High Concentrations Research Articles

Pharmacokinetic analysis of OMO-103 in patient tissues with advanced solid tumors.

e15168 Background: MYC is a pleiotropic transcription factor aberrantly expressed in up to 70% of human cancers. OMO-103 (Omomyc) is a 91-amino-acids-long polypeptide that derives from the B-HLH-LZ domain of human MYC, containing four amino acid substitutions. It is capable of forming homos and heterodimers with MYC and with MAX and blunt MYC activity by preventing its access to target DNA sequences (E-boxes) and replacing it by inactive complexes. Previous in vivo preclinical experiments showed that Omomyc blocks MYC-driven transcription and proliferation, induces apoptosis and recruitment of intratumoral immune infiltrates, significantly abrogating tumor progression and reducing tumor grading. Here, we present PK results from the first-in-human trial (NCT04808362) of OMO-103 in patients with advanced solid tumors. Methods: Patient eligibility The study included histologically or cytologically proven advanced solid tumors for which there was no curative therapy. Patients had to demonstrate measurable disease according to RECIST v.1.1 criteria as demonstrated by CT/magnetic resonance imaging and documented progression on or following the last line of therapy. Description and dose selection OMO-103 was administered by weekly I.V. infusion over 30–45 min, one treatment cycle corresponding to three infusions. Patients were treated until progression. The starting dose of 0.48 mg kg−1 was determined based on nonclinical toxicology and efficacy studies (anticipated pharmacologically active dose) and subsequent conversion to a human equivalent dose. Pharmacokinetic assays A targeted mass spectrometry (MS) assay for the absolute quantification of 4 Omomyc proteotypic peptides was developed to quantify functional OMO-103 in tumor tissue. LLOQ and linear range of the panel was determined by spiking in dilution series of recombinant OMO-103 protein into tumor tissue lysates. Finally, in the phase I trial, we used the panel for the quantification of OMO-103 in FFPE tumor biopsies from 12 patients who received i.v. injection of OMO-103. Results: MS Data show that 2 h after i.v. administration, higher concentrations of the drug are reached in the tumors compared with serum and persist there with at least one order of magnitude higher concentration than in serum 72 h after administration in preclinical models. Functional Omomyc protein could be quantified in all 12 clinical tumor biopsies from treated patients and PK results confirmed previous observations in preclinical models. where Omomyc exhibits higher tissue concentration and prolonged residency compared to plasma. Conclusions: We demonstrate the utility of targeted MS assay for precise quantification of therapeutic (mini)proteins in clinical tissue samples. Thanks to its multiplexing capability, up to 60 peptides (epitopes) can be monitored simultaneously which enables high sequence coverage and profiling of additional PD or other supporting biomarkers. Clinical trial information: NCT04808362 .

Multidimensional occurrence and diet risk of emerging contaminants in freshwater with urban agglomerations

Freshwater systems near highly urbanized areas are extremely susceptible to emerging contaminants (ECs), yet their stereoscopic persistence in aquatic ecosystems and related risks remain largely unknown. Herein, we characterized the multi-mediums distribution of 63 ECs in Baiyangdian Lake, the biggest urban lake in the North of China. We identified variations in the seasonal patterns of aquatic EC levels, which decreased in water and increased in sediment from wet to dry seasons. Surprisingly, higher concentrations and a greater variety of ECs were detected in reeds than in aquatic animals, indicating that plants may contribute to the transferring of ECs. Source analysis indicated that human activity considerably affected the distribution and risk of ECs. The dietary risk of ECs is most pronounced among children following the intake of aquatic products, especially with a relatively higher risk associated with fish consumption. Besides, a comprehensive scoring ranking method was proposed, and 9 ECs, including BPS and macrolide antibiotics, are identified as prioritized control pollutants. These findings highlight the risks associated with aquatic ECs and can facilitate the development of effective management strategies.

Non-linear responses via agglomeration and aggregation of gold nanoparticles for surface-enhanced Raman spectroscopy (SERS) coupled with chemometric analysis for chlorpyrifos detection

This study investigates the behaviour of gold nanoparticles (AuNPs) when exposed to chlorpyrifos, an agricultural pesticide, and its application in detecting the pesticide via surface-enhanced Raman spectroscopy (SERS). Under synergistic addition of NaCl, AuNPs undergo agglomeration at lower chlorpyrifos concentrations but aggregation at higher concentrations, resulting in a distinctive nonlinear SERS response. A linear relationship is obtained between 0.001 and 1 ppm with detection limit (LOD) of 0.009 ppm, while an inverse response is observed at higher concentrations (1–1000 ppm) with a LOD of 1 ppm. Combining the colorimetric response of AuNP solutions, their absorbance spectra, and principal component analysis can improve detection reliability. The assay, coupled with a simple recovery method using acetonitrile swabbing, achieves high reproducibility in detecting chlorpyrifos in cucumber, even at concentrations as low as 0.11 ppm. This approach can be tailored for various chlorpyrifos concentrations not only in cucumbers but also in different food matrices.

Systemic low-grade C-reactive protein is associated with proximal symptom spread in carpal tunnel syndrome.

Neuropathic pain is a highly prevalent condition associated with persistent disability. Some patients with neuropathic pain experience symptom spread outside neuroanatomical boundaries; these patients report more severe sensory symptoms and greater disability. However, the mechanisms behind such symptom spread are not fully understood. We used pre-surgical carpal tunnel syndrome (CTS) as a human model system of neuropathic pain to identify differences in the concentration of serologic inflammatory mediators between patients with CTS with territorial symptoms and those with proximal symptom spread to either the elbow or shoulder/neck. We performed a post-hoc analysis, comparing levels of serologic inflammatory mediators in a discovery cohort among 3 symptoms spread profiles (n = 55; n = 25 no spread, n = 21 spread to elbow, n = 9 spread to shoulder/neck). We then de-novo analysed the significantly dysregulated mediators in an independent validation cohort (n = 72; n = 34 no spread, n = 16 spread to elbow, n = 22 spread to shoulder/neck). The discovery cohort revealed higher serum concentrations of C-reactive protein (CRP) and interleukin-6 in patients with any symptom spread proximal to the wrist; interferon-γ was higher in patients with symptom spread to the elbow compared with those without proximal spread. The validation study replicated the association of higher CRP concentrations in patients with proximal spread to the elbow (no spread: median [interquartile range] 2.5 [5.4]; spread to elbow 6.2 [4.6]; spread to shoulder/neck 2.6 [3.7], P = 0.006). No other markers replicated in the validation cohort. Our findings suggest that proximal symptom spread in the context of neuropathic symptoms is associated with low-grade inflammation.

Epigallocatechin-3-gallate-synthesized gold nanoparticles modulate reactive oxygen species and antioxidant parameters in brain and heart tissues using a chicken embryo model

Chemically synthesized gold nanoparticles (AuNPs) come with drawbacks, such as biological toxicity and ecological imbalances. Nonetheless, a knowledge gap remains regarding their impact on oxidative and antioxidant parameters. Here, environmentally friendly AuNPs were synthesized using epigallocatechin-3-gallate (AuNPs-EGCG). The successful synthesis of AuNPs-EGCG were confirmed using ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, atomic force microscopy, and dynamic light scattering. Antioxidant activity was assessed using free radical 2,2-diphenyl-1-picrylhydrazyl, oxygen radical absorbance capacity, and ferric reducing antioxidant power assays, while cytotoxicity properties were evaluated in the NIH3T3 fibroblast cells. Furthermore, the impact of AuNPs-EGCG on oxidative stress was investigated in the hearts and brains of chicken embryos. AuNPs-EGCG exhibited no cytotoxicity and was not toxic for chicken embryos at higher concentrations. However, exposure to lower concentrations (100 and 30 μg/mL) caused an increase in reactive oxygen species (ROS) levels and a decrease in total antioxidant capacity in the heart and brain, resulting in a disturbance in the redox balance attributed to a reduction in catalase activity and glutathione (GSH) content, and an increase in glutathione peroxidase activity. In contrast, AuNPs-EGCG at 300 μg/mL promoted an increase in GSH levels and modulation of ROS, while also reducing vascular density in the chorioallantoic membrane. Furthermore, AuNPs-EGCG did not cause lipid or protein oxidation. The present study offers evidence that supports the investigation of how AuNPs-EGCG can modulate antioxidant defense mechanisms and assess the safety of phytoantioxidant-functionalized nanoparticles in vivo. This may lead to new and innovative strategies for the utilization of nanomaterials in biological systems.

Hexakis[p-(hydroxymethyl)phenoxy]cyclotriphosphazene as an Environmentally Friendly Modifier for Polyurethane Powder Coatings with Increased Thermal Stability and Corrosion Resistance.

Protection against fire and the corrosion of metals is necessary to ensure human safety. Most of the fire and corrosion inhibitors do not meet the ecological requirements. Therefore, effective and ecological methods of protecting metals are currently a challenge for researchers. In this work, the influence of hexakis(4-(hydroxymethyl)phenoxy)cyclotriphosphazene (HHPCP) on the characteristics of powder coatings was examined. The coatings' properties were investigated by measuring the roughness, hardness, adhesion to the steel surface, cupping, gloss, scratch resistance, and water contact angle. The thermal stability was studied by furnace test and TGA analysis. The corrosion resistance test was carried out in a 3.5% NaCl solution. The distribution of phosphazene-derived segments in the coating was examined by GD-EOS analysis. Modified coatings show better corrosion and thermal resistance and can be used for the protection of the steel surface. Their better corrosion resistance is due to the electroactive properties of the phosphazene ring and its higher concentration at the coating surface, confirmed by GD-EOS analysis. The increase in thermal resistance is due to the effect of the formation of phosphoric metaphosphoric and polyphosphoric acids during the decomposition of HHCPC, which remain in the condensed char phase and play a crucial role in surface protection.

Study on the disinfection effect of chlorine dioxide disinfectant (ClO2) on dental unit waterlines and its in vitro safety evaluation

BackgroundEnsuring the safety of dental unit waterlines (DUWLs) has become a pivotal issue in dental care practices, focusing on the health implications for both patients and healthcare providers. The inherent structure and usage conditions of DUWLs contribute to the risk of biofilm formation and bacterial growth, highlighting the need for effective disinfection solutions.The quest for a disinfection method that is both safe for clinical use and effective against pathogens such as Staphylococcus aureus and Escherichia coli in DUWLs underscores the urgency of this research.MaterialsChlorine dioxide disinfectants at concentrations of 5, 20, and 80 mg/L were used to treat biofilms of S. aureus and E. coli cultured in DUWLs. The disinfection effectiveness was assessed through bacterial counts and culturing. Simultaneously, human skin fibroblast cells were treated with the disinfectant to observe changes in cell morphology and cytotoxicity. Additionally, the study included corrosion tests on various metals (carbon steel, brass, stainless steel, aluminum, etc.).ResultsExperimental results showed that chlorine dioxide disinfectants at concentrations of 20 mg/L and 80 mg/L significantly reduced the bacterial count of S. aureus and E. coli, indicating effective disinfection. In terms of cytotoxicity, higher concentrations were more harmful to cellular safety, but even at 80 mg/L, the cytotoxicity of chlorine dioxide remained within controllable limits. Corrosion tests revealed that chlorine dioxide disinfectants had a certain corrosive effect on carbon steel and brass, and the degree of corrosion increased with the concentration of the disinfectant.ConclusionAfter thorough research, we recommend using chlorine dioxide disinfectant at a concentration of 20 mg/L for significantly reducing bacterial biofilms in dental unit waterlines (DUWLs). This concentration also ensures satisfactory cell safety and metal corrosion resistance.

Perfluoropolyether-Based Gut-Liver-on-a-Chip for the Evaluation of First-Pass Metabolism and Oral Bioavailability of Drugs.

In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.

A Novel Recombinant Modified Vaccinia Ankara Virus expressing Interleukin-13 Receptor α2 Antigen for Potential Cancer Immunotherapy.

Genetically altered recombinant poxviruses hold great therapeutic promise in animal models of cancer. Poxviruses can induce effective cell-mediated immune responses against tumor-associated antigens. Preventive and therapeutic vaccination with a DNA vaccine expressing IL-13Rα2 can mediate partial regression of established tumors in vivo, indicating that host immune responses against IL-13Rα2 need further augmentation. The aim of the study is developing a recombinant modified vaccinia Ankara (MVA) expressing IL-13RΑ2 (rMVA-IL13RΑ2) virus and study in vitro infectivity and efficacy against IL-13Rα2 positive cell lines. We constructed a recombinant MVA expressing IL-13Rα2 and a green fluorescent protein (GFP) reporter gene. Purified virus titration by infection of target cells and immunostaining using anti-vaccinia and anti-IL-13Rα2 antibodies was used to confirm the identity and purity of the rMVA-IL13Rα2. Western Blot analysis confirmed the presence of IL-13Rα2 protein (~52 kDa). Flow cytometric analysis of IL-13Rα2 negative T98G glioma cells when infected with rMVA-IL13Rα2 virus demonstrated cell-surface expression of IL-13Rα2, indicating the infectivity of the recombinant virus. Incubation of T98G-IL13α2 cells with varying concentrations (0.1-100 ng/ml) of interleukin-13 fused to truncated Pseudomonas exotoxin (IL13-PE) resulted in depletion of GFP+ fluorescence in T98G-IL13Rα2 cells. IL13-PE (10-1000 ng/ml) at higher concentrations also inhibited the protein synthesis in T98G-IL13Rα2 cells compared to cells infected with the control pLW44-MVA virus. IL13-PE treatment of rMVA-IL13Rα2 infected chicken embryonic fibroblast and DF-1 cell line reduced virus titer compared to untreated cells. rMVA-IL13Rα2 virus can successfully infect mammalian cells to express IL-13Rα2 in a biologically active form on the surface of infected cells. To evaluate the efficacy of rMVA-IL13Rα2, immunization studies are planned in murine tumor models.

Projecting Changes in the Frequency and Magnitude of Ozone Pollution Events Under Uncertain Climate Sensitivity

AbstractClimate change is projected to worsen ozone pollution over many populated regions, with larger impacts at higher concentrations. More intense and frequent ozone episodes risk setbacks to human health and environmental policy achievements. However, assessing these changes is complicated by uncertain climate sensitivity, closely related to climate model response, and internal variability in simulations projecting climate's influence on air quality. Here, leveraging a global modeling framework that one‐way couples a human activity model, an Earth system model of intermediate complexity, and an atmospheric chemistry model, we investigate the role of climate sensitivity in climate‐induced changes to high ozone pollution episodes in the United States using multiple greenhouse gas emissions scenarios, representations of climate sensitivity, and initial condition members. We bias correct and evaluate historical model simulations, identifying modeled and observed O3 episodes using extreme value theory, and extend the approach to projections of mid‐ and end‐century climate impacts. Results show that the influence of climate sensitivity can be as significant as that of greenhouse gas emissions scenario absent precursor emissions changes. Climate change is projected to increase the magnitude of the highest annually occurring O3 concentrations by over 2.3 ppb on average across the U.S. at mid‐century under a high climate sensitivity and moderate emissions scenario, but the increase is limited to less than 0.3 ppb under lower climate sensitivity. Further, we show that areas in the U.S. currently meeting air quality standards risk being pushed into non‐compliance due to a climate‐induced increase in frequency of high ozone days.

Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.

e14591 Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p <0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.

Topical Solution for Retinal Delivery: Bevacizumab and Ranibizumab Eye Drops in Anti-Aggregation Formula (AAF) in Rabbits

PurposeWet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF).MethodsBevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent.ResultsBevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies.ConclusionsBevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections.

Downstream natural gas composition across U.S. and Canada: implications for indoor methane leaks and hazardous air pollutant exposures

Previous research has shown that natural gas (NG) leaks from residential appliances are common, affecting greenhouse gas emission inventories and indoor air quality. To study these implications, we collected and analyzed 587 unburned NG samples from 481 residences over 17 North American cities for hydrocarbons, hazardous air pollutants, and organosulfur odorants. Nearly all (97% of) gas samples contained benzene (between-city mean: 2335 ppbv [95% CI: 2104, 2607]) with substantial variability between cities. Vancouver, Los Angeles, Calgary, and Denver had at least 2x higher mean benzene concentrations than other cities sampled, with Vancouver exhibiting a nearly 50x greater mean benzene level than the lowest-concentration city (Boston). We estimate that current U.S. and Canadian emissions inventories are missing an additional 25 000 [95% CI: 19 000, 34 000] and 4000 [95% CI: 3700, 5200] lbs benzene yr−1 through downstream NG leakage, respectively. Concentrations of odorants added for leak detection varied substantially across cities, indicating a lack of standardization. Houston, for instance, had 5x higher mean tert-butyl mercaptan levels than Toronto. Using these odorant measurements, we found that methane emissions as high as 0.0080–0.28 g h−1 and indoor benzene enhancements 0.0096–0.11 ppbv could go undetected by persons with an average sense of smell, with large uncertainties driven by smelling sensitivity, gas composition, and household conditions. We also observed larger leaks (>10 ppm ambient methane) in ∼4% of surveyed homes, confirming that indoor leakage occurs at varying degrees despite the presence of odorants. Overall, our results illustrate the importance of downstream NG composition to understand potential emissions, exposures, and odor-mediated leak detection levels. Given methane’s global warming potency, benzene’s toxicity, and wide variation in smelling abilities, our findings highlight the deficiencies regarding the sole reliance on odorization to alert and protect all occupants from indoor leaks.

Alleviating Heat Stress in Fattening Pigs: Low-Intensity Showers in Critical Hours Alter Body External Temperature, Feeding Pattern, Carcass Composition, and Meat Quality Characteristics.

Heat stress is a significant environmental problem that has a detrimental impact on animal welfare and production efficiency in swine farms. The current study was conducted to assess the effect of low-intensity showers, provided during critical high-temperature hours daily, on body external temperature, feeding pattern, and carcass and meat quality characteristics in fattening pigs. A total of 400 animals (200 barrows and 200 gilts) were randomly allotted in 40 pens. A shower nozzle was installed over 20 pens (half barrows and half gilts) where pigs received a low-intensity shower for 2 min in 30 min intervals from 12 to 19 h (SHO group). Another group without showers was also considered (CON). Feeder occupancy measurement, thermographic measures, and carcass and meat quality parameters were studied. In the periods with higher environmental temperatures, SHO animals showed an increase in the feeder occupancy rate compared to the CON group. A decrease in temperature was observed after the shower, regardless of the anatomical location (p < 0.005). The treatment with showers led to higher values than in the CON group of 4.72%, 3.87%, 11.8%, and 15.1% for hot carcass weight, lean meat yield, and fat thickness in Longissimus Dorsi (LD) and Gluteus Medius muscles, respectively (p < 0.01). Pork from CON showed a 14.9% higher value of drip loss, and 18.9% higher malondialdehyde concentration than SHO (p < 0.01); meanwhile, intramuscular fat content was 22.8% higher in SHO than in CON (p < 0.01). On the other hand, the CON group exhibited higher L* (2.13%) and lower a* and b* values (15.8% and 8.97%) compared to the SHO group. However, the pH20h of the CON group was significantly lower than that of the SHO group (p < 0.001), indicating a softer pH decrease. Related to fatty acids in subcutaneous outer and inner layers and intramuscular fat, the CON group showed higher ΣSFA and lower ΣMUFA and Δ9-desaturase indexes than SHO (p < 0.05). In conclusion, the amelioration of heat stress through showers at critical times should be considered an interesting tool that improves both carcass and meat quality, as well as animal welfare.

Landscape characteristics govern the impacts of beaver ponds on surface water methylmercury concentrations in boreal watersheds

Studies in boreal regions concerning the bioaccumulative neurotoxin methylmercury (MeHg) in natural wetlands and experimental reservoirs have shown that these waterbodies contribute to high MeHg levels in underlying sediments, inundated vegetation, and aquatic organisms. Beaver ponds are natural reservoirs that are ubiquitous in the Canadian boreal region and have been reported to increase downstream MeHg concentrations. However, the reported impacts of beaver ponds on stream MeHg vary widely across a limited number of studies, and factors influencing this variation are not well understood. To quantify the effect of beaver ponds on stream mercury concentrations, water samples were taken upstream and downstream of 10 in-channel beaver impoundments in northwestern Ontario, Canada. The downstream:upstream MeHg concentration ratios were related to pond and landscape characteristics to examine potential factors that play a role in determining the effect of beaver ponds on stream MeHg concentrations. Overall, MeHg concentrations were 1.6 times greater downstream of the beaver ponds, though this increase was not consistent; downstream concentrations up to 12 times greater and up to 5 times less were also observed. Landscape characteristics that can be readily obtained from existing spatial datasets or quantified using remote sensing techniques emerged as better predictors of downstream:upstream MeHg concentrations than site-specific stream chemistry parameters or pond characteristics that are more difficult to ascertain, with drier landscapes indicative of lower background MeHg export being more likely to exhibit greater increases in MeHg downstream of a beaver pond. These results suggest that the effects of beaver ponds on surface water MeHg concentrations are generally small but highly variable, and that the magnitude of the pond’s influence on stream MeHg are lessened in landscapes already conducive to higher MeHg concentrations.

Ecological risk assessment of microplastics and mesoplastics in six common fishes from the Bay of Bengal Coast

Plastic particles have emerged as a growing threat to both ecosystems and human well-being, as they are being ingested and accumulate at different trophic levels. However, microplastic and mesoplastic contamination and its risk to coastal and marine water fish have not been well studied, particularly in the northern Bay of Bengal. In this study, the presence of small-scale plastic particles (micro- and meso-sized) in the gastrointestinal tract (GIT) and muscles of six edible fish species from the northern Bay of Bengal Coast were identified and analyzed. The overall range of microplastics was 1.74 ± 0.23–3.79 ± 2.03items/g in muscle and 0.54 ± 0.22–5.96 ± 3.16 items/g in the GIT, with 16.38 ± 8.08–31.88 ± 12.09 items/individual. No mesoplastics were found in muscle tissue, but they were present in the GIT at concentrations ranging from 0.33 ± 0.27 to 0.03 ± 0.02 items/g and from 0.51 ± 0.05to 1.38 ± 1.01 items/individual. Lepturacanthus savala accumulated the most microplastics in muscle, and Harpadon nehereus had the least. In addition, the highest levels of mesoplastics were detected in the GIT of Polynemus paradiseus and the lowest was detected in the GIT of Lutjenus sanguineus. Omnivorous fish showed higher plastic concentrations than carnivorous fish, which was linked to dietary habits, feeding strategies and digestive processes. Plastic material predominantly accumulated in the GIT rather than in the muscle. The majority of ingested plastic particles were fibres (95.18 %), were violet in color (34 %), and were < 0.5 mm in size (87 %). The dominant microplastic polymers included 38 % PE, 15 % PP, 33 % PU, and 14 % CES. In contrast, the prevalent mesoplastic polymers comprised 45 % PE, 19 % PP, 13 % PS, 16 % PA, and 7 % PET. Subsequently, a hazard analysis using the polymer hazard index (PHI) revealed that plastic contamination was of distinct hazard categories for different polymer types, ranging from grade I (<1) to grade IV (100−1000). The assessment of the contamination factor (1 < CF < 3) and pollution load index (PLI > 1) indicated moderate contamination of fish by the ingestion of plastic debris. This study provides the foremost evidence for the presence of mesoplastics and microplastics in coastal and marine fish in the study region, paving the way for future investigations and policy implementation.

Does using a higher dialysate sodium concentration result in lower sodium losses with dialysis treatments?

IntroductionMany dialysis centres prescribe a uniform dialysate sodium (DialNa) concentration, but as there is no consensus on the choice of a universal DialNa, we wished to determine dialysate sodium balance comparing DialNa of 140 and < 140 mEq/L.MethodsWaste dialysate was continuously collected during sessions and thoroughly mixed, and sodium was measured in both the waste and fresh dialysate. Sodium removal was calculated as the difference in concentrations, dialysate flow rate, session time and ultrafiltration.ResultsDialysate sodium balance was measured during 139 dialysis treatments (34 DialNa 140 versus 105 DialNa < 140, median 136 mEq/L), in 111 patients, 63% male, mean age 64.0 ± 16.2 years and 33.3% diabetic. There was no difference using the higher DialNa [net loss median 482 (238–573) versus 312 (124–599) mEq], ultrafiltration losses [226 (131–280) versus 204 (125–290)mEq] and non-ultrafiltration losses [217 (0–384) versus 173 (−90 to 350)mEq]. We also compared haemodiafiltration and haemodialysis (118 versus 23 sessions), and there were no differences in net loss [311 (91–608) versus 381 (167–597)], ultrafiltration [212 (127–290) versus 169 (110–258)mEq] and non-ultrafiltration losses [180 (−51 to 386) versus 192 (−74 to 387)mEq].ConclusionsAlthough most dialysis centres prescribe a universal dialysate sodium concentration, there is no consensus on the optimum universal concentration. We found no difference in net dialysate sodium balance when comparing patients dialysing with a dialysate sodium concentration of 140 or < 140 mEq/L. Similarly, we found no differences in dialysate sodium balance between haemodiafiltration and haemodialysis sessions.

Effects of biochar types on seed germination, growth, chlorophyll contents, grain yield, sodium, and potassium uptake by wheat (Triticum aestivum L.) under salt stress

Soil salinity is a significant challenge in agriculture, particularly in arid and semi-arid regions such as Pakistan, leading to soil degradation and reduced crop yields. The present study assessed the impact of different salinity levels (0, 25, and 50 mmol NaCl) and biochar treatments (control, wheat-straw biochar, rice-husk biochar, and sawdust biochar applied @ 1% w/w) on the germination and growth performance of wheat. Two experiments: a germination study and a pot experiment (grown up to maturity), were performed. The results showed that NaCl-stress negatively impacted the germination parameters, grain, and straw yield, and agronomic and soil parameters. Biochar treatments restored these parameters compared to control (no biochar), but the effects were inconsistent across NaCl levels. Among the different biochars, wheat-straw biochar performed better than rice-husk and sawdust-derived biochar regarding germination and agronomic parameters. Biochar application notably increased soil pHs and electrical conductivity (ECe). Imposing NaCl stress reduced K concentrations in the wheat shoot and grains with concomitant higher Na concentrations in both parts. Parameters like foliar chlorophyll content (a, b, and total), stomatal and sub-stomatal conductance, and transpiration rate were also positively influenced by biochar addition. The study confirmed that biochar, particularly wheat-straw biochar, effectively mitigated the adverse effects of soil salinity, enhancing both soil quality and wheat growth. The study highlighted that biochar application can minimize the negative effects of salinity stress on wheat. Specifically, the types and dosages of biochar have to be optimized for different salinity levels under field conditions.

Foredune initiation and early development through biophysical interactions

Coastal dunes result from complex interactions between sand transport, topography and vegetation. However, uncertainty still persists due to limited quantitative analyses, integrating plant distribution and morphologic changes. This study aims to assess the initiation and maintenance of feedback processes by analysing the early development stages of incipient foredunes, combining data on the evolution of the plant cover and communities and dune morphology. Over three years, the monitoring of a newly formed dune (1 ha plot) reveals the progressive plant colonisation and the episodic accumulation of sand around vegetated areas controlled by sediment availability. Distinct colonisation rates were observed, influenced by inherited marine conditions, namely topography and presence of beach wrack. Berm-ridges provided elevations above the critical threshold for plant colonisation and surface roughness, aiding sediment accumulation. Beach wrack above this threshold led to rapid expansion and higher plant concentration. In the initial stages, vegetation cover significantly influenced sediment accumulation patterns, with higher accumulation around areas with high plant cover and low slopes or around areas with sparse vegetation but milder slopes. As the dune system matured and complexity grew, the link between vegetation cover and accumulation became nonlinear. Mid to low coverages (5–30 %) retained most of the observed accumulation, especially when coupled with steep slopes, resulting from positive feedbacks between vegetation, topography and sand transport. As foredune developed, vegetation cover and diversity increased while inherited morphologies grew vertically, explaining the emergence of dune ridge morphological types. Flat surfaces lacking wrack materials experienced a three-year delay in colonisation and sand accumulation, leading to the formation of terrace-type incipient foredunes. These observations underline feedback processes during the early stages of dune formation, with physical feedbacks primarily driving initiation and biophysical feedbacks prevailing in subsequent colonisation stages.

Cognitive symptoms in patients with cancer receiving PD-1/PD-L1 checkpoint inhibitors: Insights from a cross-sectional pilot study.

12094 Background: Cancer-related cognitive impairment is common with traditional therapeutic modalities, affecting memory, psychomotor speed, attention, and executive function of up to 75% of adults with cancer. Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as novel and efficacious treatments due to their ability to penetrate the blood-brain barrier and improve survival rates. However, they come with significant short- and long-term complications, including neurological toxicities. Despite their benefits, the impact of ICIs on cognitive function is not well understood. This study aims to examine the frequency and severity of cognitive impairment and the factors correlated among adults with cancer receiving ICIs. Methods: We collected questionnaire data on cognitive function using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) and other concurrent symptoms, as well as saliva samples of a subset of inflammatory cytokines from patients treated with PD-1/PD-L1 checkpoint inhibitors between 2022 and 2023. Sample characteristics were described using mean, frequency, and percentage. To analyze the relationship among symptoms and demographics, we used Pearson’s correlation and the Mann-Whitney U test. Saliva cytokines were analyzed using ELISA assays. This study is IRB approved. Results: Twenty-three patients (male: n=11, female: n=12) have received ICIs for an average of eight months, with a mean age of 70.87±11.63 years. 78.3% had melanoma/skin cancer, 8.7% had head and neck cancer, and 13% had other malignancies. Pembrolizumab was administered to 47.8%, and Nivolumab to 26.1%. The mean scores of FACT-Cog for perceived cognitive impairment (PCI) and perceived cognitive abilities (PCA) were 60.87±13.06 (maximum: 72) and 22.30±6.70 (maximum: 28), respectively. 26.1% of participants (n=6) reported lower scores than the cut-off in both PCI (cut-off: ≤55.1) and PCA (cut-off: ≤19.5). Lower FACT-Cog PCI scores were significantly correlated with older age ( r=-.511, p&lt;.05), greater fatigue ( r=-.483, p&lt;.05) and pain ( r=-.558, p&lt;.01). Participants with PCA and PCI scores below the cut-off showed higher mean concentrations of IL-1β (mean±SE: 188.22±133.72 vs. 80.99±14.73pg/mL), CRP (6659.47±3027.58 vs. 3910.71±1022.41pg/mL), and IL-6 (109.24±56.07 vs. 30.22±6.26pg/mL) compared to those with scores above the cut-off, although the results were not significant. This suggests that increased inflammatory cytokines may be associated with cognitive impairment. Conclusions: This preliminary study suggests that some patients may experience cognitive impairment during ICI treatment. As cancer patients are more at risk for cognitive impairment before treatment, a longitudinal study is warranted to confirm cognitive function both pre- and post-immunotherapy, along with objective measures of cognitive performance.