Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study.

Purposes Vactosertib is a new investigational inhibitor of activin receptor-like kinase 5. The objective of this study was to characterize vactosertib pharmacokinetics that are to be applied for subsequent clinical studies. Methods Vactosertib plasma concentration-time data were obtained from a multicenter, dose-escalation, first-in-human phase 1 study conducted in patients with advanced solid tumors. Each patient orally received a fixed dose of vactosertib with the range of 30 mg to 340 mg once daily under fasted condition. Pharmacokinetic analysis was performed using a non-compartmental method. Results Pharmacokinetic data were evaluable in 29 patients. Vactosertib was rapidly absorbed after the first dose with a median time to maximum concentration (tmax) of 1.2 h (interquartile range, 0.8-1.8 h) and quickly eliminated with a median terminal half-life (t1/2) of 3.2 h (2.2-4.2 h) over the dose range studied. Such trend was also observed after repeated doses for five days (median tmax, 1.5 h; median t1/2, 3.0 h). The area under the concentration-time curve within a dosing interval increased in proportion to dose. The median values of apparent clearance and volume of distribution were 29 L/h (21-44 L/h) and 133 L (77-222 L), respectively. The median accumulation ratio after repeated once-daily doses for five days was 0.87 (0.69-1.07). Conclusions Vactosertib pharmacokinetics were dose-proportional within tested dose range with negligible accumulation when administered once daily for five days. Considering the short half-life, it seems necessary to administer vactosertib twice- or thrice-daily to maintain its concentrations above minimum effective level over a dosing interval.

Effect of operational pH on biohydrogen production from food waste using anaerobic batch reactors.

This study was performed to investigate the influence of operational pH on dark H(2) fermentation of food waste by employing anaerobic batch reactors. The highest maximum H(2) yield was 1.63 mol H(2)/mol hexoseadded at operational pH 5.3, whereas the lowest maximum H(2) yield was 0.88 mol H(2)/mol hexoseadded at operational pH 7.0. With decreasing operational pH values, the n-butyrate concentration tended to increase and the acetate concentration tended to decrease. The highest hydrogen conversion efficiency of 11.3% was obtained at operational pH 5.3, which was higher than that (8.3%) reported by a previous study (Kim et al. (2011) 'Effect of initial pH independent of operational pH on hydrogen fermentation of food waste', Bioresource Technology 102 (18), 8646-8652). The new result indicates that the dark fermentation of food waste was stable and efficient in this study. Fluorescence in situ hybridization (FISH) analysis showed that Clostridium species Cluster I accounted for 84.7 and 13.3% of total bacteria at operational pH 5.3 and pH 7.0, respectively, after 48 h operation.

Association of a Bioimpedance Profile with Optical Coherence Tomography Features in Diabetic Macular Edema.

We examined the association between bioimpedance profiles and optical coherence tomography (OCT) features in patients with diabetic macular edema (DME). This cross-sectional study included 100 eyes of 100 patients with type 2 diabetes mellitus. The systemic fluid status was assessed using extracellular water-to-total body water ratio (ECW/TBW) and phase angle (PhA), which was measured using bioimpedance equipment. ECW/TBW was higher in the DR (diabetic retinopathy) with DME group than in the no DR and DR without DME groups (p = 0.007 and p = 0.047, respectively); however, no significant difference was observed between the no DR and DR without DME groups. The PhA values were significantly lower in the DR with DME group (5.45 ± 0.84) than in the no DR (6.69 ± 0.69) and DR without DME groups (6.05 ± 1.15) (p < 0.001, p = 0.032, respectively). The presence of multiple HRF (hyper-reflective foci) was associated with a significantly higher ECW/TBW (p = 0.001). In the group with the most significant HRF, PhA was lower than in those with none or moderate amounts of HRF (p < 0.05). Bioimpedance fluid profiles of patients with OCT features of DME suggest a connection between the overall systemic state, including fluid status and DME development. Further research is required to fully understand and utilize this information for effective clinical assessment and treatment planning.

Highly luminescent InP/GaP/ZnS nanocrystals and their application to white light-emitting diodes.

Highly stable and luminescent InP/GaP/ZnS QDs with a maximum quantum yield of 85% were synthesized by in situ method. The GaP shell rendered passivation of the surface and removed the traps. TCSPC data showed an evidence for the GaP shell. InP/GaP/ZnS QDs show better stability than InP/ZnS. We studied the optical properties of white QD-LEDs corresponding to various QD concentrations. Among various concentrations, the white QD-LEDs with 0.5 mL of QDs exhibited a luminous efficiency of 54.71 lm/W, Ra of 80.56, and CCT of 7864 K.

Sodium (Na+) concentration effects on metabolic pathway and estimation of ATP use in dark fermentation hydrogen production through stoichiometric analysis.

Batch experiments were conducted to investigate the effects of Na(+) concentration on hydrogen production with dark fermentation. The Na(+) concentration was varied from 0 to 8 g/L in the mixed culture using an anaerobic sludge treated by acid. The maximum hydrogen production was achieved with 1 g-Na(+)/L, whereas the hydrogen production was decreased over 2 g-Na(+)/L due to the inhibitory of Na(+). The mechanisms of Na(+) inhibition to the hydrogen production are studied using pure culture of Clostridium butyricum by calculating the energy balance. At a high sodium concentration, C. butyricum used a greater proportion of the ATP generated via fermentation for cell maintenance rather than for cell synthesis. Additionally, higher Na(+) concentrations shifted the fermentation process toward the acetate synthesis pathway instead of the butyrate pathway, and the value of Y(X/ATP) decreased. With high Na(+) concentrations, a greater ratio of hydrogen was produced via the oxidation of NADH. Excess hydrogen production decreased as the Na(+) concentration increased.

Kinetics and simulations of substrate interactions during the biodegradation of benzene, toluene, p-xylene and styrene.

Air streams commonly emitted from industrial sources generally contain various mixtures of volatile organic compounds (VOCs), and these complex mixtures can present challenges with respect to bioreactor design and applications. In this study, therefore, a modified Monod-type model using interaction parameters was employed to describe the biodegradation kinetics of mixtures of aromatic compounds by a Pseudomonas isolate. In addition, the model and estimated parameters were utilized to predict the performance of a bubble-column bioreactor for the treatment of mixtures of benzene, toluene, p-xylene, and styrene (BTXS). Benzene, toluene and styrene, as individual substrates, were actively degraded by the bacterial culture, whereas p-xylene was not degraded as a single substrate. Relative to the single substrate experiments, the degradation of benzene and toluene was inhibited by the other compounds, while the degradation of styrene was significantly stimulated in the presence of the other BTXS compounds. The cometabolic degradation of p-xylene was observed in the presence of benzene and toluene. The estimated interaction parameters indicated that the degradation of benzene was substantially inhibited in the presence of styrene, whereas the degradation of styrene was strongly stimulated by toluene. The kinetic coefficients and interaction parameters were used to successfully predict the biodegradation kinetics and performance of a bioreactor subjected to the quaternary mixture. Overall, the model was able to provide reasonable predictions when substrate interactions, including inhibition, stimulation, and cometabolism, play significant roles in biodegradation processes.

Swept-Source OCT Angiography Features in Patients after Macular Hole Surgery.

This study aimed to compare findings of optical coherence tomography (OCT) angiography (OCTA) between eyes with nearly recovered and partially recovered outer retina after full-thickness macular hole (FTMH) surgery and to identify OCTA findings associated with visual acuity. We retrospectively reviewed 30 patients who underwent surgery for idiopathic FTMH. Swept-source OCT (SS-OCT) and OCTA were performed preoperatively and at three and six months postoperatively. Subgroups were divided according to the integrity of the external limiting membranes and ellipsoid zones postoperatively. Correlations of best-corrected visual acuity six months postoperatively with SS-OCT and OCTA measurements were analyzed. There was no difference in preoperative retinal or choroidal vascular index on OCTA between the nearly and partially recovered groups. Six months postoperatively, the choriocapillaris flow-void area was significantly higher in the partially recovered group than in the fellow eye. The nearly recovered group showed better choroidal vascular flow, and vision at six months postoperatively correlated with the ratio of the operated eye's choriocapillaris flow-void area to the fellow eye. Sufficient choriocapillaris flow on OCTA is associated with better outer retinal recovery and visual outcomes after macular hole surgery.

The Contribution Ratio of Autotrophic and Heterotrophic Metabolism during a Mixotrophic Culture of Chlorella sorokiniana.

The contribution ratio of autotrophic and heterotrophic metabolism in the mixotrophic culture of Chlorella sorokiniana (C. sorokiniana) was investigated. At the early stage of mixotrophic growth (day 0-1), autotrophy contributed over 70% of the total metabolism; however, heterotrophy contributed more than autotrophy after day 1 due to the rapid increase in cell density, which had a shading effect in the photo-bioreactor. Heterotrophy continued to have a higher contribution until the available organic carbon was depleted at which point autotrophy became dominant again. Overall, the increase in algal biomass and light conditions in the photo-bioreactor are important factors in determining the contribution of autotrophy and heterotrophy during a mixotrophic culture.

Population pharmacokinetics of vactosertib, a new TGF-ß receptor type Ι inhibitor, in patients with advanced solid tumors.

PURPOSE: Vactosertib, a novel inhibitor of transforming growth factor-ß type Ι receptor, is under development for the treatment of various cancers. The objective of this study was to characterize the population pharmacokinetics of vactosertib in patients with solid tumors. METHODS: Vactosertib population pharmacokinetics was assessed by nonlinear mixed-effects modelling of plasma concentration-time data obtained from a first-in-human phase 1 trial conducted in patients with advanced solid tumors. The final population pharmacokinetic model was constructed by assessing the effect of covariates on pharmacokinetic parameters including demographic characteristics, laboratory values, hepatic and renal function, and concomitant medications. The robustness of the final model was evaluated using a bootstrap method as well as visual predictive check based on Monte Carlo simulations and goodness-of-fit plots. RESULTS: A total of 559 concentrations from 29 patients were available for pharmacokinetic analysis. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics of vactosertib. The estimates of apparent clearance (CL/F) and volume of central compartment (Vc/F) were 31.9 L/h (inter-individual variability, 0.481) and 82.9 L (inter-individual variability, 0.534), respectively. The mixture model accounts for both typical absorption profile in the majority of patients and distinct profile in some patients with uncommon gastrointestinal conditions. Body mass index was significantly associated with Vc/F. CONCLUSIONS: The model developed in this study adequately describes the population pharmacokinetics of vactosertib in patients with advanced solid tumors. The pharmacokinetic characteristics assessed using the model would provide useful quantitative information to assist the future clinical development of vactosertib.

Reduced sulfur compounds in ambient air surrounding an industrial region in Korea.

The atmospheric concentrations of several reduced sulfur compounds (RSCs) including H(2)S, CH(3)SH, DMS, CS(2), and DMDS were measured concurrently from a series of field campaigns covering multiple locations in the surroundings of a large industrial region (August 2004 to September 2005). These field studies have been designed and undertaken to inspect the concentrations of RSCs in ambient air. The RSC concentrations were found to occur in a highly variable range. H(2)S (1.06 +/- 2.07 ppb) was found to be the most abundant RSC followed by CS(2) (0.84 +/- 0.54 ppb), DMDS (0.36 +/- 1.21 ppb), DMS (0.24 +/- 0.83 ppb), and CH(3)SH (0.11 +/- 0.23 ppb). The RSC levels measured at the study area were comparable to those observed previously from other polluted environmental settings. When these RSC data were examined further in terms of spatial (industrial vs. non-industrial sites) and seasonal (summer vs. winter seasons) grouping schemes, differences in their concentration levels were statistically insignificant in most cases. In contrast, there were fairly strong variations in temporal patterns over a diurnal cycle. If these RSC concentration data were converted to diagnose the malodor strengths, their effects were in most cases insignificant with minor contribution towards odor nuisances.

Differences in eye movement range based on age and gaze direction.

PURPOSE: To determine the range of eye movement in normal human subjects and to investigate the effect of age and gaze direction on eye movement. PATIENTS AND METHODS: A prospective observational study. We enrolled 261 healthy subjects, 5-91 years of age. Photographs were obtained in the cardinal gaze positions and processed using Photoshop. The processed images were analyzed using the Image J program to measure the angle of eye movement. The angle of eye movement was quantified using a modified limbus test. We measured the angle of eye movement in adduction, abduction, elevation, and depression. RESULTS: The ranges of eye movement were 44.9 ± 7.2° in adduction, 44.2 ± 6.8° in adduction, 27.9 ± 7.6° in elevation, and 47.1 ± 8.0° in depression. The ranges of eye movement in the younger group were higher than that in the older group in adduction, abduction, and elevation (P < 0.001, P = 0.013, and P < 0.001, respectively), except in depression (P = 0.790). There were significant negative correlations between the angles of horizontal and upward gazes and age (R = -0.294 in adduction, R = -0.355 in abduction, and R = -0.506 in elevation, all P < 0.001). However, the angle of downward gaze was not significantly correlated with age (R = 0.017, P = 0.722). CONCLUSIONS: The angle of upward gaze most rapidly decreased with age than the angle of other gaze. Unlike the age-related decline of range in horizontal and upward gazes, only downward gaze was not impaired by increasing age. Differences in eye movement range based on gaze direction and their associated aging mechanisms should be considered when assessing eye movements.

Correction: Differences in eye movement range based on age and gaze direction.

Since the online publication of the above article, the authors have noted an error with the funding. The authors apologize for any convenience caused by this error.The correct funding is:This work was supported by the research fund of Hanyang University (HY-201700000000487) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2016R1C1B2015164).

Correction: Changes in the optic nerve head induced by horizontal eye movements.

[This corrects the article DOI: 10.1371/journal.pone.0204069.].

Changes in the optic nerve head induced by horizontal eye movements.

PURPOSE: To investigate the effect of eye movement on the optic nerve head (ONH) using swept-source optical coherence tomography (SS-OCT), and to measure the degree of ONH changes. METHODS: We enrolled 52 healthy subjects, 20 to 40 years of age, and performed a prospective observational study. Both ONH and macula were imaged simultaneously using wide volume scan of the SS-OCT in the primary and different gaze positions. Horizontal eye movements were used to obtain OCT images in abducted and adducted eyeball positions. Multilateral 3-dimensional registration was used to process and analyze the images to measure the degree of ONH changes. RESULTS: The mean axial length (AXL) was 25.73 ± 1.42mm and the mean spherical equivalents was -4.49 ± 2.94 D (The proportion of high myopia was 39.4%). Significant morphologic changes were observed in the ONH during both abduction and adduction. In abduction, the overall ONH tissues were elevated, and the mean area of elevation was 115,134 ± 9,424 µm2 (p<0.001). In adduction, the mean areas from two perspectives, which were nasal or temporal, and peripapillary tissues or optic nerve cupping were 95,277 ± 73,846 µm2, 34,450 ± 44,948 µm2, -108,652 ± 91,246 µm2, and -30,581 ± 46,249 µm2, respectively. Elevation in abduction (overall, nasal cup segment, and temporal cup segment; R = 0.204, 0.195 and 0.225, p = 0.038, 0.047 and 0.021, respectively) and elevation of nasal peripapillary segments in adduction were positively correlated with AXL (R = 0.346, p<0.001). CONCLUSION: We found significant morphologic changes in the ONH in both abduction and adduction and these changes were associated with AXL. Considering these morphologic changes as physical properties, it allows a better understanding of the biomechanical characteristics of the ONH.

Live bio-imaging with fully bio-compatible organic fluorophores.

We synthesized a new organic fluorescent dye named resveratrone glucoside from the photoreaction of naturally-occurring phytoalexin compound resveratrol glucoside (resveratrol-3-ß-mono-d-glucoside), which is abundant in various plants such as berries, herbs, nuts and grapes. Just like its predecessor molecule resveratrone that was previously discovered by our group, resveratrone glucoside possesses excellent optical properties including a high fluorescence quantum yield, a large Stokes' shift, and a large two-photon absorption cross section. In addition to these highly desirable properties, both fluorescent molecules can also be used as ideal bio-compatible organic fluorophores since they have remarkably low cytotoxicity, which we verified through our cell morphological study, trypan blue exclusion assay, Western blot analysis and fluorescence imaging of various live biological specimens. In particular, we note that resveratrone glucoside is much more soluble in aqueous solution because of its glycosidic side chain and therefore highly suitable for in vivo imaging. We demonstrated that resveratrone and resveratrone glucoside can be used in one- and two-photon fluorescence microscopic imaging of E. coli, yeast (S. cerevisiae), and mammalian cell lines including HeLa and MCF10A cells as well as to the live imaging and real-time tracking of the zebrafish embryo development. Both organic fluorophores can be readily obtained from a simple photoreaction of commercially available, inexpensive samples.

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub-Analysis of Phase 3 Clinical Trials.

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naïve and ART-experienced Asian subjects.

Optimum doses of Mg and P salts for precipitating ammonia into struvite crystals in aerobic composting.

It was previously reported that struvite crystals could be formed in the aerobic composting reaction provided that Mg and P salts are added [Bioresource Technology 79 (2001) 129]. The formation of struvite crystals significantly reduced gaseous loss of ammonia and resulted in substantial increase in the ammonia content in the compost, attaining 1.5%. In this context, the present study was conducted to determine the optimal doses of Mg and P salts for struvite crystallization. It was found that cumulative ammonia production was about 33-36% of the initial total nitrogen in the aerobic composting reaction, irrespective of the amounts of Mg and P salts added. The theoretical doses for complete conversion of ammonia into struvite crystals seemed to be about 33-36% of the initial nitrogen. The addition of Mg and P salts at this level, however, caused adverse effects on the degradation of organic materials. Therefore, it was concluded that the optimal doses of Mg and P salts should be about 20% of the initial nitrogen in the compost mixture not to cause any harmful effects on the composting reaction.

Iron and organo-bentonite for the reduction and sorption of trichloroethylene.

Hybrid barriers using dechlorination and immobilization were studied to remove trichloroethylene (TCE) in this study. Hybrid barriers of iron filings and organo (hexadecyltrimethylammonium, HDTMA)-bentonite were simulated in columns to assess the performance of the hybrid barriers. TCE reduction rate for the mixture of zero valent iron (ZVI) and HDTMA-bentonite was approximately seven times higher than that for ZVI, suggesting the reduction of TCE was accelerated when HDTMA-bentonite was mixed with ZVI. For the column of two separate layers of iron and HDTMA-bentonite, TCE reduction rate was nearly similar to that for ZVI alone, but the partition coefficient (Kd) was 4.5 times higher than that for ZVI only. TCE was immobilized in the first layer with HDTMA-bentonite due to sorption, and then dechlorinated in the second layer with iron filings due to reduction. The HDTMA-bentonite and minimally-desorbed HDTMA from the organo-bentonite are believed to contribute the increase in TCE concentration on iron surface so that more TCE could be available for reduction. Therefore, the incorporation of HDTMA-bentonite into ZVI not only can effectively retard the transport of chlorinated organic contaminants from landfill leachate or oil shock in subsurface environment, also can expedite the reduction rate of TCE.

Studies of spatial and temporal distribution characteristics of TSP-bound trace metals in Seoul, Korea.

In the present study, TSP-bound metal concentrations were measured from seven different urbanized locations in Seoul, Korea for the period from March 2001 through May 2002. Our measurement data were analyzed to explore the possible influences of spatial and temporal factors on metal distribution characteristics. To determine the importance of those aspects, the measured concentrations were compared between different metals and between different sites in terms of several criteria: (1) absolute concentrations and enrichment factor (EF) values; (2) coefficient of variation (CV) values of metal concentrations; (3) relative patterns of temporal variations; and (4) relative abundance of strong correlations. According to our analysis of metal distribution characteristics in the study area, the main results of our study can be summarized as follows: (1) a number of metals (e.g., Cd, Cu, and Pb) are highly enriched relative to the average crustal ratios (to Fe); (2) the behavior of Cu is found to vary irregularly, while Fe, Mn, and Pb are tightly coupled both spatially and temporally in the study area; (3) for most elements except Cu and Cd, seasonal variations are observed in a systematic manner; and (4) when compared against those observed in other parts of the world, our Cu and Cd concentrations observed in many locations of Seoul are notably high. The overall results of our study suggest that the distribution characteristics of metals can be regulated strongly by spatial and temporal factors and that such controls are distinguished very clearly between different metal types.

Effects of OLRs and HRTs on hydrogen production from high salinity substrate by halophilic hydrogen producing bacterium (HHPB).

The effects of hydraulic retention time (HRT) and organic loading rate (OLR) on hydrogen production were investigated with glucose medium containing 2% NaCl. Halophilic hydrogen producing bacterium (HHPB) Clostridium bifermentans 3AT-ma, which can survive under high salt conditions, was used. Sponge media were used as 20% of working volume. The OLR and HRT were varied in 10-60 g-glucose/L-reactor/day and 24-6h. With OLR of 20 g-glucose/L/day, shorter HRT resulted in higher hydrogen producing rate and yield. When the OLR was increased from 20 to 60 g-glucose/L-reactor/day at HRT 6h, the hydrogen production rate increased, while the hydrogen production yield decreased due to the increase and accumulation of volatile fatty acids. Biohydrogen production was possible from the salinity substrate using HHPB, and the maximum hydrogen production yield was 1.1 mol-H2/mol-glucose with optimal conditions of OLR of 20 g-glucose/L/day and HRT of 12h.