Showing papers on "Toxicity published in 2022"

T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma

Abstract: Severe immune-related adverse events (irAEs) occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). However, it is unknown whether a common baseline immunological state precedes irAE development. Here we applied mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk T cell receptor (TCR) sequencing to study peripheral blood samples from patients with melanoma treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination ICIs. By analyzing 93 pre- and early on-ICI blood samples and 3 patient cohorts (n = 27, 26 and 18), we found that 2 pretreatment factors in circulation-activated CD4 memory T cell abundance and TCR diversity-are associated with severe irAE development regardless of organ system involvement. We also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked our findings to the severity and timing of irAE onset. These results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management.

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced <i>KRAS</i>^<i>G12C</i> Solid Tumors (KRYSTAL-1)

Abstract: PURPOSE Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRAS G12C . We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRAS G12C mutation. MATERIALS AND METHODS Patients with advanced KRAS G12C -mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated. RESULTS Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRAS G12C -mutant non–small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRAS G12C -mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%). CONCLUSION Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRAS G12C mutation.

A Common Feature of Pesticides: Oxidative Stress—The Role of Oxidative Stress in Pesticide-Induced Toxicity

Abstract: Pesticides are important chemicals or biological agents that deter or kill pests. The use of pesticides has continued to increase as it is still considered the most effective method to reduce pests and increase crop growth. However, pesticides have other consequences, including potential toxicity to humans and wildlife. Pesticides have been associated with increased risk of cardiovascular disease, cancer, and birth defects. Labels on pesticides also suggest limiting exposure to these hazardous chemicals. Based on experimental evidence, various types of pesticides all seem to have a common effect, the induction of oxidative stress in different cell types and animal models. Pesticide-induced oxidative stress is caused by both reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are associated with several diseases including cancer, inflammation, and cardiovascular and neurodegenerative diseases. ROS and RNS can activate at least five independent signaling pathways including mitochondrial-induced apoptosis. Limited in vitro studies also suggest that exogenous antioxidants can reduce or prevent the deleterious effects of pesticides.

Acute Toxicity of the Tire Rubber-Derived Chemical 6PPD-quinone to Four Fishes of Commercial, Cultural, and Ecological Importance

Abstract: : N -(1,3-Dimethylbutyl)- N ′ -phenyl- p -phenylenedi-amine-quinone (6PPD-quinone), a transformation product of the rubber tire antioxidant 6PPD, has recently been identi fi ed as the chemical responsible for urban runo ff mortality syndrome in coho salmon, with a median lethal concentration (LC 50 ) of <0.1 μ g/L. Subsequent studies have failed to con fi rm comparable sensitivity in other fi sh species. Here, we investigated the acute toxicity of 6PPD-quinone to rainbow trout, brook trout, Arctic char, and white sturgeon. Fish were exposed under static renewal conditions, and exposure concentrations were veri fi ed analytically. Mortalities in brook trout occurred between 1.2 and 20 h, while mortalities began after 7 h and spanned 60 h in rainbow trout. The LC 50 s in brook trout (24 h) and rainbow trout (72 h) were 0.59 and 1.00 μ g/L, respectively. Both species showed characteristic symptoms (increased ventilation, gasping, spiraling, and loss of equilibrium) shortly before death. No mortalities were observed after exposure of either char or sturgeon for 96 h at measured concentrations as high as 14.2 μ g/L. This is the fi rst study to demonstrate the acute toxicity of 6PPD-quinone to other fi shes of commercial, cultural, and ecological importance at environmentally relevant concentrations and provides urgently needed information for environmental risk assessments of this contaminant of emerging concern.

Sources, characteristics, toxicity, and control of ultrafine particles: An overview

Abstract: Air pollution by particulate matter (PM) is one of the main threats to human health, particularly in large cities where pollution levels are continually exceeded. According to their source of emission, geography, and local meteorology, the pollutant particles vary in size and composition. These particles are conditioned to the aerodynamic diameter and thus classified as coarse (2.5–10 μm), fine (0.1–2.5 μm), and ultrafine (<0.1 μm), where the degree of toxicity becomes greater for smaller particles. These particles can get into the lungs and translocate into vital organs due to their size, causing significant human health consequences. Besides, PM pollutants have been linked to respiratory conditions, genotoxic, mutagenic, and carcinogenic activity in human beings. This paper presents an overview of emission sources, physicochemical characteristics, collection and measurement methodologies, toxicity, and existing control mechanisms for ultrafine particles (UFPs) in the last fifteen years.

Benzo[a]pyrene—Environmental Occurrence, Human Exposure, and Mechanisms of Toxicity

Abstract: Benzo[a]pyrene (B[a]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments. It is present in cigarette smoke as well as in food products, especially when smoked and grilled. Human exposure to B[a]P is therefore common. Research shows growing evidence concerning toxic effects induced by this substance. This xenobiotic is metabolized by cytochrome P450 (CYP P450) to carcinogenic metabolite: 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), which creates DNA adducts, causing mutations and malignant transformations. Moreover, B[a]P is epigenotoxic, neurotoxic, and teratogenic, and exhibits pro-oxidative potential and causes impairment of animals’ fertility. CYP P450 is strongly involved in B[a]P metabolism, and it is simultaneously expressed as a result of the association of B[a]P with aromatic hydrocarbon receptor (AhR), playing an essential role in the cancerogenic potential of various xenobiotics. In turn, polymorphism of CYP P450 genes determines the sensitivity of the organism to B[a]P. It was also observed that B[a]P facilitates the multiplication of viruses, which may be an additional problem with the widespread COVID-19 pandemic. Based on publications mainly from 2017 to 2022, this paper presents the occurrence of B[a]P in various environmental compartments and human surroundings, shows the exposure of humans to this substance, and describes the mechanisms of its toxicity.

Carbon Quantum Dots-Based Nanozyme from Coffee Induces Cancer Cell Ferroptosis to Activate Antitumor Immunity.

Abstract: Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared to natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from natural resources, especially daily food, implies a promising direction for exploring treatment strategies for human diseases. Here, we report a CQDs-based biocompatible nanozyme prepared from chlorogenic acid (ChA), a major bioactive natural product from coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation of GPX4-catalyzed lipid repair systems. In vivo, ChA CQDs dramatically suppressed the tumor growth in HepG2-tumor-bearing mice with negligible side toxicity. Particularly, in hepatoma H22-bearing mice, ChA CQDs recruited massive tumor-infiltrating immune cells including T cells, NK cells, and macrophages, thereby converting "cold" to "hot" tumors for activating systemic antitumor immune responses. Taken together, our study suggests that natural product-derived CQDs from coffee can serve as biologically safe nanozymes for anticancer therapeutics and may aid the development of nanotechnology-based immunotherapeutic.

Heavy metal–induced stress in eukaryotic algae—mechanisms of heavy metal toxicity and tolerance with particular emphasis on oxidative stress in exposed cells and the role of antioxidant response

Abstract: Abstract Heavy metals is a collective term describing metals and metalloids with a density higher than 5 g/cm 3 . Some of them are essential micronutrients; others do not play a positive role in living organisms. Increased anthropogenic emissions of heavy metal ions pose a serious threat to water and land ecosystems. The mechanism of heavy metal toxicity predominantly depends on (1) their high affinity to thiol groups, (2) spatial similarity to biochemical functional groups, (3) competition with essential metal cations, (4) and induction of oxidative stress. The antioxidant response is therefore crucial for providing tolerance to heavy metal-induced stress. This review aims to summarize the knowledge of heavy metal toxicity, oxidative stress and antioxidant response in eukaryotic algae. Types of ROS, their formation sites in photosynthetic cells, and the damage they cause to the cellular components are described at the beginning. Furthermore, heavy metals are characterized in more detail, including their chemical properties, roles they play in living cells, sources of contamination, biochemical mechanisms of toxicity, and stress symptoms. The following subchapters contain the description of low-molecular-weight antioxidants and ROS-detoxifying enzymes, their properties, cellular localization, and the occurrence in algae belonging to different clades, as well as the summary of the results of the experiments concerning antioxidant response in heavy metal-treated eukaryotic algae. Other mechanisms providing tolerance to metal ions are briefly outlined at the end.

Metabolomics Reveal Nanoplastic-Induced Mitochondrial Damage in Human Liver and Lung Cells

Abstract: Plastic debris in the global biosphere is an increasing concern, and nanoplastic (NPs) toxicity in humans is far from being understood. Studies have indicated that NPs can affect mitochondria, but the underlying mechanisms remain unclear. The liver and lungs have important metabolic functions and are vulnerable to NP exposure. In this study, we investigated the effects of 80 nm NPs on mitochondrial functions and metabolic pathways in normal human hepatic (L02) cells and lung (BEAS-2B) cells. NP exposure did not induce mass cell death; however, transmission electron microscopy analysis showed that the NPs could enter the cells and cause mitochondrial damage, as evidenced by overproduction of mitochondrial reactive oxygen species, alterations in the mitochondrial membrane potential, and suppression of mitochondrial respiration. These alterations were observed at NP concentrations as low as 0.0125 mg/mL, which might be comparable to the environmental levels. Nontarget metabolomics confirmed that the most significantly impacted processes were mitochondrial-related. The metabolic function of L02 cells was more vulnerable to NP exposure than that of BEAS-2B cells, especially at low NP concentrations. This study identifies NP-induced mitochondrial dysfunction and metabolic toxicity pathways in target human cells, providing insight into the possibility of adverse outcomes in human health.

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity

Abstract: Significance Converging evidence points to the build-up of phosphorylated α-synuclein (α-syn) at residue serine 129 (pS129) in Lewy body disease, suggesting its central role in the regulation of α-syn aggregation and neuronal degeneration. However, a comprehensive understanding of the role of α-syn phosphorylation at pS129 in α-synuclenopathies pathogenesis is still lacking. Herein, we study the phosphorylation incidence and its effect on α-syn aggregation propensity and cellular toxicity. Collectively, our data suggest that pS129 occurred subsequent to initial α-syn aggregation, lessened aggregation propensity, and attenuated cytotoxicity through diverse assays. Our findings highlight major implications for a better understanding of the role of a molecular modification on protein aggregation.

Source, bioaccumulation, degradability and toxicity of triclosan in aquatic environments: A review

Abstract: Triclosan (TCS), a lipophilic broad-spectrum biocide is widely used in personal care, acrylic, veterinary, medical and household products. It has been observed to be present in aquatic environments, animal and plant tissues around the world, and even in human blood, urine and breast milk. Under natural conditions, TCS degrades photolytically as well as through microbial action into more persistent and toxic byproducts like dioxins. Moreover, accumulation in deep water bodies or soil strata where light is not adequately available makes its degradation even more prolonged. Present review has been undertaken with an objective to highlight the concerns surrounding TCS exposure to aquatic organisms, the infiltration routes into the food chain, its persistence and accumulation, teratogenic, biochemical and cytogenic effects on a wide range of aquatic species. The widespread use of products containing TCS and potential toxicity at lethal concentrations makes it a compound of utmost concern worldwide and hence its use under permissible levels, proper disposal needs to be regulated.

Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity

Abstract: Nrf2 and NF-κB are important regulators of the response to oxidative stress and inflammation in the body. Previous pharmacological and genetic studies have confirmed crosstalk between the two. The deficiency of Nrf2 elevates the expression of NF-κB, leading to increased production of inflammatory factors, while NF-κB can affect the expression of downstream target genes by regulating the transcription and activity of Nrf2. At the same time, many therapeutic drug-induced organ toxicities, including hepatotoxicity, nephrotoxicity, cardiotoxicity, pulmonary toxicity, dermal toxicity, and neurotoxicity, have received increasing attention from researchers in clinical practice. Drug-induced organ injury can destroy body function, reduce the patients’ quality of life, and even threaten the lives of patients. Therefore, it is urgent to find protective drugs to ameliorate drug-induced injury. There is substantial evidence that protective medications can alleviate drug-induced organ toxicity by modulating both Nrf2 and NF-κB signaling pathways. Thus, it has become increasingly important to explore the crosstalk mechanism between Nrf2 and NF-κB in drug-induced toxicity. In this review, we summarize the potential molecular mechanisms of Nrf2 and NF-κB pathways and the important effects on adverse effects including toxic reactions and look forward to finding protective drugs that can target the crosstalk between the two.