Risk Of Toxicity Research Articles

Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study

BackgroundCheckpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel.MethodsMEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a “significant IrAE” (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs.DiscussionThe pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment.Trial RegistrationThe study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

Application of therapeutic nucleic acids and RNA interference to create products for personalised medicine

INTRODUCTION. Small interfering RNAs (siRNAs) are among the most promising types of therapeutic nucleic acids aiming at the inhibition of pathogenetically relevant gene expression through the RNA interference mechanism. However, the limited bioavailability and immunogenicity of siRNAs and imperfect delivery systems hinder the clinical potential and applicability of siRNA medicinal products.AIM. This study aimed to summarise recent advances in the development of siRNA medicinal products and the corresponding delivery systems, review clinical trial results, and outline future development prospects for these medicinal products.DISCUSSION. This article covers the molecular mechanisms underlying RNA interference, the considerations for siRNA development, and the techniques for effective siRNA delivery. The article dwells upon various systems for nucleic acid delivery to targeted cells. The most promising delivery systems are non-viral systems, including liposomes, exosomes, nanoparticles, polymers, cell-penetrating peptides, and GalNAc ligands. Their main advantages include their ease of complexation with nucleic acids, modification and functionalization potential, favourable safety profile, ability to cross biological barriers, and tropism to target tissues. The article summarises the information that has accumulated over the past few years in clinical trials of siRNA medicinal products for a range of conditions, including metabolic disorders, infections, and cancers, as well as hereditary, ophthalmic, renal, and hepatic diseases. Special attention is paid to siRNA medicinal products undergoing clinical trials (over 10 products) and approved for clinical use (6 products, including MIR 19, the first authorised Russian siRNA medicinal product).CONCLUSION. Ultimately, siRNA medicinal products are a promising tool for personalised medicine, exhibiting therapeutic potential for a wide range of pathological conditions. Further studies of siRNA medicinal products should aim at improving siRNA production technology to increase their bioavailability and half-life period. In addition, these studies should aim at enhancing delivery systems for these products to mitigate toxicity risks and maximise efficacy.

Influence of anti-seasonal inundation on geochemical processes of arsenic speciation in the water-level-fluctuation zone soil of the Three Gorges Reservoir, China

Since the completion of Three Gorges Dam, the water-level-fluctuation zone (WLFZ) of the Three Gorges Reservoir (TGR) experiences the periodic anti-seasonal inundation. However, knowledge for mechanisms of mobilization and transformation of arsenic (As) in WLFZ soils of the TGR remains scarce. To address this gap, a combination of field observation and simulated flooding experiments attempts to illustrate the As mobilization, the transformation between As(V) and As(III), and the factors driving these processes. The study revealed that anti-seasonal inundation (with a temperature at 13 ℃) mitigated As release from submerged soils. Interestingly, the total As and ratio of As(III) (the more toxic form of As) concentrations in porewater at 13 ℃ was lower, and the prevalence of As(III) occurred later than those at 32 °C (imitate the seasonal inundation condition). The results indicated that the As reduction and the corresponding toxic risks in submerged soils were alleviated under anti-seasonal inundation. The study proposes the reduction of As-bearing manganese (Mn) mineral assemblages and competitive adsorption of dissolved organic carbon (DOC) as primary mechanisms for As mobilization. Furthermore, microorganism-mediated detoxification/reduction processes involving DOC, nitrogen, and Mn (oxyhydr)oxides were identified as central pathways for As(III) enrichment under anti-seasonal inundation. This study enhances understandings of the biogeochemical processes and fate of As in WLFZ soils influenced by artificial regulation of the reservoir.

A new electrochemical sensor based on a screen-printed electrode modified with an ion-imprinted PEDOT for the detection and the quantification of Cd(II)

In this study, an electrochemical sensor was developed using an ion imprinting technique to create a film, facilitating rapid, sensitive, cost-effective and multiplexed determination of cadmium ions in nature. Indeed, pollution by this substance is of great concern due to its toxic health risks and its cumulative and persistent nature in living organisms. The sensor was functionalized with cyclic voltammetry by directly electropolymerizing ethylenedioxythiophene (EDOT) in the presence of Cd(II) as a template on screen-printed platinum electrodes. After electropolymerization, the structure and the morphology of the sensor ion imprinted polyethylendioxythiophene (IIP-PEDOT/SPPtE) were characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and scanning electron microscopy (SEM/EDX). The electrochemical properties of the sensor were studied by cyclic voltammetry and electrochemical impedance spectroscopy. All experimental parameters were optimized by square wave voltammetry. IIP-PEDOT/SPPtE exhibited a linear concentration range of 0.5 to 75 µg/L, a detection limit of 0.07 µg/L and a quantification limit of 0.21 µg/L. Furthermore, the proposed sensor revealed good reproducibility, high stability and high selectivity for cadmium over several potential interferents. The developed device was successfully applied to the Cd(II) detection in industrial water samples via the standard addition method. The results were compared to analyzes of the same samples by ICP-MS. A high recovery rate of around 90–102.2 % and an RSD equal to 5.8 % and 2.5 % were observed.

Detection of Cyclic Imines (CIs) Toxins in Whole Body of Shellfishes: First Monitoring Report of CIs in South Korea Shellfishes

Cyclic imines (CIs) produced by microalgal species that accumulate in the food chains of marine organisms are novel biotoxins that do not belong to the classic group of marine biotoxins. In the past, CIs were found only in limited areas; however, in recent years, rapid changes in marine ecosystems have led to widespread CIs and increased exposure to toxic risks. In this study, we analyzed seven CI toxins, GYM-A, SPX (13-desmethyl spirolide C, 13, 19-dideMe spirolide C, 20-methyl spirolide G), and PnTX-E, F, and G, using LC/MRM-MS. Shellfish samples were purchased from a domestic Korean fish market (67 samples in 2021 and 216 samples in 2022). The entire body of the shellfish was ground and extracted with 50% methanol, followed by lipophilic-specific SPE. Only GYM-A, PnTX-G, and 13-desmethyl spirolide C were detected in all analyzed samples. The maximum concentrations of GYM-A is maximum 179 ppt (ng/kg) in Crassostrea nippona (March 2022), PnTX-G is maximum 7 ppt in Anadara broughtonii (April 2022), 13-desmethyl SPX C is maximum 58 ppt in Crassostrea nippona (April 2022). The southern coast exhibited the highest frequency of detection of these toxins, which was attributed to elevated sea-surface temperatures, aligned with conducive conditions for toxin-producing phytoplankton. According to the monitoring results, there were no significant CI toxins in the shellfish; however, it is important to monitor CI toxin accumulation in shellfish because of their high risk of toxicity.

Determining the vitamin D supplementation duration to reach an adequate or optimal vitamin D status and its effect on blood lipid profiles: a longitudinal study

BackgroundRecently, Serum vitamin D (Vit. D) levels evaluation and the use of Vit. D supplements have increased substantially. There is no specific guideline for the duration of Vit. D supplementation, so yet Vit. D supplementation duration has remained a critical and controversial issue. This study aimed to determine the vit. D supplementation duration to reach an adequate or optimal Vit. D status and its effect on lipid profile.MethodsIn this longitudinal study, 345 women with different status of Vit. D levels were enrolled and followed up for one year. Eligible participants received 50,000 IU Vit. D3 (cholecalciferol) once a month for 12 consecutive months. The serum Vit. D levels and lipid profiles were measured at baseline, 3rd, 6th, and 12th months after the intervention. Participants were categorized based on Vit. D level at baseline into deficiency (< 20 ng/mL), inadequate (20–30 ng/mL), and adequate (> 30 ng/mL) groups, and the data were compared at different times between the three groups.ResultsThree deficiency (n = 73), inadequate (n = 138) and adequate (n = 134) groups of participants were followed. In all participants the average amount of Vit. D level changes were 8 ng/mL after one year of supplementation. The mean changes of serum Vit. D level in 6th and 12th months vs. 3th month was as below: In deficiency group: 4.08 ± 0.85 and 10.01 ± 1.02 ng/mL; (p < 0.001), in inadequate group: 3.07 ± 0.59 and 7.26 ± 0.78 ng/mL; (p = 0.001) and in adequate group: 2.02 ± 0.88 and 6.44 ± 1.005 ng/ml; (p = 0.001). Lipid profiles were improved in three groups. So, the mean changes of lipid profiles at the end of the study comparing with the baseline were: -5.86 ± 2.09, -7.22 ± 1.43 and − 6.17 ± 1.72 (mg/dl) for LDL (p < 0.05); -12.24 ± 3.08, -13.64 ± 3.21 and − 17.81 ± 2.94 (mg/dl) for cholesterol (p < 0.05) in deficiency, inadequate and adequate groups, respectively. For triglyceride, the mean changes were − 13.24 ± 5.78 and − 15.85 ± 7.49 (mg/dl) in deficiency and adequate groups, respectively (p < 0.05). Although the triglyceride decreased in the inadequate group at the end of the study but this difference was not significant (p = 0.67).ConclusionTaking of 50,000 IU Vit. D 3 monthly for 12 months resulted in reaching its level to adequate level in both deficiency and insufficient groups; however, in the adequate group its level did not reach above than 50 ng/mL. Therefore, 50,000 IU Vit. D3 supplementation monthly for one year can have beneficial effects on lipid profiles and there is no risk of toxicity in healthy women.

The Impact of Frailty on Chemotherapy Outcomes in Patients With Digestive System Tumors: A Systematic Review and Meta-analysis.

The prevalence of patients with digestive system tumors has been high. In recent years, frailty has been considered to be associated with poor prognosis of digestive system tumors, but there are conflicting research results. A better understanding of the relationship between frailty and outcomes after chemotherapy can help advance the development of oncology care. The aim of this study was to evaluate the effects of prechemotherapy frailty on chemotherapy toxicity, overall mortality, unplanned hospitalization, and overall survival in patients with digestive system tumors. Up to April 2023, observational studies assessing the impact of frailty on chemotherapy outcomes in patients with digestive system tumors were collected through searching 10 online research databases. Two evaluators independently extracted literature based on the inclusion and exclusion criteria and evaluated the quality of the studies using the Newcastle-Ottawa Scale. Eventually, 11 cohort studies encompassing 2380 patients were included. The meta-analysis revealed that the frail group exhibited an increased risk of overall mortality, with poorer overall survival than the nonfrail group. Frailty increases the risk of chemotherapy-induced toxic effects, unplanned hospitalization, and death in patients. However, because of this study's limited number of participants, large-sample, multicenter studies to verify these findings are required. This study provides theoretical support for incorporating frailty assessment into the nursing evaluation of patients with digestive system tumors before chemotherapy. This integration aids in predicting patients at a high risk of chemotherapy toxicity, mortality, and unplanned hospitalization, therefore providing corresponding interventions in advance to reduce adverse outcomes.

Timing of Toxicities and Non-Relapse Mortality Following CAR T Therapy in Myeloma

BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.

Investigating the Acute Toxic Effects of Urea Fertilizer on Juvenile Nile Tilapia (Oreochromis niloticus)

The research aimed to assess the acute toxicity of urea fertilizer on juveniles of Oreochromis niloticus. The findings indicated a correlation between increasing concentrations of urea fertilizer and higher mortality rates among the test organisms, with an LC50 value determined at 500 mg/l. Additionally, a rise in total dissolved solids was observed with higher concentrations of urea. Parameters such as temperature, electrical conductivity, dissolved oxygen and pH showed statistically significant (P &lt; 0.05) changes as the concentrations of urea increases. Behavioural responses during the exposure phase included heightened excitability, vigorous swimming behaviours, loss of equilibrium, culminating in mortality. These results unequivocally demonstrate that urea fertilizer at acute concentrations poses significant toxic risks to juvenile Oreochromis niloticus.

Polystyrene nanoplastics induce lipophagy via the AMPK/ULK1 pathway and block lipophagic flux leading to lipid accumulation in hepatocytes

Micro- and nanoplastic pollution has emerged as a significant global concern due to their extensive presence in the environment and potential adverse effects on human health. Nanoplastics can enter the human circulatory system and accumulate in the liver, disrupting hepatic metabolism and causing hepatotoxicity. However, the precise mechanism remains uncertain. Lipophagy is an alternative mechanism of lipid metabolism involving autophagy. This study aims to explore how polystyrene nanoplastics (PSNPs) influence lipid metabolism in hepatocytes via lipophagy. Initially, it was found that PSNPs were internalized by human hepatocytes, resulting in decreased cell viability. PSNPs were found to induce the accumulation of lipid droplets (LDs), with autophagy inhibition exacerbating this accumulation. Then, PSNPs were proved to activate lipophagy by recruiting LDs into autophagosomes and block the lipophagic flux by impairing lysosomal function, inhibiting LD degradation. Ultimately, PSNPs were shown to activate lipophagy through the AMPK/ULK1 pathway, and knocking down AMPK exacerbated lipid accumulation in hepatocytes. Overall, these results indicated that PSNPs triggered lipophagy via the AMPK/ULK1 pathway and blocked lipophagic flux, leading to lipid accumulation in hepatocytes. Thus, this study identifies a novel mechanism underlying nanoplastic-induced lipid accumulation, providing a foundation for the toxicity study and risk assessments of nanoplastics.

Antibacterial activity against multidrug-resistant Salmonella, toxicity and biochemical effects of Moringa oleifera leaf extracts in mice

Abstract. Ngemenya MN, Itoe LO, Awah LA, Asongana R, Ndip RA. 2024. Antibacterial activity against multidrug-resistant Salmonella, toxicity and biochemical effects of Moringa oleifera leaf extracts in mice. Asian J Nat Prod Biochem 22: 43-50. The emergence of multidrug resistance has significantly compromised the treatment of Salmonella infections. The anti-Salmonella activity, toxicity, and biochemical effects of Moringa oleifera Lam. leaf crude extracts were studied by disc diffusion and microdilution against Multidrug-Resistant (MDR) strains. Cytotoxicity was investigated on monkey kidney epithelial cells (LLCMK2) and acute toxicity in BALB/c mice. Both hexane (MOHEX) and methanol (MOMET) extracts produced small zones of inhibition of 8mm at 1 mg and 2 mg per disc, indicating weak activity, but the minimum inhibitory concentration showed high (0.0625 mg/mL) to low activity (10 mg/mL) activity. No minimum bactericidal concentration was recorded at the concentrations tested. The 50% cytotoxic concentration (CC50) for methanol and hexane extracts were 2524 µg/mL and 5004 µg/mL, respectively, indicating a low risk of toxicity. No mortality or adverse effects were recorded in the acute toxicity test. Both extracts had no significant effects (p &lt; 0.05) on renal function and one liver enzyme (alanine aminotransferase), but MOMET significantly increased aspartate aminotransferase (p = 0.04), suggesting possible liver toxicity. The study shows that M. oleifera leaves possess bacteriostatic activity against multidrug-resistant Salmonella and are non-toxic; hence, it is a potential alternative treatment against multidrug-resistant Salmonella. Further studies of fractions and pure natural products of the extracts should be pursued.

Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH &gt;upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade &gt;3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .

Assessment of GFR in Patients with Cancer: A Statement from the American Society of Onco-Nephrology.

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

Antibody Recognition of Human Epidermal Growth Factor Receptor-2 (HER2) Juxtamembrane Domain Enhances Anti-Tumor Response of Chimeric Antigen Receptor (CAR)-T Cells.

Chimeric antigen receptor (CAR) T cell therapy shows promise in treating malignant tumors. However, the use of human epidermal growth factor receptor-2 (HER2) CAR-T cells carries the risk of severe toxicity, including cytokine release syndrome, due to their "on-target off-tumor" recognition of HER2. Enhancing the quality and functionality of HER2 CARs could greatly improve the therapeutic potential of CAR-T cells. In this study, we developed a novel anti-HER2 monoclonal antibody, Ab8, which targets domain III of HER2, distinct from the domain IV recognition of trastuzumab. Although two anti-HER2 mAbs induced similar levels of antibody-dependent cellular cytotoxicity, trastuzumab-based CAR-T cells exhibited potent antitumor activity against HER2-positive cancer cells. In conclusion, our findings provide scientific evidence that antibody recognition of the membrane-proximal domain promotes the anti-tumor response of HER2-specific CAR-T cells.

The Role of e-Cigarette Packaging as a Health Communications Tool: A Focus Group Study With Adolescents and Adults in England and Scotland.

In the United Kingdom, e-cigarette and refill packaging must display a nicotine addiction warning. This study explored how this message is perceived, responses to alternative on-pack messages, and other options for using e-cigarette packaging to discourage youth and people who neither smoke nor use e-cigarettes while encouraging smokers to switch. Between August and September 2022, 16 focus groups (n = 70) were conducted to explore these topics with adolescents (n = 31, aged 11-17 years) and adults (n = 39, nonsmokers, smokers that use e-cigarettes, smokers that do not use e-cigarettes) in England and Scotland. While several participants thought the current nicotine addiction warning could help increase awareness of nicotine addiction, most reported that it failed to capture attention and was not a deterrent. Alternative messages shown on packs (about harm, toxicity, wellness, litter, or relative risk) received mixed responses. Relative risk messages were perceived as most beneficial for smokers switching but also thought to potentially encourage uptake among nonsmokers. Some participants considered certain harm and toxicity messages to potentially dissuade uptake. Participants proposed several ideas to reduce the appeal of e-cigarette packaging and devices to deter youth uptake, including more prominent warnings, standardized packaging, and devices that are plain or include health messages. Packaging can play a crucial role in communicating product and health messages to different consumer groups. Further consideration of how packaging and labeling can meet the needs of non-nicotine users while simultaneously reaching those who may benefit from using e-cigarettes to stop smoking is warranted. While some viewed the nicotine addiction warning required on e-cigarettes and refill packaging in the United Kingdom as helpful in raising awareness of nicotine addiction, it did not resonate with most of our sample of adolescents and adults. The findings suggest that e-cigarette packaging could be better used to encourage smokers to switch to a less harmful alternative, with relative risk messages showing promise. Furthermore, strengthening on-pack messaging (eg increasing salience and rotating messages) and reducing the appeal of packaging (eg drab colors) and devices (eg including warnings) may help increase awareness of e-cigarette harms while deterring use among adolescents and nonsmokers.

Effects of polystyrene nanoplastic size on zebrafish embryo development

Polystyrene nanoplastics (PS) require a comprehensive evaluation of their toxicity and potential risks to humans and the environment. The zebrafish model, a well-established animal model increasingly utilized for nanotoxicity assessments, was employed in this study. Our research aimed to explore the toxic effects of PS with sizes of 30, 100, 200, and 450 nm on zebrafish embryos. Exposure experiments were conducted on embryos at 4 h post-fertilization (hpf) using various concentrations of nanoparticles (20, 40, 60, 80, and 100 mg/L) until 96 hpf. Notably, PS ranging from 100 to 450 nm did not adversely affect zebrafish embryo development. However, PS with a size of 30 nm at a concentration of 100 mg/L resulted in embryo mortality but not embryonic malformations. Furthermore, our investigation confirmed the uptake of these nanoparticles by zebrafish larvae following the opening of their mouths, with the particles being found predominantly in the digestive system of the larvae. Additionally, 30 nm PS were found to significantly modulate the expression levels of genes associated with oxidative stress and apoptosis. These findings highlight the developmental impacts of 30 nm PS on zebrafish embryos, raising concerns about potential similar consequences in humans. Considering our findings, it is essential to encourage further research into the management and regulation of PS to mitigate their potential environmental and health impacts.

Metronomic chemotherapy: bridging theory to clinical application in canine and feline oncology.

Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic success. Traditionally, chemotherapy protocols are based on classic cytostatic drugs under the concept of maximum tolerated dose (MTD), which has been associated with a greater risk of toxicity and resistance. Thus, new therapeutic alternatives have emerged, such as metronomic chemotherapy (MC), introducing a new paradigm in cancer treatment. MC consists of administering low doses of chemotherapy drugs continuously over a long period of time, modulating the tumour microenvironment (TME) due to the combination of cytotoxic, antiangiogenic and immunomodulatory effects. This multi-targeted therapy has been described as a treatment option in several canine and feline cancers since 2007, with positive results already published in the literature, particularly in mammary carcinomas and soft tissue sarcomas in dogs. The aim of this review article is to describe the current knowledge about the use of MC in small animal oncology, with emphasis on its mechanisms of action, the most commonly used drugs and clinical outcome.

Fluoride exposure from consumption of some animal-based foods in an outermost region of Europe

Fluoride is an anion that is widely distributed in nature and can be found in varying levels in water supplies and foodstuffs. This study has been carried out considering the toxic effects in cases of chronic and high fluoride intake and the presence of this anion in foods of animal origin. The fluoride content in a total of 96 samples of animal origin (meat, poultry and poultry products; fish and seafood; milk, dairy products and eggs) was determined by potentiometry with a fluoride selective electrode (ISE). The overall mean concentration was 3.92 ± 6.04 mg/kg, with a minimum for milk (values below the detection limit of 0.01 mg/kg) and a maximum for shrimps (32.1 mg/kg). Seafood was found to have the highest fluoride concentrations and the estimated daily intake (EDI) and the percentage contribution to the adequate intake (AI) and upper-level intake (UL) were calculated. Overall, the percentage contribution to UL was less than 20 %. It was concluded that the intake of the analysed animal-based foods does not pose a toxic risk.

Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

PH-Responsive Charge Convertible Hyperbranched Poly(ionic liquid) Nanoassembly with High Biocompatibility for Resistance-Free Antimicrobial Applications.

As a potential alternative to antibiotics, hyperbranched poly(ionic liquid)s (HPILs) have demonstrated significant potential in combating bacterial biofilms. However, their high cation density poses a high risk of toxicity, greatly limiting their in vivo applications. In this study, we constructed a biocompatible HPIL (HPIL-Glu) from a hyperbranched polyurea core with modified terminals featuring charge-convertible ionic liquids. These ionic liquid moieties consist of an ammonium-based cation and a gluconate (Glu) organic counter. HPIL-Glu could form a homogeneous nanoassembly in water and exhibited a pH-responsive charge conversion property. Under neutral conditions, Glu shielded the positively charged surface, minimizing the toxicity. In a mildly acidic environment, Glu protonation exposes cationic moieties to biofilm eradication. Comprehensive antimicrobial assessments demonstrate that HPIL-Glu effectively kills bacteria and promotes the healing of bacteria-infected chronic wounds. Furthermore, prolonged exposure to HPIL-Glu does not induce antimicrobial resistance.