Measurement of urinary exosomal phospholipase A2 receptor is a sensitive method for diagnosis of PLA2R-associated membranous nephropathy.

Background: The discovery of phospholipase A2 receptor (PLA2R) and its antibody (aPLA2Rab) has paved the way for diagnosing PLA2R-associated membranous nephropathy (PLA2R-MN) with a high specificity of 98%. However, the sensitivity was only 40% to 83.9%, and there is ongoing discussion around determining the optimal threshold for diagnosis. Recent advancements in the use of exosomes, a novel form of "liquid biopsy," have shown great promise in identifying markers for various medical conditions. Methods: Protein mass spectrometry and western blot were applied to verify the existence of PLA2R antigen in the urine exosome. We then evaluated the efficacy of urinary exosomal PLA2R antigen alone or combined with serum aPLA2Rab level to diagnose PLA2R-MN. Results: The urinary exosomes contained a high abundance of PLA2R antigen as evidenced by protein mass spectrometry and western blot in 85 PLA2R-MN patients vs the disease controls (14 secondary MN patients, 22 non-MN patients and 4 PLA2R-negative MN patients) and 20 healthy controls. Of note, urinary exosomal PLA2R antigen abundance also had a good consistency with the PLA2R antigen level in the renal specimens of PLA2R-MN patients. The sensitivity of urinary exosomal PLA2R for diagnosing PLA2R-MN reached 95.4%, whereas the specificity was 63.3%. Combining detection of the urinary exosomal PLA2R and serum aPLA2Rab could develop a more sensitive diagnostic method for PLA2R-MN, especially for patients with serum aPLA2Rab ranging from 2 to 20 RU/mL. Conclusions: Measurement of urinary exosomal PLA2R could be a sensitive method for the diagnosis of PLA2R-MN.

Preparation, Characterization, and Properties of UV-Curable Coating Doped with Nano-SiO2.

In this study, a hydrophobic, wear-resistant ultraviolet (UV)-curable coating was investigated as an alternative to traditional coatings with low hardness and high susceptibility to scratching. The SiO2 nanoparticles were ground and modified using high-energy ball milling, during which the surface energy of nano-SiO2 particles rapidly increased as their particle size decreased. Different proportions of modified nano-SiO2 particles were added to the coating and cured into a film. The structure of the composite coating was analyzed via infrared spectroscopy, scanning electron microscopy, and X-ray diffraction, which confirmed the successful preparation of the composite coating. The mechanical and optical property tests of the coating were investigated. With a 5% nano-SiO2 content, the hardness of the coating reached 5H, whereas the adhesion was poor (2B), and the flexibility was 1. The overall comprehensive performance of the coating was best when the addition amount was 3%. The coating exhibited good hardness, flexibility, and adhesion. The hardness of the coating reached 4H, the adhesion was 4B, the flexibility was 5, the coating haze was 12.38 HZ, and the contact angle was 118°.

Personality traits and peritoneal dialysis patients' prognosis.

Objective: Peritoneal dialysis (PD) requires high patient conscientiousness. Therefore, we aimed to investigate the relationship between conscientiousness score and prognosis in PD patients.Methods: The ten-item Big Five Personality Inventory's Chinese version was used to assess the conscientiousness score. Basic clinical information, prior medical history, hematological examination results, the occurrence of the first peritonitis and catheter-related infection, the start of hemodialysis, and the time of renal transplantation were collected. The patients were split into two groups, high and low conscientiousness groups, based on the mean value of the conscientiousness score. The differences in prognostic indicators were compared between groups, and the association between conscientiousness score and prognostic indicators in PD patients was assessed.Results: Enrolled PD patients were divided into low conscientiousness group 103 and high conscientiousness group 98. There were significant differences in serum albumin (p = 0.021) and iPTH (p = 0.045) between the two groups. Multivariate Cox regression analysis identified conscientiousness score as an independent risk factor for the development of first peritonitis (HR = 0.558, 95% CI 0.400-0.779, p = 0.001) and first catheter-related infection (HR = 0.544, 95% CI 0.308-0.962, p = 0.036) in PD patients. Conscientiousness score (HR = 2.377, 95% CI 1.109-5.095, p = 0.026) was independently associated with renal transplantation.Conclusion: Conscientiousness personality is closely related to the prognosis of PD patients.

Preparation of UV-Curable Nano-WO3Coating and Its Infrared Shielding Properties.

Nano-WO3 particles are expected to find use in new shielding materials because of their significant absorption of near-infrared light in the 1400-1600 nm and 1900-2200 nm bands and high transmittance of visible light. In this study, WO3 was ground and dispersed using high-energy ball-milling to prepare a nano-WO3 dispersion using BYK331 as the dispersant and ethanol as the solvent. The prepared nano-WO3 dispersion was added to a photo-curing system and cured using UV irradiation to form films. The cured films were characterized using FT-IR, SEM, XRD, and TGA. The results showed that the nano-WO3 powder was evenly dispersed in the coating. The infrared blocking rate of the film continuously improved and the visible light transmission rate continuously decreased with increasing amounts of nano-WO3.For the film containing 6 wt%nano-WO3, the infrared blocking rate of the coating is 90%, the visible light transmittance is 70%, the hardness of the coating is 3B, and the adhesion is 3H. The thermal stability of the coating is also improved.

Effects of African BaP emission from wildfire biomass burning on regional and global environment and human health.

The vegetation burning caused by wildfires can release significant quantities of aerosols and toxic chemicals into the atmosphere and result in health risk. Among these emitted pollutants, Benzo(a)pyrene (BaP), the most toxic congener of 16 parent PAHs (polycyclic aromatic hydrocarbons), has received widespread concerns because of its carcinogenicity to human health. Efforts have been made to investigate the environmental and health consequences of wildfire-induced BaP emissions in Africa. Still, uncertainties remain due to knowledge and data gaps in wildfire incidences and biomass burning emissions. Based on a newly-developed BaP emission inventory, the present study assesses quantitatively the BaP environment cycling in Africa and its effects on other continents from 2001 to 2014. The new inventory reveals the increasing contribution of BaP emission from African wildfires to the global total primarily from anthropogenic sources, accounting for 48% since the 2000 s. We identify significantly higher BaP emissions and concentrations across sub-Saharan Africa, where the annual averaged BaP concentrations were as high as 5-8 ng/m3. The modeled BaP concentrations were implemented to estimate the lifetime cancer risk (LCR) from the inhalation exposure to BaP concentrations. The results reveal that the LCR values in many African countries exceeded the acceptable risk level at 1 × 10-6, some of which suffer from very high exposure risk with the LCR>1 × 10-4. We show that the African BaP emission from wildfires contributed, to some extent, BaP contamination to Europe as well as other regions, depending on source proximity and atmospheric pathways under favorable atmospheric circulation patterns.

Apo A1/Apo B ratio and acute coronary syndrome among peritoneal dialysis patients.

BACKGROUND: Acute coronary syndrome (ACS) is prevalent in continuous ambulatory peritoneal dialysis (CAPD) patients. However, the association between the apoprotein profile and ACS is not well known. Therefore, we aimed to investigate the relationship between apoproteins and ACS in CAPD patients. METHODS: Eighty-one CAPD patients were included in this retrospective study. The primary endpoint was ACS. Predictors were baseline apoprotein levels, particularly the ratio of apoprotein A1 (Apo A1)/apoprotein B (Apo B). Cox regression was used to determine the relationship between Apo A1/Apo B and ACS. RESULTS: During follow-up, 34 (41.98%) CAPD patients experienced an ACS. ACS patients had higher levels of total cholesterol (p = 0.03), low-density lipoprotein cholesterol (LDL-C) (p = 0.04), C-reactive protein (p = 0.01), and Apo B (p < 0.01). However, hemoglobin (p = 0.01) and Apo A1/Apo B (p < 0.01) were lower in the ACS group than the non-ACS group. Patients with Apo A1/Apo B ≥ 1.105 experienced fewer ACS compared with those with Apo A1/Apo B < 1.105 (33.33% vs. 75.56%, p = 0.03). In Cox regression, Apo A1/Apo B (RR, 0.06; 95% CI, 0.00-0.77; p = 0.03) was independently associated with ACS. CONCLUSIONS: Apo A1/Apo B was strongly associated with ACS and may be considered as a predictor of future ACS in CAPD patients.

Cardioprotective effect of anisodamine against ischemia/reperfusion injury through the mitochondrial ATP-sensitive potassium channel.

Previous clinical studies have shown that anisodamine could improve no-reflow phenomenon and prevent reperfusion arrhythmias, but whether this protective effect is related to the antagonism of the M-type cholinergic receptor or other potential mechanisms is uncertain. The aim of the present study was to investigate the role of the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) in cardioprotective effect of anisodamine against ischemia/reperfusion injury. Anisodamine and 5- hydroxydecanoic acid were used to explore the relationship between anisodamine and mitoK ATP . Using a Langendorff isolated heart ischemia/reperfusion injury model, hemodynamic parameters and reperfusion ventricular arrhythmia were evaluated; in addition, changes in myocardial infarct size, cTnI from coronary effluent and myocardial ultrastructure, as well as ATP, MDA and SOD in myocardial tissues, were detected. In the hypoxia/reoxygenation injury model of neonatal rat cardiomyocyte, cTnI release in the culture medium and levels of ATP, MDA and SOD in cardiomyocytes and mitochondrial membrane potential, were analyzed. Overall, anisodamine could significantly improve the hemodynamic indexes of isolated rat heart injured by ischemia/reperfusion, reduce the occurrence of ventricular reperfusion arrhythmia and myocardial infarction area, and improve the ultrastructural damage of myocardium and mitochondria. The in vitro results demonstrated that anisodamine could improve mitochondrial energy metabolism, reduce oxidative stress and stabilize mitochondrial membrane potential. The cardioprotective effects were significantly inhibited by 5-hydroxydecanoic acid. In conclusion, this study suggests that the opening of mitoK ATP could play an important role in the protective effect of anisodamine against myocardial ischemia/reperfusion injury.

P037 Effect of Ozanimod Treatment and Discontinuation on Absolute Lymphocyte Count in Moderate-to-Severe Ulcerative Colitis: Results from a Phase 3 Trial.

BACKGROUND: Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, which reduces migration of lymphocytes involved in adaptive immunity from lymphoid tissues to blood and inflamed tissues while preserving components of the innate immune response. Ozanimod is approved in multiple countries for the treatment of relapsing forms of multiple sclerosis and in the US for the treatment of moderately-to-severely active ulcerative colitis (UC). The reduction of circulating lymphocytes is expected based on the mechanism of action of ozanimod and thought to be an important driver of efficacy. METHODS: We assessed absolute lymphocyte count (ALC) during ozanimod induction and maintenance, and after ozanimod discontinuation, per protocol, in adults with moderately-to-severely active UC to characterize the time course of ALC reduction and recovery. The analysis included patients who received ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo once daily in True North, a phase 3 randomized trial (NCT02435992). During a 10-week induction period, patients were randomized 2:1 to double-blind treatment with ozanimod or placebo (Cohort 1) or received open-label ozanimod (Cohort 2). Patients from either cohort with a clinical response to ozanimod at week 10 were re-randomized 1:1 to double-blind treatment with ozanimod or placebo during maintenance through week 52. Placebo-treated patients with a clinical response at week 10 continued placebo during maintenance. ALC was assessed at baseline and at visits throughout induction and maintenance. RESULTS: A total of 69 patients received continuous placebo treatment, 230 received continuous ozanimod treatment, and 227 received ozanimod during induction and placebo during maintenance. In patients who received continuous placebo, mean ALC remained stable between 1.8‒2.1 x 109/L over time (normal range: 1.02‒3.36 x 109/L). In ozanimod-treated patients, mean ALC was reduced to 43%‒45% of baseline and 70%‒73% of patients had ALC shifts from normal at baseline to low (9/L) at week 10. In patients who continued ozanimod, mean ALC reductions were sustained at approximately the same level and ALC shifts from normal at baseline to low were maintained in 73%‒89% of patients during maintenance. In patients who received ozanimod induction therapy and then were re-randomized to placebo for maintenance, mean ALC recovered within 8 weeks to levels similar to baseline at induction and the proportion of patients with ALC shifts from normal at baseline to low decreased from 73% at week 10 to 6% at week 52. Fewer than 2% of ozanimod-treated patients had ALC 9/L during either induction or maintenance and ALC generally returned to ≥ 0.2 x 109/L while patients remained on ozanimod. Among those who switched from ozanimod induction to placebo maintenance, there were no occurrences of ALC 9/L at the end of maintenance. No patients with a serious/opportunistic infection had concurrent ALC 9/L. CONCLUSION: Consistent with the mechanism of action of ozanimod, ALC reductions occurred during ozanimod induction and were sustained during maintenance. Incidence of ALC 9/L was low. ALC recovered after switching to placebo and most patients did not require treatment discontinuation because of changes in ALC.

Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non-Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial.

BACKGROUND: We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non-small-cell lung cancer. PATIENTS AND METHODS: Patients with treatment-naive squamous non-small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). RESULTS: Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator's discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). CONCLUSIONS: The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.

Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study.

BACKGROUND: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma. METHODS: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing. FINDINGS: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation. INTERPRETATION: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting. FUNDING: Celgene Corporation.

Safety and efficacy of intracoronary prourokinase administration in patients with high thrombus burden.

OBJECTIVES: The study was designed to evaluate the effect of low-dose intracoronary prourokinase administration immediately after thrombus aspiration in patients with ST-segment elevation myocardial infarction (STEMI) presenting with a serious thrombus burden. METHODS: Consecutive STEMI patients with high thrombus burden received thrombus aspiration during primary percutaneous coronary intervention (PCI) were randomly assigned to study group (intracoronary prourokinase administration) or control group (intracoronary 0.9% sodium chloride administration). The primary endpoint was complete ST-segment resolution (STR) at 90 min after primary PCI, and the secondary endpoints included angiographic myocardial perfusion indexes. RESULTS: Patients in study group had a higher incidence of complete STR and myocardial blush grade 3 compared with those in control group (56.52% vs. 38.89%, P = 0.017 and 57.61% vs. 38.89%, P = 0.041). The peak cardiac troponin I value and corrected thrombolysis in myocardial infarction frame count were significantly lower in study group (52.16 ± 24.67 ng/mL vs. 60.91 ± 28.81 ng/mL, P = 0.029; and 19.57 ± 9.05 vs. 22.91 ± 10.22, P = 0.020). A significant improvement in left ventricular ejection fraction and major adverse cardiac events (MACEs)-free survival was observed in study group (55.22 ± 10.50% vs. 52.18 ± 9.39%, P = 0.041; 10.87% vs. 22.22%, P = 0.039) at the 6-month follow-up. The bleeding complication was similar in both groups (17.39% vs. 12.22%, P = 0.327). CONCLUSIONS: In STEMI patients with high thrombus burden, low-dose prourokinase intracoronary administered immediately after thrombus aspiration improves myocardial perfusion, cardiac function, and MACEs-free survival with no significant increase in major bleeding.

Predictive value of soluble suppression of tumourigenicity 2 on myocardial reperfusion.

BACKGROUND: High baseline level of soluble suppression of tumourigenicity 2 (sST2) was an independent predictor of cardiovascular death and heart failure in ST-segment elevation myocardial infarction (STEMI). AIMS: To investigate the value of serum sST2 baseline levels in predicting myocardial reperfusion in patients with STEMI undergoing primary percutaneous coronary intervention (PPCI). METHODS: Consecutive STEMI patients who underwent PPCI within 12 h after the onset of chest pain were enrolled, and were divided into Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grading (TMPG) 0/1/2 group and TMPG 3 group based on post-procedural TMPG. Baseline clinical characteristics, lesions and procedural characteristics were compared. Univariate logistic regression and multivariate linear logistic analysis were performed to identify independent predictors of impaired myocardial reperfusion (TMPG 0/1/2). Receiver-operating characteristics curve (ROC) analysis of sST2 was performed to identify the optimum cut-off value for predicting the myocardial reperfusion. RESULTS: A total of 121 patients was enrolled in this study. Univariate logistic regression analysis showed that Killip II-III, high levels of sST2 and brain natriuretic peptide were risk factors of TMPG 0/1/2. Multivariable logistic regression analysis revealed that sST2 was an independent predictor of impaired myocardial reperfusion (odds ratio 12.318, 95% confidence interval 4.567-33.220, P < 0.001). ROC curve analysis showed that the area under curve of sST2 was 0.849, and the best cut-off value was 2.003 ng/mL, with a sensitivity of 89.2% and a specificity of 67.9%. CONCLUSION: The elevated levels of sST2 on admission were associated with impaired myocardial reperfusion in STEMI patients undergoing PPCI.

Platelet-to-lymphocyte ratio is associated with cardiovascular disease in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: Chronic kidney disease (CKD) patients have a high incidence of cardiovascular disease (CVD) events, which is related to the inflammatory status of this population. Platelet-to-lymphocyte ratio (PLR) is a relatively new indicator of inflammation. The aim of this study was to investigate the relationship between PLR and the CVD events in continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: A total of 70 stable CAPD patients were included in this study from February 2014 to March 2017, and complete demographic characteristics and clinical laboratory baseline data were collected at enrollment. The primary endpoint was defined as the experienced of CVD events during the follow-up period. Binary logistic regression was used to assess the association between PLR and CVD events in CAPD patients. RESULTS: During a median follow-up period of 22 months, 28 (40%) CAPD patients experienced CVD events. Patients in the CVD event group had a high level of platelets (P < 0.01), C-reactive protein (P < 0.01), PLR (P < 0.01) and neutrophil-to-lymphocyte ratio (NLR) (P < 0.01). However, lymphocyte counts (P < 0.01) were significantly lower than patients without CVD events. Following adjusted binary regression analysis revealed no relationship between high NLR and CVD events (OR, 1.21; 95% CI, 0.52-2.85; p = 0.44). However, the correlation between high PLR and CVD events was significant (OR, 1.05; 95% CI, 1.02-1.08; p < 0.01). High PLR was confirmed as an independent predictor of CVD events. CONCLUSION: Our results demonstrated that PLR was independently associated with CVD events. High PLR can be used to predict the risk of CVD events in CAPD patients. PLR was easy to obtain and can be considered as a routine test to serve the clinic.

Biodegradation of Structurally Diverse Phthalate Esters by a Newly Identified Esterase with Catalytic Activity toward Di(2-ethylhexyl) Phthalate.

Herein, we report a double enzyme system to degrade 12 phthalate esters (PAEs), particularly bulky PAEs, such as the widely used bis(2-ethylhexyl) phthalate (DEHP), in a one-pot cascade process. A PAE-degrading bacterium, Gordonia sp. strain 5F, was isolated from soil polluted with plastic waste. From this strain, a novel esterase (GoEst15) and a mono(2-ethylhexyl) phthalate hydrolase (GoEstM1) were identified by homology-based cloning. GoEst15 showed broad substrate specificity, hydrolyzing DEHP and 10 other PAEs to monoalkyl phthalates, which were further degraded by GoEstM1 to phthalic acid. GoEst15 and GoEstM1 were heterologously coexpressed in Escherichia coli BL21 (DE3), which could then completely degrade 12 PAEs (5 mM), within 1 and 24 h for small and bulky substrates, respectively. To our knowledge, GoEst15 is the first DEHP hydrolase with a known protein sequence, which will enable protein engineering to enhance its catalytic performance in the future.

Beneficial effect of ticagrelor on microvascular perfusion in patients with ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention.

BACKGROUND: Ticagrelor significantly reduced the incidence of death, myocardial infarction, and stent thrombosis in patients with ST-segment elevation myocardial infarction (STEMI) intended for reperfusion with a primary percutaneous coronary intervention (pPCI). However, the effects of this drug on microvascular perfusion in patients presenting with STEMI have not been evaluated completely. PATIENTS AND METHODS: A total of 298 patients presenting with STEMI were randomized to either ticagrelor 180 mg loading, followed by 90 mg twice daily, or clopidogrel 600 mg loading, followed by 75 mg daily. The primary endpoint was ST-segment resolution at 90 min after pPCI. The secondary endpoints included myocardial blush grade and corrected thrombolysis in myocardial infarction frame count after the procedure. Left ventricular ejection fraction and major adverse cardiac events (MACE) at the 1- and 6-month follow-up time points were also recorded. RESULTS: There were no significant differences between the two groups with respect to baseline characteristics. Ticagrelor administration resulted in a higher rate of completed ST-segment resolution (58.67 vs. 39.86%, P=0.001), higher myocardial blush grade (2.63±0.64 vs. 2.41±0.71, P=0.005), and lower corrected thrombolysis in myocardial infarction frame count (19.68±7.38 vs. 22.35±8.30, P=0.004). At 6 months, left ventricular ejection fraction was higher (55.01±8.44 vs. 52.34±9.05%, P=0.009) in the ticagrelor group. Kaplan-Meier analysis showed that MACE-free survival had also improved in the ticagrelor group during the 1- and 6-month follow-up time points. CONCLUSION: Compared with clopidogrel, ticagrelor improves myocardial perfusion and left ventricular ejection fraction, and reduces the incidence of MACE for STEMI patients undergoing pPCI, with no significant increase in major bleeding.

nab-Paclitaxel/carboplatin in elderly patients with advanced squamous non-small cell lung cancer: a retrospective analysis of a Phase III trial.

BACKGROUND: Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. CONCLUSION: nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup.

Promotion time cure rate model with nonparametric form of covariate effects.

Survival data with a cured portion are commonly seen in clinical trials. Motivated from a biological interpretation of cancer metastasis, promotion time cure model is a popular alternative to the mixture cure rate model for analyzing such data. The existing promotion cure models all assume a restrictive parametric form of covariate effects, which can be incorrectly specified especially at the exploratory stage. In this paper, we propose a nonparametric approach to modeling the covariate effects under the framework of promotion time cure model. The covariate effect function is estimated by smoothing splines via the optimization of a penalized profile likelihood. Point-wise interval estimates are also derived from the Bayesian interpretation of the penalized profile likelihood. Asymptotic convergence rates are established for the proposed estimates. Simulations show excellent performance of the proposed nonparametric method, which is then applied to a melanoma study.

Effect of pioglitazone on the calcification of rat vascular smooth muscle cells through the downregulation of the Wnt/ß­catenin signaling pathway.

The aim of the present study was to investigate the effect and possible mechanism of pioglitazone (PIO) on the calcification of rat vascular smooth muscle cells (VSMCs) in vitro. ß­glycerophosphate (ß­GP; 10 mmol/l) was used to induce calcification of VSMCs treated with a range of concentrations (5, 10, 15 and 20 µmol/l) of PIO for 12 days. Calcium deposits were revealed by Alizarin red staining. Extracellular calcium content was detected using a calcium assay kit. Western blotting was used to measure the expression of α­smooth muscle actin (α­SMA), runt­related transcription factor 2 (Runx2), bone morphogenetic protein­2 (BMP2), ß­catenin, glycogen synthase kinase­3ß (GSK­3ß), phosphorylated (p)­GSK­3ß and cyclin­D1. A total of 10 mmol/l ß­GP, 20 µmol/l PIO and 20 µmol/l peroxisome proliferator­activated receptor γ (PPAR γ) antagonist GW9662, was added to the cell culture media. The changes of the above indexes were observed. The calcium content in the calcification group, treated with high phosphorus, increased significantly compared with the controls (P<0.05) and all different concentrations of PIO reduced extracellular calcium content (P<0.05). Alizarin red staining was positive in calcified VSMCs and PIO (20 µmol/l) intervention group was almost negative. The expressions of Runx2, ß­catenin, p­GSK­3ß, BMP2 and cyclin­D1 increased significantly in the calcification group, and treatment with 20 µmol/l PIO downregulated the expression of all the above proteins, while upregulating the expression of α­SMA. The PPAR γ antagonist GW9662 could partly inhibit the effect of PIO on calcified VSMCs. The results of the present study indicated that PIO can alleviate the calcification of rat aortic VSMCs induced by ß­GP via inhibiting the activity of the Wnt/ß­catenin signaling pathway.

The Role and Mechanism of α-Klotho in the Calcification of Rat Aortic Vascular Smooth Muscle Cells.

OBJECTIVE: To investigate the role and possible mechanism of α-Klotho in the calcification and the osteogenic transition of cultured VSMCs. METHODS: VSMCs were cultured in vitro and divided into 5 groups, each using a different medium: (1) control; (2) ß-GP; (3) ß-GP + Klotho; (4) ß-GP + LiCl; (5) ß-GP + Klotho + LiCl. Calcium deposits were visualized using Alizarin Red S staining. The calcium concentrations were determined by the o-cresolphthalein complexone method. BMP2, Runx2 and ß-catenin levels were estimated by western blotting, and the level of α-SMA was determined by using immunofluorescence at day 12. RESULTS: ß-GP induced an increase in the expression of BMP2, Runx2, and ß-catenin. The calcium content increased, and the expression of α-SMA decreased. Alizarin Red S staining was positive under the high phosphorus conditions. BMP2, Runx2, and ß-catenin levels and the calcium content decreased when the cells were cultured with rmKlotho; however, the levels of each were upregulated after treatment with the LiCl. CONCLUSIONS: Klotho can ameliorate the calcification and osteogenic transition of VSMCs induced by ß-GP. The mechanism of Klotho in preventing calcification in VSMCs may be partially mediated by the inhibition of the Wnt/ß-catenin signaling pathway.