Effect of trace element mixtures on the outcome of patients with esophageal squamous cell carcinoma: a prospective cohort study in Fujian, China.

BACKGROUND: The evidence about the effects of trace elements on overall survival(OS) of patients with esophageal squamous cell carcinoma(ESCC) is limited. This study aims to evaluate mixed effects of plasma trace elements on OS of ESCC. METHODS: This prospective cohort analysis included 497 ESCC patients with a median follow-up of 52.3 months. The concentrations of 17 trace elements were measured. We fitted Cox's proportional hazards regression, factor analysis and Bayesian kernel machine regression (BKMR) models to estimate the association between trace elements and OS. RESULTS: Our analysis found that in the single-element model, Co, Ni, and Cd were associated with an increased risk of death, while Ga, Rb, and Ba were associated with a decreased risk. Cd had the strongest risk effect among all elements. As many elements were found to be mutually correlated, we conducted a factor analysis to identify common factors and investigate their associations with survival time. The factor analysis indicated that the factor with high factor loadings in Ga, Ba and B was linked to a decreased risk of death, while the factor with high factor loadings in Co, Ti, Cd and Pb was associated with a borderline significantly increased risk. Using BKMR analysis to disentangle the interaction between elements in significant factors, we discovered that Ga interacted with Ba and both elements had U-shaped effects with OS. Cd, on the other hand, had no interaction with other elements and independently increased the risk of death. CONCLUSIONS: Our analysis revealed that Ga, Ba and Cd were associated with ESCC outcome, with Ga and Ba demonstrating an interaction. These findings provide new insights into the impact of trace elements on the survival of patients with ESCC.

Improvement of postoperative quality of life in patients with esophageal squamous cell carcinoma: does tea consumption have a role?

BACKGROUND: To investigate the effect of tea consumption on the improvement of postoperative quality of life in male patients with esophageal squamous cell carcinoma (ESCC). METHODS: The quality of life information of 290 male patients with ESCC was collected. The time to deterioration and the number of events in each area of quality of life was calculated by time-to-deterioration (TTD) model. The association between postoperative tea drinking and postoperative quality of life in male ESCC patients was investigated using the Cox proportional risk model. RESULTS: Postoperative tea-drinking patients experienced delayed TTD in multiple domains, including general health, physical, role, emotional, and cognitive function, fatigue, nausea and vomiting, dyspnea, loss of appetite, constipation, diarrhea, eating problems, difficulty swallowing, choking while swallowing saliva, dry mouth, taste difficulties, coughing, and speech problems. The multivariate Cox regression analysis showed that drinking tea after surgery improved quality of life, including physical function (HR = 0.722, 95% CI: 0.559-0.933), role function (HR = 0.740, 95% CI: 0.557-0.983), eating problems (HR = 0.718, 95% CI: 0.537-0.960), odynophagia (HR = 0.682, 95% CI: 0.492-0.945), trouble swallowing saliva (HR = 0.624, 95% CI: 0.444-0.877), coughing (HR = 0.627, 95% CI: 0.442-0.889) and speech problems (HR = 0.631, 95% CI: 0.441-0.903). Furthermore, the improvement was more significant in patients who drank tea before surgery and continued to drink tea after surgery. CONCLUSIONS: Postoperative tea drinking had a positive effect on delay in clinical deterioration and improvements in multiple functions and symptoms associated with ESCC in men.

Deoxyshikonin inhibits cisplatin resistance of non-small-cell lung cancer cells by repressing Akt-mediated ABCB1 expression and function.

Drug resistance is a large challenge for the treatment of non-small-cell lung cancer (NSCLC). Deoxyshikonin is the naphthoquinol compound with anticancer activity. However, the role and mechanism of deoxyshikonin in cisplatin resistance of NSCLC remain poorly understood. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Cell apoptosis was evaluated by flow cytometry and caspase-3 activity. We found that cisplatin-resistant A549/cis and H1299/cis cells had higher cisplatin resistance than A549 and H1299 cells, respectively. Deoxyshikonin contributed to cisplatin-induced viability inhibition and apoptosis in A549/cis and H1299/cis cells. Moreover, deoxyshikonin inhibited phosphorylation of Akt and the expression and function of ATP-binding cassette subfamily B member 1 (ABCB1). Activation of protein kinase B (Akt) pathway attenuated the effect of deoxyshikonin on cisplatin resistance and ABCB1 expression and function in A549/cis and H1299/cis cells. In conclusion, deoxyshikonin suppressed cisplatin resistance in cisplatin-resistant NSCLC cells by repressing Akt signaling-mediated ABCB1 expression.

Leptin mediates the effects of melatonin on female reproduction in mammals.

Melatonin is a natural molecule produced in the pineal gland and other tissues. It participates in numerous biological activities including the regulation of reproduction. However, the mechanism by which melatonin affects mammalian female reproductive performance is not fully investigated. In the present study, it was observed that melatonin positively regulated the level of leptin in female mouse and pig. To understand the potential association between melatonin and leptin on the female reproductive activities, the melatonin receptor 1 MT1 knockout (MT1-/- ) mouse and Leptin knockout (Leptin-/- ) pig were created. It was found that the deficiency of M T1 caused low leptin secretion and litter size in mouse. Meanwhile, the deletion of leptin in pig did not affect melatonin production, but significantly reduced follicle-stimulating hormone, estradiol-17ß (E2), and Luteinizing hormone and increased progesterone (P) at estrum stage, which also led to smaller litter size than that in control. Melatonin treatment increased the production of leptin in pigs, while the supplementary of leptin was also able to improve the ovulation number, polar body rates, and expression of StAR in MT1-/- females. Therefore, it is first time, we described that leptin is the downstream target of melatonin in regulating female reproduction. These findings provide the novel information on the physiology of melatonin in animal reproduction.

Potential Metabolic Activation of a Representative C2-Alkylated Polycyclic Aromatic Hydrocarbon 6-Ethylchrysene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells.

Exposure to polycyclic aromatic hydrocarbons (PAHs) is the major human health hazard associated with the Deepwater Horizon oil spill. C2-Chrysenes are representative PAHs present in crude oil and could contaminate the food chain. We describe the metabolism of a C2-chrysene regioisomer, 6-ethylchrysene (6-EC), in human HepG2 cells. The structures of the metabolites were identified by HPLC-UV-fluorescence detection and LC-MS/MS. 6-EC-tetraol isomers were identified as signature metabolites of the diol-epoxide pathway. O-Monomethyl-O-monosulfonated-6-EC-catechol, its monohydroxy products, and N-acetyl-l-cysteine(NAC)-6-EC-ortho-quinone were discovered as signature metabolites of the ortho-quinone pathway. Potential dual metabolic activation of 6-EC involving the formation of bis-electrophiles, i.e., a mono-diol-epoxide and a mono-ortho-quinone within the same structure, bis-diol-epoxides, and bis-ortho-quinones was observed as well. The identification of 6-EC-tetraol, O-monomethyl-O-monosulfonated-6-EC-catechol, its monohydroxy products, and NAC-6-EC-ortho-quinone supports potential metabolic activation of 6-EC by P450 and AKR enzymes followed by metabolic detoxification of the ortho-quinone through interception of its redox cycling capability by catechol-O-methyltransferase and sulfotransferase enzymes. The tetraols and catechol conjugates could be used as biomarkers of human exposure to 6-EC resulting from oil spills.

A novel mitochondrial membrane protein, Ohmm, limits fungal oxidative stress resistance and virulence in the insect fungal pathogen Beauveria bassiana.

The Hog1 mitogen-activated protein (MAP) kinase regulates environmental stress responses and virulence in the entomopathogenic fungus Beauveria bassiana. To further characterize this pathway, we constructed a subtraction library enriched for genes regulated by Hog1. One targeted gene, encoding a novel membrane protein, Ohmm (oxidative homeostasis membrane-protein-mitochondria), was uniquely identified as being downregulated in the ΔHog1 background during growth under non-stress and osmotic stress conditions, but upregulated under oxidative stress. Ohmm was an experimentally validated flavin-binding protein and targeted to the mitochondria. Deletion of Ohmm resulted in increased oxidative stress resistance, whereas overexpression caused an opposite phenotype. The ΔOhmm showed accumulation of reactive oxygen species with alterations in cell wall composition and compatible solute accumulation evident as compared with the wild type parent. Conidiation was reduced > 80%; however, conidia produced by the ΔOhmm strain germinated significantly faster than wild type cells. Insect bioassays using the greater wax moth revealed increased virulence for the ΔOhmm strain in both topical and intrahemocoel injection assays, indicating a negative effect of the presence of Ohmm with respect to pathogenesis. As predicted from our characterization, deletion of Ohmm in a ΔHog1 background rescued its oxidative sensitivity phenotype, confirming that Ohmm acts downstream of the Hog1 MAP-kinase.

Metabolism of a representative oxygenated polycyclic aromatic hydrocarbon (PAH) phenanthrene-9,10-quinone in human hepatoma (HepG2) cells.

Exposure to polycyclic aromatic hydrocarbons (PAHs) in the food chain is the major human health hazard associated with the Deepwater Horizon oil spill. Phenanthrene is a representative PAH present in crude oil, and it undergoes biological transformation, photooxidation, and chemical oxidation to produce its signature oxygenated derivative, phenanthrene-9,10-quinone. We report the downstream metabolic fate of phenanthrene-9,10-quinone in HepG2 cells. The structures of the metabolites were identified by HPLC-UV-fluorescence detection and LC-MS/MS. O-mono-Glucuronosyl-phenanthrene-9,10-catechol was identified, as reported previously. A novel bis-conjugate, O-mono-methyl-O-mono-sulfonated-phenanthrene-9,10-catechol, was discovered for the first time, and evidence for both of its precursor mono conjugates was obtained. The identities of these four metabolites were unequivocally validated by comparison to authentic enzymatically synthesized standards. Evidence was also obtained for a minor metabolic pathway of phenanthrene-9,10-quinone involving bis-hydroxylation followed by O-mono-sulfonation. The identification of 9,10-catechol conjugates supports metabolic detoxification of phenanthrene-9,10-quinone through interception of redox cycling by UGT, COMT, and SULT isozymes and indicates the possible use of phenanthrene-9,10-catechol conjugates as biomarkers of human exposure to oxygenated PAH.

Removal of Pb (II) and Zn (II) in the mineral beneficiation wastewater by using cross-linked carboxymethyl starch-g-methacrylic acid as an effective flocculant.

The cross-linked carboxymethyl starch-g-methacrylic acid (CCMS-g-MAA) was prepared by using grafting and micro-cross-linking in the one-pot preparation process. CCMS-g-MAA presented high removal capacity of Pb (II) of 57.13 mg/g at pH = 4 and high removal capacity of Zn (II) of 51.41 mg/g at pH = 5 by using a sample dosage of 0.68 g/L. Characterization results of FTIR, TG, and XRD illustrate that methacrylic acid and sodium tri-metaphosphate were successfully introduced into the structure of carboxymethyl starch. SEM characterization presented that the sample particles were amorphous aggregates with surface voids, which was favorable for the adsorption of heavy metal ions from wastewater. Adsorption isotherm results indicated that Freundlich equation could be better used to describe the adsorption process of metal ions on CCMS-g-MAA. The adsorption kinetic results indicated that the pseudo-second-order model is more suitable to describe this removal process. XPS results indicated that metal ions interacted with functional groups on the surface of flocculant, especially carboxyl groups. The removal process may be purposed that metal ions were adsorbed by porous material, and then combined with surface functional groups of the flocculant via electrostatic interaction, chelation or ion exchange. Subsequently, metal ions were separated from the wastewater with flocs precipitated in the bottom of solution via bridging and patching. The obtained results illustrated that CCMS-g-MAA was an effective material for the treatment of wastewater containing polymetallic ions besides mineral beneficiation wastewater supported by its excellent regeneration.

Cellular uptake and antiproliferative effects of 11-oxo-eicosatetraenoic acid.

Cyclooxygenases (COX) metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETE), which can then be oxidized by dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH), to oxo-eicosatetraenoic acids (ETE). We have previously established that 11-oxo-eicosatetraenoic acid (oxo-ETE) and 15-oxo-ETE are COX-2/15-PGDH-derived metabolites. Stable isotope dilution (SID) chiral liquid chromatography coupled with electron capture atmospheric pressure chemical ionization (ECAPCI) single reaction monitoring (SRM) MS has been used to quantify uptake of 11-oxo-ETE and 15-oxo-ETE in both LoVo cells and human umbilical vein endothelial cells (HUVEC). Intracellular 11-oxo- and 15-oxo-ETE concentrations reached maximum levels within 1 h and declined rapidly, with significant quantitative differences in uptake between the LoVo cells and the HUVECs. Maximal intracellular concentrations of 11-oxo-ETE were 0.02 ng/4 × 105 cells in the LoVo cells and 0.58 ng/4 × 105 cells in the HUVECs. Conversely, maximal levels of 15-oxo-ETE were 0.21 ng/4 × 105 in the LoVo cells and 0.01 ng/4 × 105 in the HUVECs. The methyl esters of both 11-oxo- and 15-oxo-ETE increased the intracellular concentrations of the corresponding free oxo-ETEs by 3- to 8-fold. 11-oxo-ETE, 15-oxo-ETE, and their methyl esters inhibited proliferation in both HUVECs and LoVo cells at concentrations of 2-10 µM, with 11-oxo-ETE methyl ester being the most potent inhibitor. Cotreatment with probenecid, an inhibitor of multiple drug resistance transporters (MRP)1 and 4, increased the antiproliferative effect of 11-oxo-ETE methyl ester in LoVo cells and increased the intracellular concentration of 11-oxo-ETE from 0.05 ng/4 × 105 cells to 0.18 ng/4 × 105 cells. Therefore, this study has established that the COX-2/15-PGDH-derived eicosanoids 11-oxo- and 15-oxo-ETE enter target cells, that they inhibit cellular proliferation, and that their inhibitory effects are modulated by MRP exporters.

Postoperative performance of the Quartet® left ventricular heart lead.

INTRODUCTION: The Quartet(®) left ventricular (LV) lead is the first with 4 pacing electrodes (tip and 3 rings) that enables pacing from 10 different pacing vectors. Postoperative performance of this lead was evaluated in a prospective, nonrandomized, multicenter IDE study. METHODS: Patients with standard indications for CRT-D were enrolled. Electrical performance and presence of phrenic nerve stimulation (PNS) were assessed during pacing from each of 10 vectors at predischarge (within 7 days), 1 month, and 3 months postimplant. RESULTS: The Quartet LV lead was implanted successfully in 170 patients (95.5% implant success rate, 68 ± 11 years, 68.5% male, LVEF: 25 ± 7%, NYHA class III: 98.3% and class IV: 1.7%). Mean follow-up was 4.7 ± 1.9 months. Capture threshold and impedance for each of the 10 LV lead pacing vectors remained stable during follow-up. LV lead dislodgement occurred in 6 (3.5%) patients and PNS was observed in 23 (13.5%) patients. PNS was resolved noninvasively in all 23 (100%) patients, either by reprogramming to pace from the additional LV lead pacing vectors alone (13 pts, 56.5%), reprogramming to pace from the additional LV lead pacing vectors and reprogramming pacing output (4 pts, 17.4%), or by reprogramming pacing output alone (6 pts, 26.1%). CONCLUSIONS: The Quartet LV lead electrical performance was stable and was associated with a high implant success and low dislodgement rate during 3-month follow-up. In all patients with PNS, the 10 pacing vectors combined with reduced output programming enabled the elimination of PNS noninvasively.

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: impact on functional activity and selectivity for dopamine D2/D3 receptors.

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.

Pressure-induced pseudoatom bonding collapse and isosymmetric phase transition in Zr2Cu: first-principles predictions.

The structural evolution of tetragonal Zr2Cu has been investigated under high pressures up to 70 GPa by means of density functional theory. Our calculations predict a pressure-induced isosymmetric transition where the tetragonal symmetry (I4/mmm) is retained during the entire compression as well as decompression process while its axial ratio (c/a) undergoes a transition from ~3.5 to ~4.2 at around 35 GPa with a hysteresis width of about 4 GPa accompanied by an obvious volume collapse of 1.8% and anomalous elastic properties such as weak mechanical stability, dramatically high elastic anisotropy, and low Young's modulus. Crystallographically, the tetragonal axial ratio shift renders this transition analogous to a simple bcc-to-fcc structural transition, which implies it might be densification-driven. Electronically, the ambient Zr2Cu is uncovered with an intriguing pseudo BaFe2As2-type structure, which upon the phase transition undergoes an electron density topological change and collapses to an atomic-sandwich-like structure. The pseudo BaFe2As2-type structure is demonstrated to be shaped by hybridized dxz + yz electronic states below Fermi level, while the high pressure straight Zr-Zr bonding is accommodated by electronic states near Fermi level with dx(2) - y(2) dominant features.

Adsorption of Pb (II) and Cu (II) by magnetic beads loaded with xanthan gum.

Green and environmentally friendly and efficient separation adsorbents have attracted much attention in the treatment of heavy metal ions wastewater. In this study, xanthan gum (XG) was supported by fly ash magnetic beads (FAMB) to prepare adsorbent XG@FAMB. The effects of XG@FAMB dosage, pH value of the solution, adsorption time, and initial Pb (II) and Cu (II) concentration on its adsorption performance for Pb (II) and Cu (II) were investigated. The results show that under the conditions of pH 6, dosage of XG@FAMB 4.0 g/L, adsorption time 120 min, and initial concentration 60 mg/L, the maximum adsorption capacity of XG@FAMB for Pb (II) and Cu (II) was 14.93 mg/g and 14.88 mg/g, respectively. The adsorption process of Pb (II) and Cu (II) by XG@FAMB could be better described by the quasi-second-order kinetic model and Langmuir isothermal adsorption model, that is, the adsorption process is monolayer adsorption controlled by chemical action. The adsorption mechanism is that Pb (II) and Cu (II) coordinate with oxygen-containing functional groups hydroxyl and carboxyl on XG@FAMB surface, accompanied by electrostatic adsorption. XG@FAMB has the advantages of environmental protection of XG and easy solid-liquid separation of FAMB, and has a good removal effect on Pb (II) and Cu (II).

Association between the Preoperative Dietary Antioxidant Index and Postoperative Quality of Life in Patients with Esophageal Squamous Cell Carcinoma: A Prospective Study Based on the TTD Model.

OBJECTIVE: Dietary antioxidants are associated with risk of death in cancer patients, and they were used to evaluate the prognosis of cancer patients. Dietary antioxidant index (DAI) can be used to evaluate dietary antioxidant content comprehensively; this study aimed to investigate the effect of preoperative DAI on health-related quality of life in patients with esophageal cell squamous carcinoma (ESCC). METHODS: Data on dietary intakes were collected using a validated food-frequency questionnaire (FFQ). DAI was calculated for all study participants based on FFQ data of each participant. The study involved conducting several follow-up activities with patients diagnosed with ESCC to evaluate their quality of life. The approach employed in the study was to conduct a telephone interview. The EORTC Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30, version 3.0) and the Esophageal Cancer Module (EORTC QLQ-OES18) were used to collect data on the quality of life of the patients; all patients completed the full follow-up. RESULTS: This prospective study was performed on 376 participants who were recruited from Fujian Cancer Hospital and First Hospital of Fujian Medical University. They all were diagnosed with ESCC. The results indicated that the time to deterioration of global health status (p = 0.043), cognitive functioning (p = 0.031), dry mouth (p = 0.019), and speech problems (p = 0.031) significantly delay in the high DAI group. Univariate and multivariate Cox regression analysis showed that global health status (HR = 0.718, 95% CI: 0.532-0.969), cognitive functioning (HR = 0.641, 95% CI: 0.450-0.913), dry mouth (HR = 0.637, 95% CI: 0.445-0.911), and speech problems (HR = 0.651, 95% CI: 0.449-0.945) were improved in the high DAI group. CONCLUSIONS: Prognostic value of preoperative DAI was significant for patients with ESCC who undergo surgical intervention. Its level was positively correlated with the postoperative quality of life of patients, which can delay and improve the occurrence of postoperative physical function and symptom deterioration.

lncRNA XIST knockdown suppresses cell proliferation and promotes apoptosis in diabetic cataracts through the miR­34a/SMAD2 axis.

According to emerging evidence, long non­coding RNAs (lncRNAs) play critical roles in diabetes. The aim of the present study was to investigate the role and mechanism of X­inactive specific transcript (XIST) in cell proliferation, migration and apoptosis in diabetic cataracts (DC). SRA01/04 lens epithelial cells were treated with high glucose (HG). The levels of XIST, microRNA (miR)­34a and SMAD family member 2 (SMAD2) were examined via reverse transcription­quantitative PCR. MTT, Transwell, wound healing and TUNEL assays were performed to examine cell proliferation, invasion, migration and apoptosis, respectively. The interaction between miR­34a and XIST or SMAD2 was verified by luciferase reporter assay. It was found that the expression of XIST was increased and that of miR­34a was decreased in DC tissues and HG­treated SRA01/04 cells. XIST knockdown or miR­34a overexpression attenuated cell proliferation and migration, and induced apoptosis in HG­treated SRA01/04 cells. XIST targeted miR­34a and regulated DC progression through miR­34a. SMAD2 was identified as a target gene of miR­34a and was positively modulated by XIST. XIST knockdown inhibited cell proliferation and migration, and accelerated apoptosis in HG­stimulated SRA01/04 cells, and these effects were abrogated by SMAD2 overexpression. In conclusion, XIST promoted cell proliferation, migration and invasion, and inhibited apoptosis, through the miR­34a/SMAD2 axis in DC.

Exploring and applying genes to enhance the resistance to Fusarium head blight in wheat.

Fusarium head blight (FHB) is a destructive disease in wheat worldwide. Fusarium graminearum species complex (FGSC) is the main causal pathogen causing severe damage to wheat with reduction in both grain yield and quality. Additionally, mycotoxins produced by the FHB pathogens are hazardous to the health of human and livestock. Large numbers of genes conferring FHB resistance to date have been characterized from wheat and its relatives, and some of them have been widely used in breeding and significantly improved the resistance to FHB in wheat. However, the disease spreads rapidly and has been severe due to the climate and cropping system changes in the last decade. It is an urgent necessity to explore and apply more genes related to FHB resistant for wheat breeding. In this review, we summarized the genes with FHB resistance and mycotoxin detoxication identified from common wheat and its relatives by using forward- and reverse-genetic approaches, and introduced the effects of such genes and the genes with FHB resistant from other plant species, and host-induced gene silencing (HIGS) in enhancing the resistance to FHB in wheat. We also outlined the molecular rationale of the resistance and the application of the cloned genes for FHB control. Finally, we discussed the future challenges and opportunities in this field.

Development and Validation of a Prognostic Model for Esophageal Adenocarcinoma Based on Necroptosis-Related Genes.

Necroptosis is a newly developed cell death pathway that differs from necrosis and apoptosis; however, the potential mechanism of necroptosis-related genes in EAC and whether they are associated with the prognosis of EAC patients remain unclear. We obtained 159 NRGs from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and performed differential expression analysis of the NRGs in 9 normal samples and 78 EAC tumor samples derived from The Cancer Genome Atlas (TCGA). Finally, we screened 38 differentially expressed NRGs (DE-NRGs). The results of the GO and KEGG analyses indicated that the DE-NRGs were mainly enriched in the functions and pathways associated with necroptosis. Protein interaction network (PPI) analysis revealed that TNF, CASP1, and IL-1B were the core genes of the network. A risk score model based on four DE-NRGs was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) regression, and the results showed that the higher the risk score, the worse the survival. The model achieved more efficient diagnosis compared with the clinicopathological variables, with an area under the receiver operating characteristic (ROC) curve of 0.885. The prognostic value of this model was further validated using Gene Expression Omnibus (GEO) datasets. Gene set enrichment analyses (GSEA) demonstrated that several metabolism-related pathways were activated in the high-risk population. Single-sample GSEA (ssGSEA) provided further confirmation that this prognostic model was remarkably associated with the immune status of EAC patients. Finally, the nomogram map exhibited a certain prognostic prediction efficiency, with a C-index of 0.792 and good consistency. Thus, the prognostic model based on four NRGs could better predict the prognosis of EAC and help to elucidate the mechanism of necroptosis-related genes in EAC, which can provide guidance for the target prediction and clinical treatment of EAC patients.

11-Oxoeicosatetraenoic acid is a cyclooxygenase-2/15-hydroxyprostaglandin dehydrogenase-derived antiproliferative eicosanoid.

Previously, we established that 11(R)-hydroxy-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (HETE) was a significant cyclooxygenase (COX)-2-derived arachidonic acid (AA) metabolite in epithelial cells. Stable isotope dilution chiral liquid chromatography (LC)-electron capture atmospheric pressure chemical ionization (ECAPCI)/mass spectrometry (MS) was used to quantify COX-2-derived eicosanoids in the human colorectal adenocarcinoma (LoVo) epithelial cell line, which expresses both COX-2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 11(R)-HETE secretion reached peak concentrations within minutes after AA addition before rapidly diminishing, suggesting further metabolism had occurred. Surprisingly, recombinant 15-PGDH, which is normally specific for oxidation of eicosanoid 15(S)-hydroxyl groups, was found to convert 11(R)-HETE to 11-oxo-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (ETE). Furthermore, LoVo cell lysates converted 11(R)-HETE to 11-oxo-ETE and inhibition of 15-PGDH with 5-[[4-(ethoxycarbonyl)phenyl]azo]-2-hydroxy-benzeneacetic acid (CAY10397) (50 µM) significantly suppressed endogenous 11-oxo-ETE production with a corresponding increase in 11(R)-HETE. These data confirmed COX-2 and 15-PGDH as enzymes responsible for 11-oxo-ETE biosynthesis. Finally, addition of AA to the LoVo cells resulted in rapid secretion of 11-oxo-ETE into the media, reaching peak levels within 20 min of starting the incubation. This was followed by a sharp decrease in 11-oxo-ETE levels. Glutathione (GSH) S-transferase (GST) was found to metabolize 11-oxo-ETE to the 11-oxo-ETE-GSH (OEG)-adduct in LoVo cells, as confirmed by LC-MS/MS analysis. Bromodeoxyuridine (BrdU)-based cell proliferation assays in human umbilical vein endothelial cells (HUVECs) revealed that the half-maximal inhibitory concentration (IC(50)) of 11-oxo-ETE for inhibition of HUVEC proliferation was 2.1 µM. These results show that 11-oxo-ETE is a novel COX-2/15-PGDH-derived eicosanoid, which inhibits endothelial cell proliferation with a potency that is similar to that observed for 15d-PGJ(2).

TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway.

Transmembrane protein (TMEM) is a family of protein that spans cytoplasmic membranes and allows cell-cell and cell-environment communication. Dysregulation of TMEMs has been observed in multiple cancers. However, little is known about TMEM116 in cancer development. In this study, we demonstrate that TMEM116 is highly expressed in non-small-cell lung cancer (NSCLC) tissues and cell lines. Inactivation of TMEM116 reduced cell proliferation, migration and invasiveness of human cancer cells and suppressed A549 induced tumor metastasis in mouse lungs. In addition, TMEM116 deficiency inhibited PDK1-AKT-FOXO3A signaling pathway, resulting in accumulation of TAp63, while activation of PDK1 largely reversed the TMEM116 deficiency induced defects in cancer cell motility, migration and invasive. Together, these results demonstrate that TMEM116 is a critical integrator of oncogenic signaling in cancer metastasis.

The effects of intrinsic apoptosis on cystogenesis in PKD1-deficient ADPKD pig model.

BACKGROUND: Apoptosis is a form of cell death that plays a critical role in the maintenance of tissue homeostasis involving the development and elimination of unwanted cells. Dysregulation of apoptosis appears to be associated in the pathogenesis of many human diseases. Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease and is mainly caused by mutations in PKD1. Previous studies proved that increased cell death occurred in ADPKD patients and animal models. However, the role of apoptosis in kidney cystogenesis is not clear. METHODS: In current study, due to the high similarities between human and pig, PKD1-deficient (PKD1+/-) pigs and PKD1-knockdown (PKD1KD) pig kidney epithelial cells were used to investigate the mechanisms of apoptosis in driving cystogenesis. RESULTS: In PKD1+/- pigs, increased intrinsic and extrinsic apoptosis were found at ages of 1 month and 3 months, whereas the autophagy and pyroptosis were not altered. Meanwhile, the intrinsic apoptosis was activated along with untouched extrinsic apoptosis in PKD1KD pig kidney cells. Thus, the intrinsic apoptosis played important roles in cystogenesis. CONCLUSIONS: This work provides detail analysis of the roles of different cell death types during cystogenesis in ADPKD pig model. The results suggested a potential new strategy for the diagnosis and treatment of ADPKD by targeting intrinsic apoptosis.