Multiple Toxicity Research Articles

Mycotoxin toxicity and its alleviation strategy on female mammalian reproduction and fertility.

Mycotoxin, a secondary metabolite of fungus, found worldwide and concerning in crops and food, causing multiple acute and chronic toxicities. Its toxic profile includes hepatotoxicity, carcinogenicity, teratogenicity, estrogenicity, immunotoxicity, and neurotoxicity, leading to deleterious impact on human and animal health. Emerging evidence suggests that it adversely affects perinatal health, progeny by its ability to cross placental barriers. Due to its wide occurrence and potential toxicity on reproductive health, it is essential to understand the mechanisms of mycotoxin-related reproductive toxicity. This review summarizes the toxicities and mechanisms of mycotoxin on maternal and offspring reproduction among mammalian species. Approaches for effective mycotoxin alleviation are also discussed, providing strategies against mycotoxin contamination. The profound mycotoxin toxicities in female mammalian reproduction affect follicle assembly, embryo development, and fetus growth, thereby decreasing offspring fertility. Factors from endocrine system such as hypothalamic-pituitary-gonadal axis and gut-ovarian axis, placenta ABC transporters, organelle and cytoskeleton dynamics, cell cycle control, genomic stability, and redox homeostasis are found to be closely related to mycotoxin toxicities. Approaches from physical, chemical, biological, and supplementation of natural antioxidants are discussed for the mycotoxin elimination, while their applications are not widespread. Available ways for mycotoxin and its toxicities alleviation need further study. Since a species-, time-, and dose-specific response might exist in mycotoxin toxicities, more consideration should be given to the protocols for mycotoxin toxicity studies, such as experimental animal models, exposure duration, and dosage. Specific mechanism for mycotoxin, especially form a molecular biology perspective, could be investigated with multi-omics technologies and advanced imaging techniques. Mass spectrometry with algorithms may provide more accurate exposure assessments, and be further helpful to identify the high-risk individuals in the future.

Air-water exchange: Toxicities, risks and PAHs compounds in the three gorges reservoir of China.

Air-water exchange is inevitably accompanied by the transportation of contaminants between atmosphere and water, which significantly leads to the alterations of toxicity and risks. However, the resulting changes of toxicity and risk in water and air due to the cross-interfacial transport of pollutants are still unclear. In this study, the water and atmospheric samples at the Pengxi River located in the Three Gorges Reservoir (TGR), China, were collected in winter and summer seasons respectively. The contaminated water exhibited higher toxicity effects than air in multiple toxicity endpoint tests. Besides, waters collected during winter exhibited greater toxicity effects than in summer. The concentrations of ΣPAHs were 48.0-445ngL-1 in the water and 9.44-82.3ng/m3 in the air, with ΣPAHs significantly higher in winter than in summer for water samples. Notably, the 2-3 ring PAHs showed a tendency to volatilize from water to air and may increase atmospheric toxicity, whereas the 4-6 ring PAHs tend to be deposited from air to water and may heighten toxicity in the water. Correlation analysis indicated that PAHs were important toxicants in the air, posing higher incremental carcinogenic risk, particularly during winter. Thus, the changes in toxicity and risk caused by the water-air exchange of pollutants cannot be ignored. This research contributes to a deeper understanding of the changes in toxicity effects and health risks caused by the air-water exchange of pollutants. The importance of considering the toxic effects and health concerns of micropollutants in the air as important as in water is emphasized.

Adipose tissue as target of environmental toxicants: focus on mitochondrial dysfunction and oxidative inflammation in metabolic dysfunction-associated steatotic liver disease.

Obesity, diabetes, and their cardiovascular and hepatic comorbidities are alarming public health issues of the twenty-first century, which share mitochondrial dysfunction, oxidative stress, and chronic inflammation as common pathophysiological mechanisms. An increasing body of evidence links the combined exposure to multiple environmental toxicants with the occurrence and severity of metabolic diseases. Endocrine disruptors (EDs) are ubiquitous chemicals or mixtures with persistent deleterious effects on the living organisms beyond the endocrine system impairment; in particular, those known as metabolism-disrupting chemicals (MDCs), increase the risk of the metabolic pathologies in adult organism or its progeny. Being largely lipophilic, MDCs mainly target the adipose tissue and elicit mitochondrial dysfunction by interfering with mitochondrial bioenergetics, biogenesis, dynamics and/or other functions. Plastics, when broken down into micro- and nano-plastics (MNPs), have been detected in several human tissues, including the liver. The harmful interplay between inflammatory and redox processes, which mutually interact in a positive feed-back loop, hence the term oxidative inflammation ("OxInflammation"), occurs both at systemic and organ level. In both liver and adipose tissue, oxinflammation contributes to the progression of the metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, it has been reported that individuals with MASLD may be more susceptible to the harmful effects of toxicants (mainly, those related to mitochondria) and that chronic exposure to EDs/MDCs or MNPs may play a role in the development of the disease. While liver has been systematically investigated as major target organ for ambient chemicals, surprisingly, less information is available in the literature with respect to the adipose tissue. In this narrative review, we delve into the current literature on the most studied environmental toxicants (bisphenols, polychlorinated biphenyls, phthalates, tolylfluanid and tributyltin, per-fluoroalkyl and polyfluoroalkyl substances, heavy metals and MNPs), summarize their deleterious effects on adipose tissue, and address the role of dysregulated mitochondria and oxinflammation, particularly in the setting of MASLD.

Tucaresol - Cyclophosphamide Combination Therapy: Proposal for a Safe, Affordable Alternative to CAR T-Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy is a newer immunotherapeutic process in which genetic engineering is used to incorporate a receptor protein into a patient's T-cells thereby permitting the modified T-cells to recognize and eradicate tumors. Initially, CAR T-cell therapy was reserved as a last resort when standard cancer treatments failed to provide significant efficacy but subsequently, CAR T-cell therapy is finding use against earlier stage cancers. Since 2017, seven CAR T-cell therapies have attained FDA approval for treatment of hematological cancers. The latest approval, November 8, 2024, is for treatment of B-cell acute lymphoblastic leukemia. However, CAR T-cell therapy does not always provide a lasting anticancer response which leads to loss of tumor remission. The percent loss of tumor remission depends upon the type of hematological cancer being treated. Although currently limited to hematological cancers, CAR T-cell therapy provides cancer patients a significant increase in survival unattainable with traditional cancer treatment regimens. However, two significant issues accompany CAR T-cell therapy. The first is multiple toxicity issues which although occurring individually in a low percentage of patients, taken together constitute a significant probability of encountering a potentially fatal side effect. The second problem is the high cost of CAR T-cell therapy starting at $450,000 US per treatment. Contributing to both of these problems is the fact that CAR T-cell therapy is labor intensive which will exacerbate existing clinical facilities already challenged by a myriad of mutating pathogens and an aging population. Against this setting is proposed therapy consisting of clinical stage and FDA approved anticancer drugs with excellent safety records. Proposed herein is combination therapy with Tucaresol, up-regulates CD4+ and CD8+ T-cells, and cyclophosphamide, down-regulates Treg cells, as a convenient, cost effective cancer treatment.

Conjugation Chemistry Markedly Impacts Toxicity and Biodistribution of Targeted Nanoparticles, Mediated by Complement Activation.

Conjugation chemistries are a major enabling technology for the development of drug delivery systems, from antibody-drug conjugates to antibody-targeted lipid nanoparticles inspired by the success of the COVID-19 vaccine. However, here it is shown that for antibody-targeted nanoparticles, the most popular conjugation chemistries directly participate in the activation of the complement cascade of plasma proteins. Their activation of complement leads to large changes in the biodistribution of nanoparticles (up to 140-fold increased uptake into phagocytes of the lungs) and multiple toxicities, including a 50% drop in platelet count. It is founded that the mechanism of complement activation varies dramatically between different conjugation chemistries. Dibenzocyclooctyne, a commonly used click-chemistry, caused aggregation of conjugated antibodies, but only on the surface of nanoparticles (not in bulk solution). By contrast, thiol-maleimide chemistry do not activate complement via its effects on antibodies, but rather because free maleimide bonded to albumin in plasma, and clustered albumin is then attacked by complement. Using these mechanistic insights, solutions are engineered that reduced the activation of complement for each class of conjugation chemistry. These results highlight that while conjugation chemistry is essential for the future of nanomedicine, it is not innocuous and must be designed with opsonins like complement in mind.

Ninety-Day Subchronic Toxicology of Individual and Combined Toxicants from the Thermal Processing of Lipid-Rich Foods.

Oxidative derivatives of triacylglycerols (ox-TGs), aldehydes, and 3-monochloropropane-1,2-diol esters (3-MCPDE) were simultaneously evaluated in a 90-day subchronic study, focusing on biological indicators, biochemical indicators, and serum metabolomics as the first part of integrated toxicity and interactions. After 90 days of feeding Kunming mice, coexposure to combined toxicants significantly inhibited the trend of liver weight gain, reduced the levels of total bilirubin (TBIL) and direct bilirubin (DBIL), and decreased uric acid (UA) compared to individual toxicant exposure. A total of 21 and 31 biomarkers in female and male mice were identified, respectively. Co-exposure to combined toxicants might mitigate the changes in cytidine, CDP, dUMP, and dUDP involved in purine and pyrimidine metabolism caused by a single exposure, but exacerbate the changes in l-tryptophan, 5-hydroxy-l-tryptophan, and 5-hydroxyindoleacetic acid, which are involved in tryptophan metabolism. These results provided new insights into a comprehensive toxicity and interaction evaluation model of multiple combined toxicants in food.

Tucaresol-Cyclophosphamide Combination Therapy: Proposal for a Safe, Affordable Alternative to CAR T-Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy is a newer immunotherapeutic process in which genetic engineering is used to incorporate a receptor protein into a patient’s T-cells thereby permitting the modified T-cells to recognize and eradicate tumors. Initially, CAR T-cell therapy was reserved as a last resort when standard cancer treatments failed to provide significant efficacy but subsequently, CAR T-cell therapy is finding use against earlier stage cancers. Since 2017, seven CAR T-cell therapies have attained FDA approval for treatment of hematological cancers. The latest approval, November 8, 2024, is for treatment of B-cell acute lymphoblastic leukemia. However, CAR T-cell therapy does not always provide a lasting anticancer response which leads to loss of tumor remission. The percent loss of tumor remission depends upon the type of hematological cancer being treated. Although currently limited to hematological cancers, CAR T-cell therapy provides cancer patients a significant increase in survival unattainable with traditional cancer treatment regimens. However, two significant issues accompany CAR T-cell therapy. The first is multiple toxicity issues which although occurring individually in a low percentage of patients, taken together constitute a significant probability of encountering a potentially fatal side effect. The second problem is the high cost of CAR T-cell therapy starting at $450,000 US per treatment. Contributing to both of these problems is the fact that CAR T-cell therapy is labor intensive which will exacerbate existing clinical facilities already challenged by a myriad of mutating pathogens and an aging population. Against this setting is proposed therapy consisting of clinical stage and FDA approved anticancer drugs with excellent safety records. Proposed herein is combination therapy with Tucaresol, up-regulates CD4+ and CD8+ T-cells, and cyclophosphamide, down-regulates Treg cells, as a convenient, cost effective cancer treatment.

Patulin-degrading enzymes sources, structures, and mechanisms: A review.

Patulin (PAT), a fungal secondary metabolite with multiple toxicities, is an unavoidable contaminant in fruit and vegetable processing, posing potential health risks to consumers and causing significant economic losses to the global food industry. Traditional control strategies, such as physical and chemical methods, face several challenges, including low efficiency, high costs, and unverified safety. In contrast, microbial degradation of patulin is considered a more efficient and environmentally friendly approach, which has become a popular research focus. However, there is still insufficient research on the key degradation enzymes involved in microorganisms. Therefore, this review comprehensively summarizes recent research progress on the biological degradation of patulin, with a focus on microbial species capable of degrading patulin, the degradation enzymes they express, potential degradation mechanisms, and the toxicity of degradation products, while providing prospects for future research. It offers valuable insights for controlling patulin in food and stimulates further investigation. Ultimately, this review aims to promote the development of efficient and eco-friendly methods to mitigate patulin contamination in fruits and vegetables.

Apolipoprotein E and Apolipoprotein E receptor 2 signaling as drug targets in Alzheimer’s disease

AbstractBackgroundAllelic variation in apolipoprotein E (APOE) is by far the greatest contributor to Alzheimer’s disease (AD) after age, but the mechanisms underlying how APOE impacts on the pathology of AD remain undefined. While most research is focusing on mechanisms associated with the presence of the APOE risk allele, several aspects of APOE biology remain poorly understood. In particular, the physiological relevance of APOE receptors and their impact on disease progression have been overlooked.MethodFerroptosis was induced in N27 neurons using multiple agents (erastin, RSL3) and toxicity was evaluated using different viability assays (MTT, Propidium iodide, LDH) and ferroptosis. N27 neurons were transfected with a plasmid encoding APOER2‐GFP fusion protein or a GFP‐expressing control vector, while recombinantly expressed and purified APOE was used as an APOE source.ResultHere, we present data supporting a function of APOE in tandem with APOER2 in protecting neurons from ferroptosis. Ferroptosis is a cell death pathway characterized by the accumulation of lethal lipid hydroperoxides resulting from iron‐dependent oxidation of polyunsaturated fatty acids. APOER2 expression in neurons resulted in increase in glutathione peroxidase 4 (GPX4) expression, which functions by converting toxic lipid peroxides into non‐toxic lipid alcohol and thus increases resistance to ferroptosis. We further report that APOER2 expression potentiates APOE‐mediated protection from ferroptotic cell death in in N27 neurons. Further mechanistic studies are ongoing to validate the underlying mechanism and the involved signaling cascades.ConclusionWe present evidence for the involvement of APOE and APOER2 in neuronal protection from ferroptotic cell death. These findings represent new drug targets that can be explored to slowdown neurodegeneration in AD.Funding: This study was supported by grants from the Alzheimer’s Association and National Health & Medical Research Council of Australia.

Rap1 and mTOR signaling pathways drive opposing immunotoxic effects of structurally similar aryl-OPFRs, TPHP and TOCP.

Aryl organophosphorus flame retardants (aryl-OPFRs), commonly used product additives with close ties to daily life, have been regrettably characterized by multiple well-defined toxicity risks. Triphenyl phosphate (TPHP) and tri-o-cresyl phosphate (TOCP), two structurally similar aryl-OPFRs, were observed in our previous study to exhibit contrasting immunotoxic effects on THP-1 macrophages, yet the underlying mechanisms remain unclear. This study sought to address the knowledge gap by integrating transcriptomic and metabolomic analyses to elucidate the intricate mechanisms. During individual omics analyses, we unfortunately only obtained highly similar results for both TPHP and TOCP, failing to identify the key reasons for their differences. These results revealed comparable disturbances induced by both compounds, including disruptions in nucleic acid synthesis and energy metabolism, blocking ADP to ATP conversion by reducing TCA cycle intermediates, consequently leading to ATP depletion. However, through integrative analysis, specific pathways affected by each compound were successfully identified, shedding light on their unique effects. TPHP reduced GTP levels necessary for Rap1 activation, thereby inhibiting phagocytosis and adhesion of THP-1 macrophages. Conversely, TOCP stimulated the mTOR signaling pathway, enhancing phosphorylation of downstream proteins S6K, RHOA, and PKC, consequently promoting immune responses. This study not only clarified the distinct immunotoxic mechanisms of TPHP and TOCP but also provided critical insights into how structural variations in aryl-OPFRs can lead to markedly different immune responses, thereby informing future risk assessments and regulatory strategies for these compounds.

Near-Infrared Two-Photon J-Aggregation-Induced Organic Fluorescent Dots with Large Stokes-Shift for Ratiometric Imaging of Hypochlorous Acid in Living Cells and Brains of AD Mice.

Alzheimer's disease (AD) is characterized by multiple toxicity from various biomarkers, and it is very important to monitor the fluctuation of biomarker level in brain tissues to track its early onset, illness progression, and therapeutic effect. Hypochlorous acid (HOCl) is confirmed to be a reliable biomarker to extend the scope of diagnosis. However, the practical applications of the developed conjugated small molecule fluorescent probes for detecting HOCl are often restricted to a large extent by their low solubility, aggregation-caused quenching (ACQ), unsatisfactory fluorescence brightness, small Strokes-shift, and lack of self-correcting ratiometric emitters. In this study, a J-aggregation-induced organic fluorescent dot (PBT dots), is reported which is facilely developed by co-assembling newly designed organic molecule PBT with polymer DSPE-PEG, for ClO- imaging in living brain-derived Endothelial (bEnd.3) cells and brain tissues of AD mice. The developed two-photon PBT dots show NIR emission at 715nm, large Stokes-shift of 245nm, quick response within 2s, ratiometric sensing properties, and favorable blood-brain barrier (BBB) penetrate ability. The results demonstrate that HOCl level is elevated in AD mouse brain, and PBT dot holds promise as an imaging probe to understand and reveal AD pathologies.

Bridging organ transcriptomics for advancing multiple organ toxicity assessment with a generative AI approach

Translational research in toxicology has significantly benefited from transcriptomic profiling, particularly in drug safety. However, its application has predominantly focused on limited organs, notably the liver, due to resource constraints. This paper presents TransTox, an innovative AI model using a generative adversarial network (GAN) method to facilitate the bidirectional translation of transcriptomic profiles between the liver and kidney under drug treatment. TransTox demonstrates robust performance, validated across independent datasets and laboratories. First, the concordance between real experimental data and synthetic data generated by TransTox was demonstrated in characterizing toxicity mechanisms compared to real experimental settings. Second, TransTox proved valuable in gene expression predictive models, where synthetic data could be used to develop gene expression predictive models or serve as “digital twins” for diagnostic applications. The TransTox approach holds the potential for multi-organ toxicity assessment with AI and advancing the field of precision toxicology.

LC-OCT for early diagnosis and characterization of dermatologic adverse events to oncologic drugs and correlation to histopathology.

Targeted and immune therapies have recently been associated with the occurrence of multiple cutaneous toxicities, often challenging to differentiate by clinical examination alone without histology. Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive and innovative imaging technique that has been shown to be almost as effective as histology in diagnosing several skin conditions. Our study aimed to assess the effectiveness of LC-OCT in predicting the clinical evolution of early maculopapular eruptions related to antineoplastic targeted therapy and immunotherapy. In the period between May 2023 and December 2023, consecutive patients with clinical cutaneous maculopapular reactions caused by oncologic targeted therapy or immunotherapy were enrolled at the dermatologic outpatient clinic of the Fondazione Policlinico A. Gemelli IRCCS, Rome. Patients underwent clinical dermatological examination, video-dermoscopy, LC-OCT, and incisional skin biopsy of a target cutaneous lesion. To investigate the evolutionary pattern of maculopapular lesions (psoriasic eruption, lichenoid eruption, eczematous eruption, bullous eruption), LC-OCT and histopathological images have been compared based on specific characteristics (hyperkeratosis, acanthosis, spongiosis; papillomatosis; lichenoid inflammatory infiltrate; presence of intraepidermal/subepidermal cleavage plan with formation of a bulla). Eighteen patients were included in this study (11 males, 7 females, median age 64.5). LC-OCT demonstrated an overall concordance with histology of 77.8%, with a Cohen's Kappa of 0.69 (P < 0.0001). Sensitivity exceeded 70%, and specificity was ≥88.2%. The Area Under the Curve (AUC) ranged from 0.9 to 1 for psoriasis and lichenoid eruption and from 0.7 to 0.9 for eczematous and bullous eruption. LC-OCT appears to be a promising tool for the early differential diagnosis of adverse skin reactions related to targeted therapy and immunotherapy, offering the potential to avoid skin biopsies in fragile cancer patients.

Metabolite identification of emerging disinfection byproduct dibromo-benzoquinone in vivo and in vitro: Multi-strategy mass-spectrometry annotation and toxicity characterization

Halobenzoquinones (HBQs) are emerging disinfection byproducts (DBPs) of high toxicity and also are shared active toxic intermediates of multiple halogenated organic pollutants. Due to the strong oxidizing property and electrophilicity, HBQs exhibit extremely diverse metabolism pathways in organisms. The identification of toxic-decisive metabolites is pivotal, albeit challenging, for understanding the toxicity mechanisms of HBQs. We employed dibromo-benzoquinone (DBBQ) as a representative HBQ, and established a systematic analytical strategy using high-resolution mass spectrometry, which collectively coupled suspect screening (SS), mass defect filtering (MDF), product ion filtering (PIF), isotopic signature filtering (ISF), and molecular networking (MN). As a result, 20 biotransformation products of DBBQ were identified in vivo and in vitro, involving metabolism reactions such as hydroxylation, methylation, methoxylation, acetylation, sulfonation, glucuronidation, glutathionylation, dimerization, and conjugation with amino acids or fatty acids. Quantitative structure-activity relationship (QSAR) analysis and cytotoxicity experiments consistently demonstrated the significantly high toxicity of the fatty acid conjugate compared to the parent compound DBBQ and other metabolites, pinpointing the important role of the fatty acid conjugation in determining the metabolism and toxicity of HBQs. The research conducted a comprehensive evaluation of the metabolism of a typical HBQ with the combination of multiple analytical and toxicity characterization methods, therefore screen out the most important metabolism pathway of HBQs.

Valence switching of bismuth in ferricyanide as cathode materials for sodium-ion batteries

Sodium-ion batteries (SIBs) are considered potential alternatives to lithium-ion batteries, and the key to their widespread use lies in finding efficient and cost-effective cathode materials. Ferricyanides have emerged as promising candidates for SIBs cathodes due to their low cost and open channel structure allowing for favorable ion and electron transport. However, traditional ferricyanides such as Prussian blue (PB) and its analogs (PBAs) have a limited two-electron transfer capacity, which hampers their practical application. Bi-based ferricyanide materials with multiple valence states, low toxicity and abundant resources are attractive for electrochemical reactions and enable multiple electron transfers to develop high-capacity cathode materials. In this study, we synthesized a rod-like BiHCF·4H2O sample using a simple coprecipitation method. After dehydration, the rod-like BiHCF compounds with a robust framework and reduced lattice water defects demonstrated good electrochemical performance in SIBs. The rod-like BiHCF electrode exhibited a specific capacity of 221 mAh g−1 at 20 mA g−1 based on a three-electron transfer of Bi3+/Bi0. A full SIBs composed of a BiHCF cathode and Bi anode demonstrated acceptable performance, indicating potential for practical applications. This work provides valuable insights into the development of redox-active site substitution strategies for high performance positive electrode materials in SIBs.

Longitudinal latent overall toxicity (LOTox) profiles in osteosarcoma: a new taxonomy based on latent Markov models

Due to the presence of multiple types of adverse events (AEs) with different levels of severity, the analysis of longitudinal toxicity data is a difficult task in cancer research. The current literature primarily relies on descriptive-based methods and lacks models that can effectively quantify the overall toxic burden experienced by patients over treatment without losing details of the impact of each AE. In this work, a novel taxonomy based on latent Markov models and compositional data techniques is proposed to model the Latent Overall Toxicity (LOTox) condition of each patient over cycles of treatment. Starting from observed categories of severity of multiple toxicities, the goal is to delineate distinct LOTox conditions and retrieve patients’ probabilities of being in a specific condition at a given cycle, as well as their risk of experiencing “worse" overall toxicity statuses compared to a reference “good" toxic condition. The proposed approach is applied to longitudinal toxicity data from the MRC BO06/EORTC 80931 randomized controlled trial for patients with osteosarcoma. The population of interest includes 377 patients who had successfully completed the six-cycle treatment. Personal characteristics and observed information on six toxicities are used to infer the unobserved LOTox status over the six cycles of chemotherapy. Provided that longitudinal toxicity data are available, the developed procedure is a flexible approach that can be adapted and applied to other cancer studies.

Current insights into yeast application for reduction of patulin contamination in foods: A comprehensive review.

Patulin, a fungal secondary metabolite with multiple toxicities, is widely existed in a variety of fruits and their products. This not only causes significant economic losses to the agricultural and food industries but also poses a serious threat to human health. Conventional techniques mainly involved physical and chemical methods present several challenges include incomplete patulin degradation, high technical cost, and fruit quality decline. In comparison, removal of mycotoxin through biodegradation is regarded as a greener and safer strategy which has become popular research. Among them, yeast has a unique advantage in detoxification effect and application, which has attracted our attention. Therefore, this review provides a comprehensive account of the yeast species that can degrade patulin, degradation mechanism, current application status, and future challenges. Yeasts can efficiently convert patulin into nontoxic or low-toxic substances through biodegradation. Alternatively, it can use physical adsorption, which has the advantages of safety, high efficiency, and environmental friendliness. Nevertheless, due to the inherent complexity of the production environment, the sole utilization of yeast as a control agent remains inherently unstable and challenging to implement on a large scale in a practical manner. Integration control, enhancement of yeast resilience, improvement of yeast cell wall adsorption capacity, and research on additional patulin-degrading enzymes will facilitate the practical application of this approach. Furthermore, we analyzed the feasibility of the yeast commercial application in patulin reduction and provided suggestions on how to enhance its commercial value, which is of great significance for the control of mycotoxins in food products.

Checkpoint inhibitor therapy: Immune-related adverse event management.

Treatment with immune checkpoint inhibitors for cancer is associated with a high prevalence of multiple immune-related toxicities. Immune-related adverse events (irAEs) can occur anytime during treatment and up to 3 months after treatment. This article discusses checkpoint inhibitor therapy and describes the implementation of a patient education program focused on recognizing immunotherapy irAEs and their toxicities.

Characteristics of drug-related deaths where individuals are found submerged in a bath or hot tub in the United Kingdom, 1997-2023.

Recent media reports highlight that drug-related fatalities can occur while individuals are immersed in water in domestic settings. We aimed to determine the case characteristics, circumstances of death and type of implicated drugs among individuals dying due to unintentional drug-related causes found immersed in a bath or hot tub. Retrospective cohort study in the United Kingdom using coronial records from the National Programme on Substance Abuse Deaths, 1997-2023. Information was available on decedent socio-demographics, characteristics of death and drugs implicated in death. One hundred fifty-six decedents were found immersed in the bath and six in a hot tub, a mean of 6.4 deaths per year (SD 3.7; range 1-13). Overall decedents were predominantly male (n = 94, 58.0%), of White ethnicity (n = 98, 60.5%) with a mean age of 40 years (SD 13; range 19-74). Only 12 decedents had any physical contributory factor to death other than poisoning or drowning. The median number of drugs detected at post-mortem was 3 (interquartile range 2, 5) with multiple drug toxicity implicated in the majority of cases (n = 90, 55.6%). The most common implicated drugs were heroin (n = 53, 32.7%), alcohol (n = 46, 28.4%) and cocaine (n = 33, 20.4%). Over the last two decades in the United Kingdom there have been consistent numbers of unintentional drug-related deaths each year where individuals were found in a bath or hot tub. Polysubstance, opioid and alcohol use are overrepresented. Targeted advice to avoid bathing while intoxicated would appear to be an appropriate harm reduction message.

RRx-001 Affects Multiple Toxicities in Patients Receiving Concomitant Chemoradiation for Head and Neck Cancers: Observations of the PREVLAR Phase II Trial

PURPOSE Phase IIa trial results suggested that RRx-001, an nucleotide-binding domain-like receptor protein 3 inhibitor and nuclear factor erythroid 2–related factor 2 activator, attenuated severe oral mucositis (SOM) in patients treated with concomitant chemoradiation (CRT) for oral cancer (OC) and oropharyngeal cancer (OPC). Given the shared pathobiology of CRT injury among other exposed tissues, we initiated a secondary analysis of reported adverse events (AEs) to assess RRx-001's potential benefit on non-SOM regimen-related toxicities. METHODS PREVLAR was an open-label randomized trial that has been completed and published. Patients were treated with CRT for locally advanced OC or OPC. Arms 1-3 received doses of RRx-001 twice a week beginning 2 weeks before the start of CRT. Arm 2 (n = 11) received additional RRx-001 once during weeks 2 and 5. Arm 3 (n = 13) received RRx-001 once a week for the first 6 weeks of CRT. Arm 4 (n = 10) received CRT only. Patients received standard intensity modulated radiation therapy (daily fractions of 2-2.2 Gy/minimum cumulative dose of 55 Gy) plus cisplatin. Comprehensive toxicity assessment was based on reported AEs graded using Common Terminology Criteria for Adverse Events v5.0 and categorized with the Medical Dictionary for Regulatory Activities. A two-sided Fisher's exact test was performed to compare AE incidences between RRx-001 arms and standard of care in a secondary analysis of the data. Overall false-positive rate in Fisher's exact test was controlled via Hochberg's adjustment method. RESULTS Compared with the control cohort, patients receiving RRx-001 demonstrated fewer AEs attributable to their CRT regimen. Statistically significant differences in AE incidences favoring RRx-001 were dependent on the RRx-001 dosing regimen. CONCLUSION This secondary analysis suggests that RRx-001 infusion may reduce multiple, biologically related AEs associated with a standard CRT regimen. More broadly, it suggests that it is possible that agents that effectively target central pathobiology targets may mitigate more than one toxicity.