Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis.

BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 µg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER: NCT02749630.

Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia: A Randomized, Phase 2 Trial.

OBJECTIVES: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia. DESIGN: Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL). SETTING: Hospitals. PATIENTS: Hospitalized adults with severe COVID-19 pneumonia. INTERVENTIONS: Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28. MEASUREMENTS AND MAIN RESULTS: The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active. CONCLUSIONS: Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

Acid-Promoter-Free Ethylene Methoxycarbonylation over Ru-Clusters/Ceria: The Catalysis of Interfacial Lewis Acid-Base Pair.

The interface of metal-oxide plays pivotal roles in catalytic reactions, but its catalytic function is still not clear. In this study, we report the high activity of nanostructured Ru/ceria (Ru-clusters/ceria) in the ethylene methoxycarbonylation (EMC) reaction in the absence of acid promoter. The catalyst offers 92% yield of MP with TOF of 8666 h-1, which is about 2.5 times of homogeneous Pd catalyst (∼3500 h-1). The interfacial Lewis acid-base pair [Ru-O-Ce-Vö], which consists of acidic Ce-Vö (oxygen vacancy) site and basic interfacial oxygen of Ru-O-Ce linkage, acts as active site for the dissociation of methanol and the subsequent transfer of hydrogen to the activated ethylene, which is the key step in acid-promoter-free EMC reaction. The combination of 1H MAS NMR, pyridine-IR and DFT calculations reveals the hydrogen species derived from methanol contains Brönsted acidity. The EMC reaction mechanism under acid-promoter-free condition over Ru-clusters/ceria catalyst is discussed.

Pharmacokinetics and Exposure-Response Analysis of RG7667, a Combination of Two Anticytomegalovirus Monoclonal Antibodies, in a Phase 2a Randomized Trial To Prevent Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients.

RG7667, a novel combination of two anticytomegalovirus (anti-CMV) monoclonal IgG1 antibodies (MCMV5322A and MCMV3068A), was designed to block CMV entry into host cells. It was developed as a potential therapy for preventing CMV infection and disease in transplant recipients. RG7667 was assessed for preventing CMV infection in a phase 2a trial with CMV-seronegative recipients of kidney transplants from CMV-seropositive donors. The patients received 4 intravenous doses of RG7667 (10 mg/kg of body weight of each antibody, n = 60) or placebo (n = 60) at the time of the transplant and at 1, 4, and 8 weeks after the transplant. Serum samples were collected for pharmacokinetic (PK) analysis and antidrug antibody (ADA) evaluation. To guide future dose selection, the relationships between RG7667 exposure and pharmacological activity were evaluated. MCMV5322A and MCMV3068A exposures were confirmed in all RG7667-treated patients. Mean clearances for MCMV5322A and MCMV3068A were 2.97 and 2.65 ml/day/kg, respectively, and the terminal half-lives of MCMV5322A and MCMV3068A were 26.9 and 27.4 days, respectively. The ADA incidence was low and was not associated with lower drug exposure. Patients with RG7667 or component antibody exposures greater than the respective median values had a lower incidence of viremia at 12 weeks and 24 weeks after transplantation and a longer delayed time to detectable CMV viremia than patients with exposures less than the median values. MCMV5322A and MCMV3068A exhibited expected IgG1 PK profiles in high-risk kidney transplant recipients, consistent with the earlier PK behavior of RG7667 in healthy subjects. Higher drug exposure was associated with better anti-CMV pharmacological activity. (This study has been registered at ClinicalTrials.gov under identifier NCT01753167.).

The Synthesis of Quinazolinones from Olefins, CO, and Amines over a Heterogeneous Ru-clusters/Ceria Catalyst.

Quinazolinones, an important class of heterocyclic compounds, have been widely used in pharmaceuticals because of their biological activity. However, the efficient and economical synthesis of quinazolinones has remained a challenge. A novel synthetic approach has now been developed to produce quinazolinones from olefins, CO, and amines over heterogeneous Ru-clusters/ceria catalyst in the absence of acids, bases, and oxidants. Furthermore, H2 O is generated as the only by-product. A series of quinazolinones with aromatic or non-aromatic substituents can be obtained in yields of up to 99 %. The Ru-clusters/ceria can be reused at least four times. The analysis of the E-factor (environmental impact factor) for the synthesis of 2-ethyl quinazolinone suggests that this system is more environmentally friendly than other processes reported previously.

[Epidemiological survey of asthma among children aged 0-14 years in 2010 in urban Zhongshan, China].

OBJECTIVE: To investigate the prevalence, current treatment, and clinical characteristics of asthma, as well as the risk factors for this disease, among children aged 0-14 years in 2010 in urban Zhongshan, China. METHODS: A total of 10 336 children aged 0-14 years were selected from urban Zhongshan by cluster random sampling. The Third National Childhood Asthma Epidemiological Questionnaire 2010 was used to analyze the prevalence, current treatment, and clinical characteristics of childhood asthma, as well as the risk factors for this disease. RESULTS: Asthma was diagnosed in 179 cases (1.73%). The prevalence of asthma in male children was significantly higher than that in female children (2.25% vs 1.16%; P<0.01). Of the 179 patients, severe attacks were common in 104 cases (58.1%), 110 cases (61.5%) had slow onset, 102 cases (57.0%) had gradually relieved conditions, 61 cases (34.1%) suffered from asthma during seasonal transition, and 150 cases (83.8%) developed asthma due to respiratory tract infection. Among all asthmatic children, 71.5% had been treated with inhaled corticosteroids, and 71.5% had been treated with bronchodilator. The multivariate logistic regression analysis showed that a history of penicillin allergy, a family history of allergy, food allergy, eczema, allergic rhinitis, cesarean delivery, family mould, and perinatal passive smoking were independent risk factors for childhood asthma. CONCLUSIONS: The prevalence of childhood asthma in urban Zhongshan is on a high level, and is associated with gender. The treatment of asthma has been standardized, but still needs further improvement. The onset of asthma attack is influenced by various factors.

[Incidence of wheezing and chronic cough in children aged 3-14 years in rural and urban areas of Zhongshan, China: a questionnaire survey].

OBJECTIVE: To investigate the incidence of wheezing and chronic cough in children aged 3-14 years in different living areas of Zhongshan, China. METHODS: According to the unified program of the 2010 national epidemiological survey of asthmatic children aged 0-14 years, a questionnaire survey of the children aged 3-14 years in rural and urban areas of Zhongshan was conducted. RESULTS: A total of 15 763 children were included in the survey. Among all participants, 8 248 were from the urban area, and 7 515 from the rual area; 8 306 were boys, and 7 457 were girls. The percentage of children with a history of wheezing was significantly higher in the urban group than in the rural group (6.6% vs 3.2%; P<0.05), and it was significantly higher in boys than in girls for each group (P<0.05). The urban group had a significantly higher percentage of individuals who had wheezing in the past one year than the rural group (2.8% vs 1.5%; P<0.05), and this percentage was significantly higher in boys than in girls for each group (P<0.05). Compared with the rural group, the urban group had a significantly higher percentage of individuals who had chronic cough (duration 1 year) (7.9% vs 3.1%; P<0.05). The above indices were relatively high in children under 6 years of age, and all but the percentage of girls who had wheezing in the past one year in both rural and urban areas showed significant differences between all age groups. CONCLUSIONS: The incidence of wheezing and chronic cough varies with age, sex, and living area for children aged 3-14 years in Zhongshan, and it is relatively high under 6 years of age, in the urban area, and among boys.

The paradoxical role of zinc on microglia.

Zinc is an essential trace element for humans, and its homeostasis is essential for the health of the central nervous system. Microglia, the resident immune cells in the central nervous system, play the roles of sustaining, nourishing, and immune surveillance. Microglia are sensitive to microenvironment changes and are easily activated to M1 phenotype to enhance disease progression or the M2 phenotype to improve peripheral nerves injury repair. Zinc is requisite for microglial activation, However, the cytotoxicity outcome of zinc against microglia, the activated microglia phenotype, and activated microglia function are ambiguous. Herein, we have reviewed the neurological function of zinc and microglia, particularly the ambiguous role of zinc on microglia. We also pay attention to the role of zinc homeostasis on microglial function within the central nervous system disease. Finally, we observe the relationship between zinc and microglia, attempting to design new therapeutic measures against major nervous system disorders.

Sialic Acid Mediated Endothelial and Hepatic Uptake: A Mechanism based Mathematic Model Elucidating the Complex Pharmacokinetics and Pharmacodynamics of Efmarodocokin Alfa, a Variably Glycosylated Fusion Protein.

Sialic acid (SA) is crucial for protecting glycoproteins from clearance. Efmarodocokin alfa (IL-22Fc), a fusion protein agonist that links IL-22 to the crystallizable fragment (Fc) of human IgG4, contains 8 N-glycosylation sites and exhibits heterogeneous and variable terminal sialylation biodistribution. This presents a unique challenge for Pharmacokinetic (PK) and Pharmacodynamic (PD) analysis and cross-species translation. In this study, we sought to understand how varying SA levels and heterogeneous distribution contribute to IL-22Fc's complex PKPD properties. We initially used homogenous drug material with varying SA levels to examine PKPD in mice. Population PKPD analysis based on mouse data revealed that SA was a critical covariate simultaneously accounting for the substantial between subject variability (BSV) in clearance (CL), distribution clearance (CLd), and volume of distribution (Vd). In addition to the well-established mechanism by which SA inhibits ASGPR activity, we hypothesized a novel mechanism by which decrease in SA increases the drug uptake by endothelial cells. This decrease in SA, leading to more endothelial uptake, was supported by the neonatal Fc receptor (FcRn) dependent cell-based transcytosis assay. The population analysis also suggested in vivo EC50 (IL-22Fc stimulating Reg3ß) was independent on SA, while the in-vitro assay indicated a contradictory finding of SA-in vitro potency relationship. We created a mechanism based mathematical (MBM) PKPD model incorporating the decrease in SA mediated endothelial and hepatic uptake, and successfully characterized the SA influence on IL-22Fc PK, as well as the increased PK exposure being responsible for increased PD. Thereby, the MBM model supported that SA has no direct impact on EC50, aligning with the population PKPD analysis. Subsequently, using the MBM PKPD model, we employed 5 subpopulation simulations to reconstitute the heterogeneity of drug material. The simulation accurately predicted the PKPD of heterogeneously and variably sialylated drug in mouse, monkey and human. The successful prospective validation confirmed the MBM's ability to predict IL-22Fc PK across variable SA levels, homogenous to heterogeneous material, and across species (R2=0.964 for clearance prediction). Our model prediction suggests an average of 1 mol/mol SA increase leads to a 50% increase in drug exposure. This underlines the significance of controlling sialic acid levels during lot-to-lot manufacturing.

Heterogeneous ceria catalyst with water-tolerant Lewis acidic sites for one-pot synthesis of 1,3-diols via Prins condensation and hydrolysis reactions.

The use of a heterogeneous Lewis acid catalyst, which is insoluble and easily separable during the reaction, is a promising option for hydrolysis reactions from both environmental and practical viewpoints. In this study, ceria showed excellent catalytic activity in the hydrolysis of 4-methyl-1,3-dioxane to 1,3-butanediol in 95% yield and in the one-pot synthesis of 1,3-butanediol from propylene and formaldehyde via Prins condensation and hydrolysis reactions in an overall yield of 60%. In-depth investigations revealed that ceria is a water-tolerant Lewis acid catalyst, which has seldom been reported previously. The ceria catalysts showed rather unusual high activity in hydrolysis, with a turnover number (TON) of 260, which is rather high for bulk oxide catalysts, whose TONs are usually less than 100. Our conclusion that ceria functions as a Lewis acid catalyst in hydrolysis reactions is firmly supported by thorough characterizations with IR and Raman spectroscopy, acidity measurements with IR and (31)P magic-angle-spinning NMR spectroscopy, Na(+)/H(+) exchange tests, analyses using the in situ active-site capping method, and isotope-labeling studies. A relationship between surface vacancy sites and catalytic activity has been established. CeO(2)(111) has been confirmed to be the catalytically active crystalline facet for hydrolysis. Water has been found to be associatively adsorbed on oxygen vacancy sites with medium strength, which does not lead to water dissociation to form stable hydroxides. This explains why the ceria catalyst is water-tolerant.

Impact of climate change on the geographical distribution and niche dynamics of Gastrodia elata.

Background: Gastrodia elata is widely used in China as a valuable herbal medicine. Owing to its high medicinal and nutrient value, wild resources of G. elata have been overexploited and its native areas have been severely damaged. Understanding the impacts of climate change on the distribution of this endangered species is important for the conservation and sustainable use of G. elata. Methods: We used the optimized maximum entropy model to simulate the potential distribution of G. elata under contemporary and future time periods (1970-2000, 2050s, 2070s, and 2090s) and different climate change scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). Under these conditions, we investigated the key environmental factors influencing the distribution of G. elata as well as the spatial and temporal characteristics of its niche dynamics. Results: With high Maxent model accuracy (AUCmean = 0.947 ± 0.012, and the Kappa value is 0.817), our analysis revealed that annual precipitation, altitude, and mean temperature of driest quarter are the most important environmental factors influencing the distribution of G. elata. Under current bioclimatic conditions, the potentially suitable area for G. elata in China is 71.98 × 104 km2, while the highly suitable region for G. elata growth is 7.28 × 104 km2. Our models for three future periods under four climate change scenarios indicate that G. elata can maintain stable distributions in southern Shaanxi, southwestern Hubei, and around the Sichuan basin, as these areas are highly suitable for its growth. However, the center of the highly suitable areas of G. elata shift depending on different climatic scenarios. The values of niche overlap for G. elata show a decreasing trend over the forecasted periods, of which the niche overlap under the SSP3-7.0 scenario shows the greatest decrease. Discussions: Under the condition of global climate change in the future, our study provides basic reference data for the conservation and sustainable utilization of the valuable and endangered medicinal plant G. elata. It is important to carefully choose the protection area of G. elata wild resources according the suitable area conditions modeled. Moreover, these findings will be valuable for providing insights into the breeding and artificial cultivation of this plant, including the selection of suitable areas for planting.

Tuning Redistribution of CuOx Nanoparticles on TiO2 Support.

Nanoparticles exhibit unique catalytic performance, depending on their nanoscale size. However, controlling the particle size of the supported catalysts is still challenging. Here, we present a method for tunable redistribution of CuOx nanoparticles on rutile TiO2 support by physically adding pristine TiO2. The redistribution is driven by the work function difference (WFD) between the TiO2 support and the TiO2 additive, both of which exhibit distinct values, as determined through Kelvin probe force microscopy and electron binding energy analysis. Addition of TiO2 with lower work function (rutile) promotes electron transfer toward the CuOx/TiO2 composite, resulting in nanoparticle aggregation, while addition of TiO2 with higher work function (anatase) results in smaller CuOx on TiO2. The increase in particle size and electron density of CuOx, driven by the addition of rutile TiO2, promoted the complete conversion of nitrobenzene (100%) within 5 h. This is 2.7 times that of dispersed and degraded CuOx driven by mixing with anatase TiO2 (36.9%).

[Risk factors for bronchial asthma in school children].

OBJECTIVE: To investigate the roles of the residential environment and eating habits in the pathogenesis of bronchial asthma in school children. METHODS: One hundred and twenty-nine children between 6-12 years who were diagnosed with asthma were enrolled. Two hundred and fifty-eight healthy age- and gender-matched children were used as the control group. A questionaire which included 23 factors related to respiratory tract anaphylactic diseases such as residential environment and eating habits were completed by the children's parents. RESULTS: Logistic regression analysis showed that 6 variances out of 16 agents of the residential environment, the experience of raising pets, the type of floor, the type of pillow, the type of quilts, the heating equipments and the house area, were entered into the regression equation; none of the 7 variances of eating inhabits was entered into it. CONCLUSIONS: The residential environment plays an impotent role in the pathogenesis of bronchial asthma in children. The incidence of bronchial asthma in children can be reduced by the improvement of the residential environment.

Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1alpha.

Postconditioning (PostC) has regenerated interest as a mechanical intervention against myocardial ischemia/reperfusion injury, but its molecular mechanisms remain elusive. This study tested the hypothesis that hypoxia inducible factor-1alpha (HIF-1alpha) plays a role in PostC-induced cardioprotection. Male Wistar rats were subjected to 30 min ischemia followed by 3 h of reperfusion (Control). PostC with 3 cycles of 10 s reperfusion and 10 s re-occlusion was applied at the onset of reperfusion. Relative to the Sham group, HIF-1alpha protein level was increased by 2.9-fold in the Control group, but its level was enhanced by 5.8-fold with PostC (P < 0.01 vs. Control). However, HIF-1alpha protein level was further augmented by 2.0-fold and 3.3-fold, respectively, when the prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG, 40 mg/kg, i.p.) was given at 24 h before ischemia in both Control and PostC groups. PostC reduced infarct size by 24% compared with the Control (27 +/- 4.2% vs. 36 +/- 5.2%, P < 0.01), consistent with significant lower levels of plasma creatine kinase activity, index of cardiomyocyte apoptosis and caspase-3 activity. Although pretreatment with DMOG significantly reduced infarct size relative to the Control, the infarct-sparing effect of PostC was remarkably enhanced when DMOG was given before PostC (18 +/- 2.0% vs. 27 +/- 4.2% in PostC alone, P < 0.05). There was a significant linear inverse relationship between HIF-1alpha protein level and infarct size (r = -0.799, P < 0.01) among all groups. Furthermore, along with up-regulated HIF-1alpha expression, the levels of iNOS mRNA and protein were significantly increased in the PostC alone and DMOG plus PostC groups. In conclusion, these data suggest that HIF-1alpha is involved in cardioprotection by PostC and pharmacological augmentation of HIF-1alpha expression that enhances the infarct-sparing effect of PostC; iNOS, the downstream gene of HIF-1alpha, may participate in signaling pathways in mediating PostC's protection.

Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death in the world. Despite cisplatin is a commonly used chemotherapeutic drug for the colorectal cancer treatment, resistance of cancer cells to cisplatin restricts its clinical efficacy. It is important to explore the potential mechanisms and take strategies to sensitize colorectal cancer cells to cisplatin treatment. METHODS: Differences of TRIM32 and miR-519d expression between colorectal cancer cells and human normal colon epithelial cells were evaluated by qRT-PCR and Western blot assays. Cytotoxicity of cisplatin against colorectal cancer cells was tested by CCK-8 assay. Generation of reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis was measured by flow cytometry. Dual-luciferase reporter assay was used to validate the association between miR-519d and TRIM32. RESULTS: Significant increase of TRIM32 expression in colorectal cancer tissues and cell lines was observed. TRIM32 negatively regulated the cisplatin sensitivity in colorectal cancer cells. Mechanically, overexpression of TRIM32 was induced by decrease of miR-519d. Exogenous miR-519d can inhibit the expression of TRIM32 and thus promoted the cisplatin-induced apoptosis through the mitochondrial pathway. CONCLUSION: Overexpression of TRIM32 was induced by the absence of miR-519d in colorectal cancer. MiR-519d can be used as a sensitizer during the cisplatin-based chemotherapy of colorectal cancer.

The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase.

OBJECTIVE: Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor γ (PPARγ (PPARγ (PPARγ) has been reported to attenuate atherosclerosis formation; however, the underlying mechanisms are not fully understood. The present study was designed to determine whether myeloperoxidase (MPO) mediates HC-induced endothelial dysfunction and the role of the PPARγ agonist pioglitazone (PIO) in attenuating endothelial dysfunction. METHODS: Male Wistar rats were fed with normal or high cholesterol diets for 8 weeks. HC rats were randomized to receive dapsone (DDS, the MPO inhibitor) during the last 6 days or PIO for the remaining 4 weeks. Vascular endothelial function was determined by comparing vasorelaxation to ACh, an endothelium-dependent vasodilator, and SNP, an endothelium-independent vasodilator in vascular rings in vitro. The vascular MPO activity, NO x content, and cGMP level were measured by the MPO activity assay kit, NO assay kit, and cGMP RIA kit. RESULTS: Compared with rats fed with normal diet, endothelium-dependent vasodilation, NO x content, and cGMP level were decreased, and MPO activity was increased in thoracic aortas of rats fed with HC diet. There was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NO x content and cGMP level, and improved endothelium-dependent vasodilation function in HC rats, which was essentially the same as that seen with DDS. And, there was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity in the HC group and the PIO intervention group. CONCLUSION: MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing the NO biological activity and impairing the NO/cGMP/cGK signaling pathway. PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction.

Overall Survival Benefit in Rectal Cancer After Neoadjuvant Radiotherapy and Adjuvant Chemotherapy: A Propensity-Matched Population-Based Study.

BACKGROUND: It is well known that neoadjuvant radiotherapy could reduce local recurrence followed by surgical resection. However, evidence about oncologic efficacy of radiotherapy and survival benefit of adjuvant chemotherapy after neoadjuvant radiotherapy is still lacking. METHODS: This retrospective propensity score-matched cohort study identified patients with pathologically confirmed rectal cancer and receiving surgery with curative intent from the Surveillance, Epidemiology, and End Results database from 2004 through 2014. Overall survival was compared using the stratified log-rank test. Multivariate Cox regression analysis was used for identifying risk factor and developing prediction nomogram. RESULTS: A total of 22,008 (11,004 for each group) propensity-matched patients were identified. In the context of receiving adjuvant chemotherapy after surgical resection, there was no significant difference in terms of overall survival between surgery alone group and neoadjuvant radiotherapy and surgery group, whether for stage I (log-rank test p = 0.467), stage II (log-rank test p = 0.310), or stage III (p = 0.994). In case of receiving a prior combination therapy of neoadjuvant radiotherapy and surgery, the following adjuvant chemotherapy could significantly improve overall survival for patients with stage I (log-rank test p <0.001), stage II (log-rank test p = 0.038), and stage III (log-rank test p = 0.014). Nomogram integrating clinicopathologic factors was developed to predict survival benefit associated with neoadjuvant radiotherapy. Calibration and ROC curves validated promising performance for the nomogram. CONCLUSION: Patients with rectal cancer underwent neoadjuvant radiotherapy yield acceptable outcomes and are more likely to benefit from adjuvant chemotherapy in terms of overall survival. These data would be evidential for advocating consistency in guideline adherence to the use of adjuvant chemotherapy after neoadjuvant radiotherapy.

Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/reperfusion injury and the involvement of hypoxia inducible factor-1alpha upregulation.

Hyperlipidemia is regarded as an independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia/reperfusion (I/R) injury. Ischemic postconditioning (Postcon) has been demonstrated to attenuate the myocardial injury induced by I/R in normal conditions. But the effect of ischemic Postcon on hyperlipidemic animals is unknown. Hypoxia inducible factor-1 (HIF-1) has been demonstrated to play a central role in the cardioprotection by preconditioning, which is one of the protective strategies except for Postcon. The aim of this study was to determine whether Postcon could reduce myocardial injury in hyperlipidemic animals and to assess whether HIF-1 was involved in Postcon mechanisms. Male Wistar rats underwent the left anterior descending coronary occlusion for 30 min followed by 180 min of reperfusion with or without Postcon after fed with high fat diet or normal diet for 8 weeks. The detrimental indices induced by the I/R insult included infarct size, plasma creatine kinase activity and caspase-3 activity. Results showed that hyperlipidemia remarkably enhanced the myocardial injury induced by I/R, while Postcon significantly decreased the myocardial injury in both normolipidemic and hyperlipidemic rats. Moreover, both hyperlipidemia and I/R promoted the HIF-1alpha expression. Most importantly, we have for the first time demonstrated that Postcon further induced a significant increase in HIF-1alpha protein level not only in normolipidemic but also in hyperlipidemic conditions. Thus, Postcon reduces the myocardial injury induced by I/R in normal and hyperlipidemic animals, and HIF-1alpha upregulation may involve in the Postcon-mediated cardioprotective mechanisms.

Capping experiments reveal multiple surface active sites in CeO2 and their cooperative catalysis.

Understanding of surface active sites (SAS) of CeO2 is crucial to its catalytic applications. In the present study, we have employed capping experiments, DFT calculations, and spectroscopic characterization to study pristine CeO2 catalyst. We find that multiple SAS coexist on the CeO2 surface: oxygen vacancies as redox sites and the coordinately unsaturated Ce cations near the oxygen vacancies and the neighboring oxygen ions as Lewis acid-base sites. Dimethylsulfoxide (DMSO), pyridine, and benzoic acid are utilized to cap the redox sites, Lewis acid sites, and base sites, respectively. Selective capping on the redox site does not have much effect on the acid-base catalysis, and vice versa, indicating the distinct surface proximity and independent catalysis of these SAS. We draw attention to a relationship between the well-known redox sites and the surface Lewis acid and Lewis base pairs on CeO2 surface, which are responsible for driving various heterogeneous catalytic reactions.

Effectiveness of metal oxide catalysts for the degradation of 1,4-dioxane.

1,4-dioxane, commonly used as a solvent stabilizer and industrial solvent, is an environmental contaminant and probable carcinogen. In this study, we explored the concept of using metal oxides to activate H2O2 catalytically at neutral pH in the dark for 1,4-dioxane degradation. Based on batch kinetics measurements, materials that displayed the most suitable characteristics (high 1,4-dioxane degradation activity and high H2O2 consumption efficiency) were ZrO2, WO x /ZrO2, and CuO. In contrast, materials like TiO2, WO3, and aluminosilicate zeolite Y exhibited both low 1,4-dioxane degradation and H2O2 consumption activities. Other materials (e.g., Fe2O3 and CeO2) consumed H2O2 rapidly, however 1,4-dioxane degradation was negligible. The supported metal oxide WO x /ZrO2 was the most active for 1,4-dioxane degradation and had higher H2O2 consumption efficiency compared to ZrO2. In situ acetonitrile poisoning and FTIR spectroscopy results indicate different surface acid sites for 1,4-dioxane and H2O2 adsorption and reaction. Electron paramagnetic resonance measurements indicate that H2O2 forms hydroxyl radicals (˙OH) in the presence of CuO, and unusually, forms superoxide/peroxyl radicals (˙O2 -) in the presence of WO x /ZrO2. The identified material properties suggest metal oxides/H2O2 as a potential advanced oxidation process in the treatment of 1,4-dioxane and other recalcitrant organic compounds.