Combination of Epicardial Adipose Tissue and Left Atrial Low-Voltage Areas Predicting Atrial Fibrillation Recurrence after Radiofrequency Ablation.

INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia, with radiofrequency catheter ablation (RFCA) being first-line therapy. However, the high rate of post-ablation recurrence necessitates the identification of predictors for recurrence risk. Left atrial low-voltage areas (LA-LVASs), reflecting atrial fibrosis, have been confirmed to be related to recurrence of AF. Recently, epicardial adipose tissue (EAT) has been studied due to its role in initiating and maintaining AF. In this study, we try to evaluate the significance of the combined use of left atrial epicardial adipose tissue (LA-EAT) and percentage of LA-LVAs (LA-LVAs%) for predicting the recurrence of AF. METHODS: A total of 387 patients with AF who had undergone RFCA for the first time were followed up for 1, 3, 6, and 12 months. They were divided into two groups: the recurrence group (n = 90) and the non-recurrence group (n = 297). Before the ablation, all patients underwent computed tomography angiography examination of the left atrium, and the LA-EAT was measured using medical software (Advantage Workstation 4.6, GE, USA). After circumferential pulmonary vein isolation, a three-dimensional mapping system was used to map the LA endocardium and evaluate the LA-LVAs in sinus rhythm. RESULTS: After a median follow-up of 10.2 months, 90 patients developed AF recurrence after RFCA. Compared to patients without recurrence, the volume of LA-EAT (33.45 ± 13.65 vs. 26.27 ± 11.38; p < 0.001) and the LA-LVAs% (1.60% [0%, 9.99%] vs. 0.00% [0%, 2.46%]; p < 0.001) was significantly higher. Multivariate analysis indicated that PersAF, LA-EAT volume, and LA-LVAs% were independent predictors. Compared to PersAF (AUC 0.628; specificity 0.646; sensitivity 0.609), LA-EAT volume (AUC 0.655; specificity 0.675; sensitivity 0.586), or LA-LVAs% (AUC 0.659; specificity 0.836; sensitivity 0.437), the combined use of LA-EAT volume and LA-LVAs% offers higher accuracy for predicting AF recurrence after ablation (AUC 0.738; specificity 0.761; sensitivity 0.621). CONCLUSION: The combined LA-EAT and LA-LVAs% can effectively predict the risk of AF recurrence after radiofrequency ablation.

Two-lung ventilation with artificial pneumothorax on cerebral desaturation and early postoperative cognitive outcome: a randomized controlled trial.

BACKGROUND: The effect of two lung ventilation (TLV) with carbon dioxide artificial pneumothorax on cerebral desaturation and postoperative neurocognitive changes in elderly patients undergoing elective minimally invasive esophagectomy (MIE) is unclear. OBJECTIVES: The first aim of this study was to compare the effect of TLV and one lung ventilation (OLV) on cerebral desaturation. The second aim was to assess changes in early postoperative cognitive outcomes of two ventilation methods. METHODS: This prospective, randomized, controlled trial enrolled patients 65 and older scheduled for MIE. Patients were randomly assigned (1:1) to TLV group or OLV group. The primary outcome was the incidence of cerebral desaturation events (CDE). Secondary outcomes were the cumulative area under the curve of desaturation for decreases in regional cerebral oxygen saturation (rSO2) values below 20% relative to the baseline value (AUC.20) and the incidence of delayed neurocognitive recovery. RESULTS: Fifty-six patients were recruited between November 2019 and August 2020. TLV group had a lower incidence of CDE than OLV group [3 (10.71%) vs. 13 (48.14%), P = 0.002]. TLV group had a lower AUC.20 [0 (0-35.86) % min vs. 0 (0-0) % min, P = 0.007], and the incidence of delayed neurocognitive recovery [2 (7.4%) vs. 11 (40.7%), P = 0.009] than OLV group. Predictors of delayed neurocognitive recovery on postoperative day 7 were age (OR 1.676, 95% CI 1.122 to 2.505, P = 0.006) and AUC.20 (OR 1.059, 95% CI 1.025 to 1.094, P < 0.001). CONCLUSION: Compared to OLV, TLV had a lower incidence of CDE and delayed neurocognitive recovery in elderly patients undergoing MIE. The method of TLV combined with carbon dioxide artificial pneumothorax may be an option for these elderly patients. Chinese Clinical Trial Registry (identifier: ChiCTR1900027454).

Both hormones and energy-rich compounds play a role in the mitigation of elevated pH on aluminum toxicity in Citrus sinensis leaves.

The contribution of plant hormones and energy-rich compounds and their metabolites (ECMs) in alleviating aluminum (Al) toxicity by elevated pH remains to be clarified. For the first time, a targeted metabolome was applied to identify Al-pH-interaction-responsive hormones and ECMs in Citrus sinensis leaves. More Al-toxicity-responsive hormones and ECMs were identified at pH 4.0 [4 (10) upregulated and 7 (17) downregulated hormones (ECMs)] than those at pH 3.0 [1 (9) upregulated and 4 (14) downregulated hormones (ECMs)], suggesting that the elevated pH improved the adaptation of hormones and ECMs to Al toxicity in leaves. The roles of hormones and ECMs in reducing leaf Al toxicity mediated by elevated pH might include the following aspects: (a) improved leaf growth by upregulating the levels of jasmonoyl-L-isoleucine (JA-ILE), 6-benzyladenosine (BAPR), N6-isopentenyladenosine (IPR), cis-zeatin-O-glucoside riboside (cZROG), and auxins (AUXs), preventing Al toxicity-induced reduction of gibberellin (GA) biosynthesis, and avoiding jasmonic acid (JA)-mediated defense; (b) enhanced biosynthesis and accumulation of tryptophan (TRP), as well as the resulting increase in biosynthesis of auxin, melatonin and secondary metabolites (SMs); (c) improved ability to maintain the homeostasis of ATP and other phosphorus (P)-containing ECMs; and (d) enhanced internal detoxification of Al due to increased organic acid (OA) and SM accumulation and elevated ability to detoxify reactive oxygen species (ROS) due to enhanced SM accumulation. To conclude, the current results corroborate the hypotheses that elevated pH reduces Al toxicity by upregulating the ability to maintain the homeostasis of ATP and other P-containing ECMs in leaves under Al toxicity and (b) hormones participate in the elevated pH-mediated alleviation of Al toxicity by positively regulating growth, the ability to detoxify ROS, and the internal detoxification of Al in leaves under Al toxicity. Our findings provide novel insights into the roles of hormones and ECMs in mitigating Al toxicity mediated by the elevated pH.

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein.

Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that l-glutamine:d-fructose-6-phosphate amidotransferase 1 (GFAT1), a rate-limiting enzyme of the hexosamine biosynthesis pathway, which produces uridine diphosphate-N-acetyl-ß-glucosamine, a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon gamma (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.

Circular RNA WHSC1 exerts oncogenic properties by regulating miR-7/TAB2 in lung cancer.

Circular RNA is a newly discovered member of non-coding RNA (ncRNA) and regulates the target gene by acting as a micro-RNA sponge. It plays vital roles in various diseases. However, the functions of circular RNA in non-small cell lung cancer (NSCLC) remain still unclear. Our data showed that circ-WHSC1 was highly expressed in NSCLC cells and tissues. Both in vitro and in vivo experiments showed that circ-WHSC1 promoted NSCLC proliferation. circ-WHSC1 also promoted the migration and invasion of lung cancer cells. Through bioinformatic analysis and functional experiments, we showed that circ-WHSC1 could act as a sponge for micro-RNA-7 (miR-7) and regulate the expression of TAB2 (TGF-beta activated kinase one binding protein two). Inhibition of the circ-WHSC1/miR-7/TAB2 pathway could effectively attenuate lung cancer progression. In summary, this study confirmed the existence and oncogenic function of circ-WHSC1 in NSCLC. The research suggests that the circ-WHSC1/miR-7/TAB2 axis might be a potential target for NSCLC therapy.

CircMED13L_012 promotes lung adenocarcinoma progression by upregulation of MAPK8 mediated by miR-433-3p.

BACKGROUND: Metastasis and disease refractoriness remain as major challenges for non-small cell lung cancer (NSCLC) treatment and understanding the underlying molecular mechanisms is of scientific and clinical value. Therefore, in this study, we aimed to explore the effects of circMED13L_012 on the proliferation, migration, invasion and drug-resistance of NSCLC tumor cells. METHODS: In this study, we utilized clinical samples and NSCLC cell lines to explore the association between circMED13L_012 expressions and tumor cell metastasis and chemo resistance. CCK8 and transwell assay were conducted to explore the impact of circMED13_012 on NSCLC tumor proliferation and migrative capabilities. Dual-luciferase reporter gene assay was conducted to validate the circMED13L_012 interaction network. RESULTS: Our results demonstrated that circMED13L_012 exhibited significantly elevated average level in our clinical samples of NSCLC, compared with normal tissues. circMED13L_012 level was positively correlated with disease stage and metastatic status. Increased circMED13L_012 expression was associated with the enhanced migration, proliferation and chemo resistance of NSCLC cell lines. Further experiments indicated that circMED13L_012 promoted malignant behavior of NSCLC tumor cells by targeting MAPK8 through modulation miR-433-3p expression. CONCLUSIONS: Our study for the first time demonstrated that circMED13L_012-miR-433-3p-MAPK8 axis played important role for NSCLC pathogenesis, which could be potential therapeutic target for the development of future NSCLC treatment.

CYP2J2 and EETs protect against pulmonary arterial hypertension with lung ischemia-reperfusion injury in vivo and in vitro.

BACKGROUND: Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia-reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo. METHODS: CYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by intraperitoneal injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with anoxia/reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs. RESULTS: CYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by the activation of PPARγ; the anti-apoptotic effects might be mediated by the PI3K/AKT pathway. CONCLUSIONS: CYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.

Prepregnancy BMI, gestational weight gain and risk of childhood atopic dermatitis: A systematic review and meta-analysis.

BACKGROUND: Maternal weight before and during pregnancy influences the health of offspring. Several observational studies have investigated a link between the risk of childhood atopic dermatitis (AD) and prepregnancy maternal body mass index (BMI) and gestational weight gain (GWG), but the conclusions of these studies were inconsistent. The aim of this review was to evaluate the association between the risk of childhood AD and prepregnancy maternal BMI and GWG. METHODS: The PubMed, Embase, Cochrane, Web of Science, and Scopus databases were searched from inception to February 2, 2021. Observational studies investigating the association between the risk of childhood AD and prepregnancy maternal BMI and GWG were included. Fixed- or random-effects models with inverse variance weights were used to calculate pooled risk estimates. Subgroup analysis and sensitivity analysis were used to explore the sources of heterogeneity. RESULTS: Thirteen studies with a total of 114 485 participants were included. Ten studies reported prepregnancy maternal BMI, and five reported GWG. Maternal underweight was associated with a higher risk of childhood AD (odds ratio [OR] = 1.06; 95% confidence interval [CI], 1.02-1.10). Continuous BMI was not related to childhood AD (OR = 1.00; 95% CI, 0.98-1.02). In comparison with normal GWG, moderate/very high GWG increased the risk of childhood AD (OR = 1.05; 95% CI, 1.02-1.08; OR = 1.13; 95% CI, 1.07-1.19, respectively), while low GWG decreased the risk (OR = 0.92; 95% CI, 0.89-0.96). Excessive GWG relative to recommendations was associated with a higher risk of childhood AD (OR = 1.05; 95% CI, 1.01-1.10), while a lower risk of childhood AD was associated with inadequate GWG relative to recommendations (OR = 0.87, 95% CI: 0.83-0.91). CONCLUSIONS: Maternal underweight, high GWG, and excessive GWG relative to recommendations are associated with an elevated risk of childhood AD, while low GWG and inadequate GWG relative to recommendations decreased the risk. Weight management before and during pregnancy is encouraged for primary prevention of childhood AD.

E2F1-induced ferritin heavy chain 1 pseudogene 3 (FTH1P3) accelerates non-small cell lung cancer gefitinib resistance.

Long noncoding RNAs (lncRNAs) have been identified to be critical regulator for various human diseases and emerging evidence illustrate the essential function of lncRNAs in the non-small cell lung cancer (NSCLC). Here, our research team tried to identify the roles of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) in the NSCLC, as well as its molecular mechanism. LncRNA microarray analysis revealed that ferritin heavy chain 1 pseudogene 3 (FTH1P3) was up-regulated in the gefitinib-resistant cells (PC9/GR). Clinically, lncRNA FTH1P3 high-expression was closely correlated with NSCLC patients' unfavorable prognosis. Gain and loss of functional experiments revealed that FTH1P3 promoted the proliferation and invasion of NSCLC cells in vitro, and FTH1P3 knockdown repressed the tumor growth in vivo. Mechanistically, transcription factor E2F1 accelerated the transcription of FTH1P3. RNA immunoprecipitation and chromatin immunoprecipitation experiments showed that FTH1P3 can recruit lysine-specific demethylase 1 (LSD1) and epigenetically repress the TIMP3, thereby accelerating the tumorigenesis of NSCLC. In summary, these findings suggest that FTH1P3 plays a critical role in the gefitinib resistance and progression of NSCLC, providing a potential novel prognostic marker for NSCLC.

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small-cell lung cancer cells.

Platinum anticancer agents are essential components in chemotherapeutic regimens for non-small-cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum-based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino-sugar N-acetyl-glucosamine for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by the combination of cisplatin with HBP inhibition. Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFATimpaired cell proliferation and exerted synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose-regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response (UPR). Suppressing GFAT activity resulted in downregulation of BiP that activated inositol-requiring enzyme 1α, a sensor protein of UPR, and exacerbated cisplatin-induced cell apoptosis. These data identify GFAT-mediated HBP as a target for improving platinum-based chemotherapy for NSCLC.

Muc1 knockout potentiates murine lung carcinogenesis involving an epiregulin-mediated EGFR activation feedback loop.

Mucin 1 (MUC1) is a tumor antigen that is aberrantly overexpressed in various cancers, including lung cancer. Our previous in vitro studies showed that MUC1 facilitates carcinogen-induced EGFR activation and transformation in human lung bronchial epithelial cells (HBECs), which along with other reports suggests an oncogenic property for MUC1 in lung cancer. However, direct evidence for the role of MUC1 in lung carcinogenesis is lacking. In this study, we used the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J mouse lung tumor model to investigate the effect of whole-body Muc1 knockout (KO) on carcinogen-induced lung carcinogenesis. Surprisingly, lung tumor multiplicity was significantly increased in Muc1 KO compared to wild-type (WT) mice. The EGFR/AKT pathway was unexpectedly activated, and expression of the EGFR ligand epiregulin (EREG) was increased in the lung tissues of the Muc1 KO compared to the WT mice. EREG stimulated proliferation and protected against cigarette smoke extract (CSE)-induced cytotoxicity in in vitro cultured human bronchial epithelial cells. Additionally, we determined that MUC1 was expressed in human fibroblast cell lines where it suppressed CSE-induced EREG production. Further, suppression of MUC1 cellular activity with GO-201 enhanced EREG production in lung cancer cells, which in turn protected cancer cells from GO-201-induced cell death. Moreover, an inverse association between MUC1 and EREG was detected in human lung cancer, and EREG expression was inversely associated with patient survival. Together, these results support a promiscuous role of MUC1 in lung cancer development that may be related to cell-type specific functions of MUC1 in the tumor microenvironment, and MUC1 deficiency in fibroblasts and malignant cells results in increased EREG production that activates the EGFR pathway for lung carcinogenesis.

A comparison of cervical delta-shaped anastomosis and circular stapled anastomosis after esophagectomy.

BACKGROUND: The delta-shaped anastomosis has been reported to reduce anastomotic complications for a decade. However, little has been written comparing this technique with the circular stapler technique. The objective of this retrospective study was to assess the safety and efficacy of cervical delta-shaped anastomosis after esophagectomy. METHODS: Medical records of patients with esophageal squamous cell carcinoma who underwent McKeown (three-incision) esophagectomy between September 2013 and June 2015 were reviewed. Either circular stapled anastomosis (CSA) or delta-shaped anastomosis (DSA) was performed at the cervical stage. The clinical characteristics and short-term outcome were retrospectively assessed to identify the differences between the two groups. RESULTS: A total of 81 patients were included in this study. The clinical characteristics were similar between the two groups. Cervical anastomotic leakage occurred in 3 (7.7%) of 39 patients in the DSA group and in 8 (19%) of 42 patients in the CSA group (P = 0.197). The average anastomotic orifice width was 16.1 ± 4.9 mm and 11.7 ± 2.2 mm, respectively (P < 0.001). The incidence of anastomotic stenosis was 2.6% (1/39) and 23.5% (10/42) in the DSA and CSA groups, respectively (P = 0.007). There was no significant difference in surgical duration, blood loss, pulmonary complication, postoperative mortality, time of hospitalisation and time of ICU stay between the two groups. CONCLUSIONS: Delta-shaped anastomosis may be an effective alternative method for gastroesophageal anastomosis after esophagectomy, with lower incidence of leakage and stenosis.

Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide.

The interaction between epithelial and stromal cells through soluble factors such as cytokines plays an important role in carcinogenesis. Breaking this cancer-promoting interaction poses an opportunity for cancer prevention. The tumor-promoting function of interleukin 6 (IL-6) has been documented; however, the underlying mechanisms of this function in lung carcinogenesis are not well elucidated. Here, we show that benzo[a]pyrene diol epoxide (BPDE, the active metabolite of cigarette smoke carcinogen benzo[a]pyrene)-induced human bronchial epithelial cell (HBEC) transformation was enhanced by IL-6 in vitro. The carcinogen/IL-6-transformed cells exhibited higher expression of STAT3 (signal transducer and activator of transcription 3) when compared with cells transformed by BPDE alone. Constitutive STAT3 activation drove cell proliferation and survival through anti-apoptosis gene expression. We further show that quercetin, a dietary compound having preventive properties for lung cancer, decreased BPDE-stimulated IL-6 secretion from human lung fibroblasts through inhibition of the NF-κB and ERK pathways. The inhibition was accomplished at clinically achievable concentrations of the compound. Finally, quercetin blocked IL-6-induced STAT3 activation in HBECs, and IL-6 enhancement of HBEC transformation by BPDE was abolished by quercetin treatment. Altogether, our data reveal novel mechanisms for IL-6 in lung carcinogenesis and for the preventive role of quercetin in the process. © 2015 Wiley Periodicals, Inc.

Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway.

Although receptor-interacting protein 1 (RIP1) is well known as a key mediator in cell survival and death signaling, whether RIP1 directly contributes to chemotherapy response in cancer has not been determined. In this report, we found that, in human lung cancer cells, knockdown of RIP1 substantially increased cytotoxicity induced by the frontline anticancer therapeutic drug cisplatin, which has been associated with robust cellular reactive oxygen species (ROS) accumulation and enhanced apoptosis. Scavenging ROS dramatically protected RIP1 knockdown cells against cisplatin-induced cytotoxicity. Furthermore, we found that, in RIP1 knockdown cells, the expression of the hydrogen peroxide-reducing enzyme catalase was dramatically reduced, which was associated with increased miR-146a expression. Inhibition of microRNA-146a restored catalase expression, suppressed ROS induction, and protected against cytotoxicity in cisplatin-treated RIP1 knockdown cells, suggesting that RIP1 maintains catalase expression to restrain ROS levels in therapy response in cancer cells. Additionally, cisplatin significantly triggered the proteasomal degradation of cellular inhibitor of apoptosis protein 1 and 2 (c-IAP1 and c-IAP2), and X-linked inhibitor of apoptosis (XIAP) in a ROS-dependent manner, and in RIP1 knockdown cells, ectopic expression of c-IAP2 attenuated cisplatin-induced cytotoxicity. Thus, our results establish a chemoresistant role for RIP1 that maintains inhibitor of apoptosis protein (IAP) expression by release of microRNA-146a-mediated catalase suppression, where intervention within this pathway may be exploited for chemosensitization.

CYP2J2 and EETs protect against lung ischemia/reperfusion injury via anti-inflammatory effects in vivo and in vitro.

BACKGROUND: Injurious inflammatory response is critical to the development of lung ischemia/reperfusion injury (LIRI). The cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert an anti-inflammatory effect on the cardiovascular system. We therefore cytochrome hypothesized that CYP2J2 overexpression and pretreatment with exogenous EETs may have the potential to reduce LIRI. METHODS: A rat model was used to mimic the condition of LIRI by clamping the left pulmonary hilum for 60 minutes, followed by reperfusion for 2 hours. Moreover, we developed a cell model using human pulmonary artery endothelial cells by anoxia for 8 hours, followed by reoxygenation for 16 hours to determine the anti-inflammatory effect and mechanism of CYP2J2 overexpression and exogenous 11,12-EET. RESULTS: Lung ischemia/reperfusion increased lung wet/dry and lung weight/body weight ratios, protein concentration in bronchoalveolar lavage fluid and concentrations of pro-inflammatory, including mediators in serum IL-1ß, IL-8, TNF-α, sP- and sE-selectin, and decreased concentration of anti-inflammatory mediator IL-10. Ischemia/reperfusion also leaded to pulmonary edema and inflammation under light microscopy. Furthermore, activation of NF-κB p65 and degradation of IκBα were remarkably increased in ischemia/reperfusion lung tissues. While CYP2J2 overexpression significantly inhibited the above effects (p<0.05). In vitro data further confirmed the anti-inflammatory effect of CYP2J2 overexpression and 11,12-EET, an effect that may probably be mediated by PPARγ activation. CONCLUSION: CYP2J2 overexpression and administration of exogenous EETs can protect against LIRI via anti-inflammatory effects. This can be a novel potential strategy for prevention and treatment of LIRI.

Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway.

BACKGROUND/AIMS: Bradykinin has been shown to exert a variety of protective effects against vascular injury, and to reduce the levels of several factors involved in the coagulation cascade. A key determinant of thrombin generation is tissue factor (TF). However, whether bradykinin can regulate TF expression remains to be investigated. METHODS: To study the effect of bradykinin on TF expression, we used Lipopolysaccharides (LPS) to induce TF expression in human umbilical vein endothelial cells and monocytes. Transcript levels were determined by RT-PCR, protein abundance by Western blotting. In the in vivo study, bradykinin and equal saline were intraperitoneally injected into mice for three days ahead of inferior cava vein ligation that we took to induce thrombus formation, after which bradykinin and saline were injected for another two days. Eventually, the mice were sacrificed and tissues were harvested for tests. RESULTS: Exogenous bradykinin markedly inhibited TF expression in mRNA and protein level induced by LPS in a dose-dependent manner. Moreover, the NO synthase antagonist L-NAME and PI3K inhibitor LY294002 dramatically abolished the inhibitory effects of bradykinin on tissue factor expression. PI3K/Akt signaling pathway activation induced by bradykinin administration reduced the activity of GSK-3ß and MAPK, and reduced NF-x03BA;B level in the nucleus, thereby inhibiting TF expression. Consistent with this, intraperitoneal injection of C57/BL6 mice with bradykinin also inhibited the thrombus formation induced by ligation of inferior vena cava. CONCLUSION: Bradykinin suppressed TF protein expression in human umbilical vein endothelial cells and monocytes in vitro; in line with this, it inhibits thrombus formation induced by ligation of inferior vena cava in vivo.

CYP2J2 and EETs Protect against Oxidative Stress and Apoptosis in Vivo and in Vitro Following Lung Ischemia/Reperfusion.

BACKGROUND: Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to epoxyeicosatrienoic acids (EETs). EETs exert various biological effects, including anti-inflammatory, anti-apoptotic, pro-proliferation, pro-angiogenesis, anti-oxidation, and anti-fibrosis effects. However, little is known about the role of CYP2J2 and EETs in lung ischemia/reperfusion injury. In this study, we examined the effects of exogenous EETs or CYP2J2 overexpression on lung ischemia/reperfusion injury in vivo and in vitro. METHODS AND RESULTS: CYP2J2 gene was stably transfected into rat lungs via pcDNA3.1-CYP2J2 plasmid delivery, resulting in increased EETs levels in the serum and lung. A rat model of lung ischemia/reperfusion injury was developed by clamping the left lung hilum for 1 hour, followed by reperfusion for 2 hours. We found that CYP2J2 overexpression markedly decreased the levels of oxidative stress and cell apoptosis in lung tissues induced by ischemia/reperfusion. Moreover, we observed that exogenous EETs, or CYP2J2 overexpression, enhanced cell viability, decreased intracellular reactive oxygen species (ROS) generation, inhibited mitochondrial dysfunction, and attenuated several apoptotic signaling events in a human pulmonary artery endothelial cells (HPAECs)-based anoxia/reoxygenation model. These apoptotic events included activation of NADPH oxidase, collapse of mitochondrial transmembrane potential, and activation of pro-apoptotic proteins and caspase-3. These effects were mediated, at least partially, by the PI3K/Akt signaling pathway. CONCLUSION: These results reveal that CYP2J2 overexpression and exogenous EETs can protect against oxidative stress and apoptosis following lung ischemia/reperfusion in vivo and in vitro, suggesting that increasing the level of EETs may be a novel promising strategy to prevent and treat lung ischemia/reperfusion injury.

Clinicopathological and prognostic significance of hypoxia-inducible factor-1α in esophageal squamous cell carcinoma: a meta-analysis.

Published literatures on the prognostic value of hypoxia-inducible factor-1α (HIF-1α) overexpression in esophageal squamous cell carcinoma (ESCC) are conflicting and heterogeneous. We performed a meta-analysis to more precisely evaluate the clinicopathological and prognostic value of HIF-1α in patients with ESCC. Searches were applied to MEDLINE, Pubmed, Embase, Cochrane Library, Web of Science, and Chinese BioMedical Literature Databases until September 10, 2013, without language restrictions. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were used to estimate the effects. Twelve studies with 942 ESCC patients were selected to evaluate the correlation between HIF-1α and overall survival (OS), disease-free survival (DFS), response to chemoradiation (RC), and clinicopathological features. HIF-1α overexpression was significantly associated with poor OS (HR 1.78, 95% CI 1.41-2.24), DFS (HR 1.91, 95% CI 1.15-3.18), and RC (HR 3.56, 95% CI 1.68-7.53). Besides, HIF-1α overexpression was significantly associated with stage (OR 2.90, 95% CI 1.97-4.27), lymph node metastasis (OR 1.86, 95% CI 1.39-2.49), depth of invasion (OR 2.45, 95% CI 1.24-4.86), lymphatic invasion (OR 2.28, 95% CI 1.46-3.56), distant metastasis (OR 2.04, 95% CI 1.19-3.50), and vascular endothelial growth factor (OR 3.67, 95% CI 1.81-7.46). Our results indicate that HIF-1α overexpression can potently predict the poor prognosis and chemoradiation resistance for ESCC. Large prospective studies with multivariable survival analyses are now needed to confirm the clinical utility of HIF-1α as an independent prognostic marker.

KBStyle: Fast Style Transfer Using a 200 KB Network With Symmetric Knowledge Distillation.

Convolutional Neural Networks (CNNs) have achieved remarkable progress in arbitrary artistic style transfer. However, the model size of existing state-of-the-art (SOTA) style transfer algorithms is immense, leading to enormous computational costs and memory demand. It makes real-time and high resolution hard for GPUs with limited memory and limits the application on mobile devices. This paper proposes a novel arbitrary artistic style transfer algorithm, KBStyle, whose model size is only 200 KB. Firstly, we design a style transfer network where the style encoder, content encoder, and corresponding decoder are custom designed to guarantee low computational cost and high shape retention. Besides, the weighted style loss function is presented to improve the performance of style migration. Then, we propose a novel knowledge distillation method (Symmetric Knowledge Distillation, SKD) for encoder-decoder-based style transfer models, which redefines the knowledge and symmetrically compresses the encoder and decoder. With the SKD, the proposed style transfer network is further compressed by 14 times to achieve the KBStyle. Experimental results demonstrate that the proposed SKD method achieves comparable results with other SOTA knowledge distillation algorithms for style transfer. Besides, the proposed KBStyle achieves high-quality stylized images. And the inference time of the KBStyle on an Nvidia TITAN RTX GPU is only 20 ms when the resolutions of the content image and style image are both 2k-resolution ( 2048×1080 ). Moreover, the 200 KB model size of KBStyle is much smaller than the SOTA models and facilitates style transfer on mobile devices.

Transcriptomic analysis of the defense response in "Cabernet Sauvignon" grape leaf induced by Apolygus lucorum feeding.

To investigate the molecular mechanism of the defense response of "Cabernet Sauvignon" grapes to feeding by Apolygus lucorum, high-throughput sequencing technology was used to analyze the transcriptome of grape leaves under three different treatments: feeding by A. lucorum, puncture injury, and an untreated control. The research findings indicated that the differentially expressed genes were primarily enriched in three aspects: cellular composition, molecular function, and biological process. These genes were found to be involved in 42 metabolic pathways, particularly in plant hormone signaling metabolism, plant-pathogen interaction, MAPK signaling pathway, and other metabolic pathways associated with plant-induced insect resistance. Feeding by A. lucorum stimulated and upregulated a significant number of genes related to jasmonic acid and calcium ion pathways, suggesting their crucial role in the defense molecular mechanism of "Cabernet Sauvignon" grapes. The consistency between the gene expression and transcriptome sequencing results further supports these findings. This study provides a reference for the further exploration of the defense response in "Cabernet Sauvignon" grapes by elucidating the expression of relevant genes during feeding by A. lucorum.