Sulforaphane inhibits the migration and invasion of BPDE-induced lung adenocarcinoma cells by regulating NLRP12.

This study aims to explore the impact and underlying mechanism of sulforaphane (SFN) intervention on the migration and invasion of lung adenocarcinoma induced by 7, 8-dihydroxy-9, 10-epoxy-benzo (a) pyrene (BPDE). Human lung adenocarcinoma A549 cells were exposed to varying concentrations of BPDE (0.25, 0.50, and 1.00 µM) and subsequently treated with 5 µM SFN. Cell viability was determined using CCK8 assay, while migration and invasion were assessed using Transwell assays. Lentivirus transfection was employed to establish NLRP12 overexpressing A549 cells. ELISA was utilized to quantify IL-33, CXCL12, and CXCL13 levels in the supernatant, while quantitative real-time PCR (qRT-PCR) and Western Blot were used to analyze the expression of NLRP12 and key factors associated with canonical and non-canonical NF-κB pathways. Results indicated an increase in migratory and invasive capabilities, concurrent with heightened expression of IL-33, CXCL12, CXCL13, and factors associated with both canonical and non-canonical NF-κB pathways. Moreover, mRNA and protein levels of NLRP12 were decreased in BPDE-stimulated A549 cells. Subsequent SFN intervention attenuated BPDE-induced migration and invasion of A549 cells. Lentivirus-mediated NLRP12 overexpression not only reversed the observed phenotype in BPDE-induced cells but also led to a reduction in the expression of critical factors associated with both canonical and non-canonical NF-κB pathways. Collectively, we found that SFN could inhibit BPDE-induced migration and invasion of A549 cells by upregulating NLRP12, thereby influencing both canonical and non-canonical NF-κB pathways.

Research on Flow Patterns of Two-Phase Fracturing Fluid in Hydraulic Fracture Considering the Fluid Leak-off.

In in situ-generated proppant fracturing technology without proppant injection, the distribution of the flow pattern of two-phase fracturing fluid in the fracture determines the concentration of proppant particles formed by phase change in different positions. Therefore, the study of a two-phase fracturing fluid flow pattern is of great significance to reveal the formation mechanisms of different flow patterns and guide the on-site implementation of the technology. This paper establishes a mathematical model for the two-phase fracturing fluids in fractures based on their physical properties and presents numerical experiments on the flow pattern of two-phase fracturing fluids under different conditions of injection displacement, interfacial tension, and phase change liquid (PCL) ratio. The results show that at lower injection displacements, such as 3 or 4 m3/min, it is easier to form striped shape distributions, and at higher injection displacements, such as 5 or 6 m3/min, it is easier to form droplet shape distributions. When the interfacial tension is low (15 mN/m), PCL shrinks less and is distributed in strips; when the interfacial tension is high (25, 35, and 45 mN/m), PCL shrinks more and mainly forms droplet-shaped distributions. PCL tends to form discrete droplet shape distributions at PCL volume fractions of 10, and 20%. At 30% volume fraction, PCL is distributed in strips, and at 40% volume fraction, PCL forms strips of a larger size. These findings reveal the changing pattern of two-phase fracturing fluid flow and enrich the theoretical system of in situ-generated proppant fracturing technology, which can provide theoretical support for the on-site implementation of this technology.

AURKA inhibition induces Ewing's sarcoma apoptosis and ferroptosis through NPM1/YAP1 axis.

Ewing's sarcoma (ES) is a rare and highly aggressive malignant tumor arising from bone and soft tissue. Suffering from intractable or recurrent diseases, the patients' therapy options are very limited. It is extremely urgent to identify novel potential therapeutic targets for ES and put them into use in clinical settings. In the present study, high-throughput screening of a small molecular pharmacy library was performed. The killing effect of the Aurora kinase A (AURKA) inhibitor TCS7010 in ES cells was identified, and AURKA was selected as the research object for further study. Disparate suppressants were adopted to study the cell death manner of TCS7010. TCS7010 and RNA silencing were used to evaluate the functions of AURKA in the apoptosis and ferroptosis of ES cells. Co-immunoprecipitation assay was used to investigate the correlation of AURKA and nucleophosmin1 (NPM1) in ES. Nude-mice transplanted tumor model was used for investigating the role of AURKA in ES in vivo. Investigations into the protein activities of AURKA were conducted using ES cell lines and xenograft models. AURKA was found to be prominently upregulated in ES. The AURKA expression level was remarkably connected to ES patients' shorter overall survival (OS) and event-free survival (EFS). Furthermore, AURKA inhibition markedly induced the apoptosis and ferroptosis of ES cells and attenuated tumorigenesis in vivo. On the part of potential mechanisms, it was found that AURKA inhibition triggered the apoptosis and ferroptosis of ES cells through the NPM1/Yes1 associated transcriptional regulator (YAP1) axis, which provides new insights into the tumorigenesis of ES. AURKA may be a prospective target for clinical intervention in ES patients.

Glucose Oxidase of a Crucifer-Specialized Insect: A Potential Role in Suppressing Plant Defense via Modulating Antagonistic Plant Hormones.

Glucose oxidase (GOX) is a representative compound found in most insect saliva that can suppress plant-defensive responses. However, little is known about the origin and role of GOX in the crucifer-specialized pest Plutella xylostella. In this study, we showed obvious regurgitation from the larval gut of P. xylostella and identified abundant peptides highly similar to known GOX. Three PxGOX genes were verified with PxGOX2 preferentially expressed in the gut. The heterologously expressed PxGOX2 confirmed its function to be a GOX, and it was detected in plant wounds together with the gut regurgitant. Further experiments revealed that PxGOX2 functioned as an effector and may suppress defensive responses in plant through the production of H2O2, which modulates levels of antagonistic salicylic acid and jasmonic acid. However, excessive H2O2 in the host plant may be neutralized by peroxidase, thus forming defensive feedback. Our findings provided new insights into understanding the GOX-mediated insect-plant interactions.

Lung proteomics combined with metabolomics reveals molecular characteristics of inflammation-related lung tumorigenesis induced by B(a)P and LPS.

Inflammatory microenvironment may take a promoting role in lung tumorigenesis. However, the molecular characteristics underlying inflammation-related lung cancer remains unknown. In this work, the inflammation-related lung tumorigenesis mouse model was established by treated with B(a)P (1 mg/mouse, once a week for 4 weeks), followed by LPS (2.5 µg/mouse, once every 3 weeks for five times), the mice were sacrificed 30 weeks after exposure. TMT-labeled quantitative proteomics and untargeted metabolomics were used to interrogate differentially expressed proteins and metabolites in different mouse cancer tissues, followed by integrated crosstalk between proteomics and metabolomics through Spearman's correlation analysis. The result showed that compared with the control group, 103 proteins and 37 metabolites in B(a)P/LPS group were identified as significantly altered. By searching KEGG pathway database, proteomics pathways such as Leishmaniasis, Asthma and Intestinal immune network for IgA production, metabolomics pathways such as Vascular smooth muscle contraction, Linoleic acid metabolism and cGMP-PKG signaling pathway were enriched. A total of 22 pathways were enriched after conjoint analysis of the proteomic and metabolomics, and purine metabolism pathway, the unique metabolism-related pathway, which included significantly altered protein (adenylate cyclase 4, ADCY4) and metabolites (L-Glutamine, guanosine monophosphate (GMP), adenosine and guanosine) was found. Results suggested purine metabolism may contribute to the inflammation-related lung tumorigenesis, which may provide novel clues for the therapeutic strategies of inflammation-related lung cancer.

The activation of SIRT1 ameliorates BPDE-induced inflammatory damage in BEAS-2B cells via HMGB1/TLR4/NF-κB pathway.

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the metabolite of environmental pollutant benzo(a)pyrene (B(a)P) could induce pulmonary toxicity and inflammation. SIRT1, an NAD+ -dependent histone deacetylase, is known to regulate inflammation in the occurrence and development of various diseases, but its effects on BPDE-induced acute lung injury are still unknown. The present study aimed to explore the role of SIRT1 in BPDE-induced acute lung injury. Here, human bronchial epithelial (HBE) cells (BEAS-2B) cells were stimulated with BPDE at different concentrations (0.50, 0.75, and 1.00 µmol/L) for 24 h, we found that the levels of cytokines in the supernatant were increased and the expression of SIRT1 in cells was down-regulated, at the same time, BPDE stimulation up-regulated the protein expression of HMGB1, TLR4, and p-NF-κBp65 in BEAS-2B cells. Then the activator and inhibitor of SIRT1 were used before BPDE exposure, it was shown that the activation of SIRT1 significantly attenuated the levels of inflammatory cytokines and HMGB1, and reduced the expression of HMGB1, AC-HMGB1, TLR4, and p-NF-κBp65 protein; while these results were reversed by the inhibition of SIRT1. This study revealed that the SIRT1 activation may protect against BPDE-induced inflammatory damage in BEAS-2B cells by regulating the HMGB1/TLR4/NF-κB pathway.

Multiphysics Modeling and Simulation of a Light-Controlled Variable Damping System.

In this paper, a light-controlled variable damping system (LCVDS) is proposed based on PLZT ceramics and electrorheological fluid (ERF). The mathematical models for the photovoltage of PLZT ceramics and the hydrodynamic model for the ERF are established, and the relationship between the pressure difference at both ends of the microchannel and the light intensity is deduced. Then, simulations are conducted by applying different light intensities in the LCVDS to analyze the pressure difference at both ends of the microchannel using COMSOL Multiphysics. The simulation results show that the pressure difference at both ends of the microchannel increases with the increase in light intensity, which is consistent with results from the mathematical model established in this paper. The error rate of the pressure difference at both ends of the microchannel is within 13.8% between the theoretical and simulation results. This investigation lays the foundation for the application of light-controlled variable damping in future engineering.

Oral spleen tyrosine kinase/Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study.

BACKGROUND: Gusacitinib is an oral inhibitor of Janus and Spleen tyrosine kinases. METHODS: The efficacy and safety of gusacitinib were evaluated in a double-blind, placebo-controlled, multicenter, phase 2 study in 97 chronic hand eczema patients randomized (1:1:1) to placebo or gusacitinib (40 or 80 mg) for 12 weeks (part A). Then, in part B (through week 32), the patients received gusacitinib. RESULTS: At week 16, patients receiving 80 mg gusacitinib showed a 69.5% (P <.005) decrease in the modified total lesion-symptom score versus 49.0% for 40 mg (P =.132), and 33.5% for placebo. Considerable improvement in Physician's Global Assessment was seen in 31.3% of patients receiving 80 mg versus 6.3% of placebo (P <.05). A 73.3% decrease in the hand eczema severity index versus placebo (21.7%) occurred in patients receiving 80 mg (P <.001). Patients receiving 80 mg experienced a considerable decrease in hand pain (P <.05). As early as week 2, considerable reductions over placebo in modified total lesion-symptom score (P <.005), Physician's Global Assessment (P =.04), and hand eczema severity index (P <.01) were observed (80 mg gusacitinib). Adverse events included upper respiratory infection, headache, nausea, and nasopharyngitis. CONCLUSIONS: Gusacitinib showed rapid improvement in chronic hand eczema patients and was well tolerated, warranting further investigations.

Programmed cell death protein-1/programmed death-ligand 1 blockade enhances the antitumor efficacy of adoptive cell therapy against non-small cell lung cancer.

BACKGROUND: Cytokine-induced killer (CIK) cells and natural killer (NK) cells are employed by two different approaches to adoptive cell immunotherapy for cancer. It has been reported that adoptive cell immunotherapy could prolong the overall survival (OS) of advanced cancer patients. The introduction of agents that induce immune checkpoint blockades has improved the efficacy of immune-mediated therapy for metastatic cancers. However, the effects of combining a checkpoint inhibitor with CIK cells or NK cells to target non-small cell lung cancer (NSCLC)remain unknown. METHODS: The present study investigated the effects of combining CIK cells with a programmed cell death protein-1 (PD-1) inhibitor (an anti-PD-1 monoclonal antibody). During the expansion cultivation, the addition of the PD-1 antibody promoted CIK-mediated cytotoxicity in H1975 lung adenocarcinoma cells. Co-cultivation of CIK cells with the PD-1 antibody for 6 days induced CD3+CD56+ T cell expansion, with increases in the levels of CD107a and interferon γ (IFN-γ). RESULTS: When NK cells were co-cultured with 5 µg/mL of an anti-programmed death-ligand 1 (PD-L1) mAb for 24 hours at an effector cell: target ratio of 10:1, it led to more potent cytotoxicity compared to other time points and concentrations. However, combining NK cells with the anti-PD-L1 mAb showed no significant advantages over treatment with NK cells alone. CONCLUSIONS: Our results suggest that combining CIK cells with PD-1 blockade before transfusion might improve the efficiency of CIK therapy for NSCLC patients. This effect does not seem to occur for NK cell therapy.

A systematic and genome-wide correlation meta-analysis of PD-L1 expression and targetable NSCLC driver genes.

BACKGROUND: Studies have shown that the ligand of programmed cell death protein 1 (B7-H1, CD274 or PD-L1) is related to lung cancer driver genes. Although studies have examined the association between lung cancer driver gene mutations or expression and PD-L1 expression, the present studies have not been mined the correlation systematically and genome-widely. METHODS: All relevant published PD-L1 articles with driver genes data and the RNA-seq dataset from The Cancer Genome Atlas (TCGA) were analyzed. We performed meta-analysis for data included in the selected literature, and then independently explored the correlation between genes by co-expression analysis of RNA-seq data in the TCGA database. RESULTS: A sum of 9,934 lung cancer cases were collected from 34 published studies. Higher PD-L1 expression was associated with wild-type epidermal growth factor receptor (EGFR) [odds ratio (OR): 0.68, 95% confidence interval (CI): 0.48-0.96, P=0.03], Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (OR: 1.27, 95% CI: 1.02-1.58, P=0.03) or non-adenocarcinoma histology (OR: 0.68, 95% CI: 0.47-0.98, P=0.04). In addition, our analysis from TCGA data indicated that, compared with lung adenocarcinoma, the expression of PD-L1 was significantly higher than that of squamous cell carcinoma patients (P=0.023). The expression of targetable driver genes showed no correlations with PD-L1 expression in non-small cell lung cancer (NSCLC). CONCLUSIONS: Our results suggest the presence of EGFR wild-type, KRAS gene mutations or squamous cell carcinoma were associated with high PD-L1expression, which provides potential benefited population for the administration of PD-1/PD-L1 blockade in human lung cancer.

RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers.

RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer.

Rapid determination of six carcinogenic primary aromatic amines in mainstream cigarette smoke by two-dimensional online solid phase extraction combined with liquid chromatography tandem mass spectrometry.

A fully automated, rapid, and reliable method for simultaneous determination of six carcinogenic primary aromatic amines (AAs), including o-toluidine (o-TOL), 2, 6-dimethylaniline (2, 6-DMA), o-anisidine (o-ASD), 1-naphthylamine (1-ANP), 2-naphthylamine (2-ANP), and 4-aminobiphenyl (4-ABP), in mainstream cigarette smoke was established. The proposed method was based on two-dimensional online solid phase extraction combined with liquid chromatography tandem mass spectrometry (SPE/LC-MS/MS). The particulate phase of the mainstream cigarette smoke was collected on a Cambridge filter pad and pretreated via ultrasonic extraction with 2% formic acid (FA), while the gas phase was trapped by 2% FA without pretreatment for determination. The two-dimensional online SPE comprised of two cartridges with different absorption characteristics was applied for sample pretreatment. Analysis was performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) under multiple reaction monitoring mode. Each sample required about 0.5h for solid phase extraction and analysis. The limit of detections (LODs) for six AAs ranged from 0.04 to 0.58ng/cig and recoveries were within 84.5%-122.9%. The relative standard deviations of intra- and inter-day tests for 3R4F reference cigarette were less than 6% and 7%, respectively, while no more than 7% and 8% separately for a type of Virginia cigarette. The proposed method enabled minimum sample pretreatment, full automation, and high throughput with high selectivity, sensitivity, and accuracy. As a part of the validation procedure, fifteen brands of cigarettes were tested by the designed method.

Unusual Formal [1+4] Annulation through Tandem P(NMe2 )3 -Mediated Cyclopropanation/Base-Catalyzed Cyclopropane Rearrangement: Facile Syntheses of Cyclopentenimines and Cyclopentenones.

An unusual formal [1+4] annulation of α-dicarbonyl compounds with 1,1-dicyano-1,3-dienes has been realized, leading to facile syntheses of cyclopentenimines and cyclopentenones in a unique manner. Mechanistic investigation implies that this reaction takes place through a P(NMe2 )3 -mediated cyclopropanation followed by a base-catalyzed cyclopropane rearrangement. It therefore represents an unprecedented [1+4] annulation mode involving Kukhtin-Ramirez adducts.

P(NMe2)3-mediated reductive [1+4] annulation of isatins with enones: a facile synthesis of spirooxindole-dihydrofurans.

A novel P(NMe2)3-mediated reductive [1+4] annulation reaction between isatins and enones has been developed, providing the facile synthesis of spirooxindole-dihydrofurans. This reaction unveils the first practical approach to construct five-membered cyclic motifs via a Kukhtin-Ramirez adduct involved [1+4] annulation mode.

Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?

PURPOSE: Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. METHODS: Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. RESULTS: Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. CONCLUSION: Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States.

PURPOSE: Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA. METHOD: Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed. RESULTS: The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers. CONCLUSION: Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

Simultaneous determination of 11 monohydroxylated PAHs in human urine by stir bar sorptive extraction and liquid chromatography/tandem mass spectrometry.

A simple and sensitive method for simultaneous determination of 11 monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) in human urines has been developed based on stir bar sorptive extraction (SBSE) and liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). Factors that may influence the extraction efficiency, such as pH value of matrix, extraction time, desorption solvents and desorption time were optimized. Validation results showed that the method has high sensitivity (quantification limits of 1-3 pg/mL), good reproducibility (RSD between 3.1 and 13.0%) and spiked recoveries (71.9-133.2%). The proposed method was also applied to analysis urines of smokers and nonsmokers, ten trace OH-PAHs were determined and compared between two groups. For the ease operation and satisfactory validiation results, SBSE coupled to HPLC-MS/MS may be an excellent alternative method for trace analysis of OH-PAHs in human urines.

A novel testosterone 2% gel for the treatment of hypogonadal males.

Testosterone replacement therapy (TRT) can improve the symptoms, signs, and well being of hypogonadal men by restoring serum testosterone concentrations to physiologic levels. This multicenter, open-label noncomparative trial of men with hypogonadism evaluated the pharmacokinetic profile and safety of a novel testosterone 2% gel (Fortesta™ Gel), administered once daily to the front and inner thighs at starting doses of 40 mg/d. The metered-dose delivery system allowed dose adjustments in 10-mg increments between 10 and 70 mg/d. Of the 149 patients enrolled, 138 patients (92.6%) completed the study and 129 patients (86.6%) were included in the efficacy analysis. On day 90, mean testosterone concentration (C(avg) [0-24 hours] ± SD) was 438.6 ± 162.5 ng/dL. Overall, 100 (77.5%) patients achieved serum total testosterone concentrations within the normal physiologic range (≥ 300 and ≤ 1140 ng/dL). On day 90, mean testosterone C(max) (± SD) was 827.6 ± 356.5 ng/dL. On day 90, a total of 122 patients (94.6%) had C(max) levels of 1500 ng/dL or less and 2 patients (1.6%) had values between 1800 and 2500 ng/dL. Similar results for C(avg) (0-24 hours) and C(max) were observed on day 35. All enrolled patients were included in the safety analysis. Testosterone 2% gel was generally well tolerated, with the most common adverse events (AE) being mild and moderate skin reactions. There were no serious AEs related to testosterone 2% gel. Once-daily testosterone 2% gel restored levels of testosterone in more than 75% of patients, with low risk of supraphysiologic testosterone levels. Patients may find this a suitable option for TRT because of its application site and low volume.

Comparison of the Revised Air Quality Index with the PSI and AQI indices.

Air pollution indices are commonly used to indicate the level of severity of air pollution to the public. The Pollution Standards Index (PSI) was initially established in response to a dramatic increase in the number of people suffering respiratory irritation due to the deteriorating air quality. The PSI was subsequently revised and implemented by the USEPA in 1999, and became known as the Air Quality Index (AQI) that includes data relating to particle suspension, PM2.5, and a selective options of either 8-hour or 1-hour ozone concentration during increased O3 periods. Yet, the costs of launching a network of PM2.5 monitoring stations are prohibitively high for many countries to implement the AQI from the PSI system in the foreseeable future. Therefore, the purpose of this research is to discuss the optimal method of assessing air quality using the latest developed Revised AQI (RAQI), a system that serves as an alternative to the PSI and AQI systems. The feasibility, effectiveness, and the differences between RAQI, AQI, and PSI in their applications to several air pollution conditions are also studied in this research. The results show that southern Taiwan's suspended particulates have significantly greater impact on PM2.5/PM10 ratios than in central and northern metropolitan areas, and that the ratios are higher in Taiwan as a whole compared to many other countries. We also found that the RAQI shows more significant results compared to the PSI and AQI as it has a wider coverage of the range of pollutant concentration levels.

Effect of timing of dosing in relation to food intake on the pharmacokinetics of esomeprazole.

AIM: To investigate the pharmacokinetics of esomeprazole before a high-fat meal vs. fasting. METHODS: This open-label, randomized, crossover study consisted of two 5-day dosing periods of esomeprazole 40 mg per day. On days 1 and 5, subjects received esomeprazole 15 min before a high-fat meal (fed) or 4 h before a non-high-fat meal (fasting). RESULTS: On days 1 and 5, ratio of fed to fasting area under the plasma concentration-time curve [0.56, 90% confidence interval (CI) 0.50, 0.64, and 0.78, 90% CI 0.74, 0.82, respectively] and peak plasma concentration (0.34, 90% CI 0.28, 0.41, and 0.47, 90% CI 0.41, 0.52, respectively) were outside of the limits of bioequivalence. CONCLUSIONS: Esomeprazole bioavailability was reduced when taken within 15 min before eating a high-fat meal vs. that while fasting.