The effect of microplastics on the depuration of hydrophobic organic contaminants in Daphnia magna: A quantitative model analysis.

Microplastics are emerging pollutants that can absorb large amounts of hydrophobic organic contaminants (HOCs). However, no biodynamic model has yet been proposed to estimate their effects on HOC depuration in aquatic organisms, where the HOC concentrations are time-varying. In this work, a microplastic-inclusive biodynamic model was developed to estimate the depuration of HOCs via ingestion of microplastics. Several key parameters of the model were redefined to determine the dynamic HOC concentrations. Through the parameterized model, the relative contributions of dermal and intestinal pathways can be distinguished. Moreover, the model was verified and the vector effect of microplastics was confirmed by studying the depuration of polychlorinated biphenyl (PCB) in Daphnia magna (D. magna) with different sizes of polystyrene (PS) microplastics. The results showed that microplastics contributed to the elimination kinetics of PCBs because of the fugacity gradient between the ingested microplastics and the biota lipids, especially for the less hydrophobic PCBs. The intestinal elimination pathway via microplastics would promote overall PCB elimination, contributing 37-41 % and 29-35 % to the total flux in the 100 nm and 2 µm polystyrene (PS) microplastic suspensions, respectively. Furthermore, the contribution of microplastic uptake to total HOC elimination increased with decreasing microplastic size in water, suggesting that microplastics may protect organisms from HOC risks. In conclusion, this work demonstrated that the proposed biodynamic model is capable of estimating the dynamic depuration of HOCs for aquatic organisms. The results can shed light on a better understanding of the vector effects of microplastics.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Joint effect of nanoplastics and humic acid on the uptake of PAHs for Daphnia magna: A model study.

Nanoplastics (NPs) are emerging pollutants which can adsorb large amounts of hydrophobic organic compounds (HOCs) and be ingested by aquatic organisms. NPs interact with dissolved organic matter (DOM) and result in significant impacts on the bioaccumulation of HOCs in the actual environment. For the first time, the joint effects of two complex matrices on the bioaccumulation of polycyclic aromatic hydrocarbons (PAHs) to Daphnia magna (D. magna) were studied by modeling calculation. The complex matrices, nano-sized polystyrene (PS) and/or humic acid (HA), were under environmentally realistic concentrations. A biodynamic model was modified and the uptake fluxes from all exposure pathways were quantified using the experimental data. A flux estimation showed that the bioaccumulation amounts at equilibrium were mostly dependent on dermal uptake (≥99.3 % of the total). The PS matrix would retard the intestinal uptake process in D. magna, especially for the less hydrophobic PAHs; while the HA or the HA-PS matrix would facilitate the mass transfer of PAHs from the matrix to lipids in the gut. Moreover, the biota matrix accumulation factor (BMAF) were calculated to verify the biodynamic model. This work is helpful to clarify the bioaccumulation effects of PAHs in complex environmental systems.

Sorption properties of hydrophobic organic chemicals to micro-sized polystyrene particles.

It has been reported that microplastics (MPs) have strong affinity for hydrophobic organic chemicals (HOCs) and can be ingested accidentally by aquatic organisms, posing a potential threat to the environment. To date, the sorption data used in modelling to clarify the mechanism were mostly obtained in varied sampling durations and regions from different works, which might cause inevitable deviation in modelling results. The current study aimed to illustrate the sorption properties of HOCs to the micro-sized polystyrene (PS). The sorption behaviors of HOCs to the PS were investigated at a certain pre-equilibrium status, and the theoretical analysis was taken into consideration. A bottle-shaped passive dosing system was designed to measure the concentration ratio of HOCs in different phases of the exposure suspension at a certain time (logaMP), including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) with logKow ranging from 3.17 to 10.20, between water and PS MPs with different dimensions (diameters of 100 nm, 1 µm and 2 µm, respectively). The calculated logaMP ranged from 3.73 to 8.34, and a positive correlation was found between logaMP and log1r0 (r0 is the MP radius). The results indicated that HOCs would diffuse into the PS particles, but the mass transfers inside the particles were slow and would be negligible in some environmental cases. Under theoretical considerations, the diffusion through the boundary layer of the particle was considered as the dominating process because it was fast, and the contributions of absorbed amounts on the particle surface were larger for smaller PS particles (i.e. 100-nm PS). This study could provide applicable data for further exploring the effects of micro-sized plastics on the HOCs in environmental samples.

Investigating the toxicities of different functionalized polystyrene nanoplastics on Daphnia magna.

Nanoplastics (NPs) spread widely with water and air current, and they can accumulate in aquatic organisms, even penetrating biofilms, which may cause persistent toxicity and potential hazards. This current study aimed to reveal the toxicological mechanism of different functionalized polystyrene (PS) NPs on Daphnia magna (D. magna) by investigating toxicity endpoints in individual level and biochemical level. In this study, acute toxicity, behavioral parameters and biomarker responses of D. magna was measured in the exposure of different functionalized PS NPs (plain PS, PS-p-NH2, PS-n-NH2 and PS-COOH). The results indicated that when exposed to the plain PS, ROS induction would activate MAPKs, thereby causing lethality and adverse behavior effects on D. magna; while the functionalized PS NPs were less toxic than the plain PS, especially for PS-p-NH2 which was severely flocculated after exposure, thus showing no immobilization at the investigated concentrations. Also, the antioxidant system was mainly stimulated due to the direct interaction with the cell surface receptor, which was different from the plain PS. Consequently, this work suggests significant effects of functional groups on NPs for environmental toxicity studies, and provides a better understanding of the toxicological mechanism on the toxicity of PS NPs toward D. magna.

Efficacy and safety of probiotics in the treatment of Candida-associated stomatitis.

This study aimed at evaluating the short-term efficacy and safety of probiotics as an aid in the treatment of Candida-associated stomatitis in a randomised controlled trial. A total of 65 patients were randomly assigned to receive oral local antifungal agents alone (gargle 2% sodium bicarbonate solution for 30 s, wait 10 min and then apply 2% nystatin paste) or these agents plus local probiotics (the mixture of Bifidobacterium longum, Lactobacillus bulgaricus and Streptococcus thermophilus) three times per day for 4 weeks. Parameters related to hyperaemia, visual analogue scale scores, culture of resting saliva and a lingual dorsum swab and adverse reactions were assessed or recorded in the beginning, middle and end of treatment. Although the baseline characteristics of the participants were similar, both groups showed a significant reduction in pain level and hyperaemia on the tongue mucosa (P = 0.000) after 4-week application. However, despite the reduction in hyperaemia in the probiotic group, these improvements did not display statistically significant differences. The detection rate of Candida spp. was 100% before treatment and 8.21% in the experimental group and 34.6% in the control group after treatment. The detection rate of Candida spp. decreased (P = 0.000) in both groups and was significantly lower in the probiotic group than the control group (P = 0.038). Other analysed micro-organisms, including the decreased detection rate for Lactobacillus spp. (P = 0.049) and the increased detection rate for Staphylococcus epidermidis (P = 0.019), did not display consistent change trends in the probiotics group. Compared with conventional antifungal therapies for oral candidiasis, the inclusion of locally administered probiotics helped improve certain clinical conditions and reduced the prevalence of Candida spp., although the impact of probiotics on oral bacterial species remains to be further studied.

The relationship among symptoms, sleep disturbances and quality of life in patients with interstitial cystitis.

PURPOSE: We conducted a retrospective analysis to determine associations among symptoms, sleep disturbances and quality of life in responder and nonresponder groups of patients with interstitial cystitis. MATERIALS AND METHODS: Patients in a multidose pentosan polysulfate sodium clinical trial with a diagnosis of interstitial cystitis who were randomized to 300 mg pentosan polysulfate sodium per day (128) completed the Interstitial Cystitis Symptom Index, an adapted Medical Outcomes Study Sleep scale and the Medical Outcomes Study Short Form-12 Health Survey at baseline, and at weeks 8, 16, 24 and 32. Responders were defined as those achieving a 30% or greater reduction in Interstitial Cystitis Symptom Index score from baseline to study end point (week 32 or last observation carried forward). RESULTS: A positive correlation at baseline was observed between sleep scores and Short Form-12 physical and mental components (r = 0.43 and 0.37, respectively, p <0.0001). Patients showed statistically significant improvement in Interstitial Cystitis Symptom Index and sleep scores by week 32. Responders (48, 43%) had a mean change in sleep score of 11.8 +/- 22.4 while nonresponders (64, 57%) had a mean change of 1.6 +/- 15.7 (p = 0.0055 between groups). The reduction in Interstitial Cystitis Symptom Index score correlated with improvement in sleep score from baseline to study end point (r = -0.33, p = 0.0003). At the study end point responders demonstrated a significant improvement in the Short Form-12 physical component compared with baseline (p <0.0001). CONCLUSIONS: Reduction in interstitial cystitis symptoms may be associated with patient reported improvement in sleep and quality of life.

Improvement in sexual functioning in patients with interstitial cystitis/painful bladder syndrome.

INTRODUCTION: Sexual functioning is one of the strongest predictors of poorer quality of life (QOL) in patients diagnosed with interstitial cystitis/painful bladder syndrome (IC/PBS). AIMS: To examine the relationship between symptom reduction and sexual functioning in patients with IC/PBS. METHODS: Patients with IC/PBS were treated with 300 mg/day pentosan polysulfate sodium for 32 weeks. MAIN OUTCOME MEASURES: Patients completed the O'Leary-Sant Interstitial Cystitis Symptom Index, Short Form-12 QOL, and Medical Outcomes Study Sexual Functioning Scale at baseline, and at 8, 16, 24, and 32 weeks. Treatment responders were defined as those achieving a >/=30% reduction in symptom index from baseline. RESULTS: A total of 128 patients were included in the analyses. At baseline, mean symptom index, QOL (physical and mental), and sexual functioning scores were 12.3, 41.7, 45.9, and 56.1, respectively. Patients showed statistically significant improvement in symptom and sexual functioning scores at weeks 8, 16, 24, and 32. At week 32, the mean change in symptom index score from baseline was -2.97 (standard deviation [SD] = 4.66, P < 0.0001), and the mean change in sexual functioning score from baseline was 8.9 (SD = 32.9, P = 0.0054). Reduction in symptom index score was moderately correlated with improvement in sexual functioning score at the end of study (r = -35, P = 0.0002). Positive correlation was observed at the end of the study between the mean change scores of sexual functioning score and physical and mental QOL components (r = 0.46, P < 0.0001 and r = 0.29, P = 0.0023, respectively). Patients achieving a >/=30% reduction in symptom index (responder, N = 47; 44%) had an adjusted mean change in sexual functioning score of 19.8 (standard error [SE] = 4.69), while nonresponders (N = 59, 56%) had an adjusted mean change -0.49 (SE = 4.17) (between groups, P = 0.0020). CONCLUSIONS: Sexual dysfunction is moderate to severe in patients with IC/PBS and impacts significantly on QOL. Reduction in symptoms was associated with improvement in the patient-reported outcomes of sexual function.