resource (TIMER) and UALCAN database. Next, we investigated the correlations between the expression and potential prognostic value of PDSS1 in pan-cancer by Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter and further confirmed our finding in our study of 139 patients with HCC. Furthermore, we correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules in HCC tissue by TIMER. Finally, its potential immune-related mechanism was explored by Gene Set Enrichment Analysis (GSEA). Results: Multiple datasets demonstrate that PDSS1 is up-regulated in HCC tissues compared with adjacent tissues, which was validated at mRNA (databases) and protein levels (our cohort). Patients with higher PDSS1 expression had shorter overall survival and relapse-free survival. In addition, PDSS1 expression was positively related to early recurrence and served as an independent poor prognostic factor for HCC. Patients with higher PDSS1 expression had lower CD8+ T cells in HCC tissue, and PDSS1 deteriorates T cell exhaustion by promoting T cell surface inhibitory receptors' secretion and immunosuppressive cell proliferation. Furthermore, PDSS1 was positively correlated with the WNT, TGFß, VEGF, and other signaling pathways in HCC. Conclusion: PDSS1 is a potential prognostic biomarker and immunotherapy target for hepatocellular carcinoma.

Prolonged activated partial thromboplastin time predicts poor short-term prognosis in patients with acute pancreatitis: A retrospective cohort study.

It is unclear whether activated partial thromboplastin time (APTT) is predictive of survival in patients with acute pancreatitis (AP). Our study aimed to investigate the relationship between APTT and short-term prognosis in AP. From the Medical Information Mart for Intensive Care (MIMIC)-IV database, a total of 844 patients with AP were randomly divided into the training cohort (n = 591) and the validation cohort (n = 253) at a ratio of 7:3. Based on their APTT values, the patients were divided into the normal and high groups. The primary outcome of this study was 30- and 60-day survival. Kaplan-Meier survival analysis and Cox regression models were used to analyze associations between groups and outcomes. The training and validation cohort matched well on all parameters (p > 0.05). In terms of 30- and 60-day survival, Kaplan-Meier survival curves from both training and validation cohorts demonstrated a lower survival probability for patients in the high APTT group than the normal group (log-rank p < 0.05). In the training cohort, patients in the high APTT group had a statistically significantly higher risk of death than those in the normal group after controlling for possible confounders in Cox regression (p < 0.05). For the high APTT group, the hazard ratios (95% confidence interval [CI]) were 1.63 (95% CI 1.10, 2.61, p = 0.035) and 1.49 (95% CI 1.01, 2.38, p = 0.041), respectively. APTT performed as well as BISAP, Ranson, and APACHE II models in predicting 30- and 60-day survival in patients with AP. The results above have been verified in the validation cohort. Prolonged APTT in patients with AP may increase the risk of short-term death.