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Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher amount of PAC compared to mature milk. Exosomal formulation of PAC (ExoPAC) showed higher antiproliferative activity and inhibition of colony formation against A549 cells compared with PAC alone, and also showed antiproliferative activity against a drug-resistant variant of A549. To further enhance its efficacy, exosomes were attached with a tumor-targeting ligand, folic acid (FA). FA-ExoPAC given orally showed significant inhibition (>50%) of subcutaneous tumor xenograft while similar doses of PAC showed insignificant inhibition. In the orthotopic lung cancer model, oral dosing of FA-ExoPAC achieved greater efficacy (55% growth inhibition) than traditional i.v. PAC (24–32% growth inhibition) and similar efficacy as i.v. Abraxane (59% growth inhibition). The FA-ExoPAC given i.v. exceeded the therapeutic efficacy of Abraxane (76% growth inhibition). Finally, wild-type animals treated with p.o. ExoPAC did not show gross, systemic or immunotoxicity. Solvent-based PAC caused immunotoxicity which was either reduced or completely mitigated by its exosomal formulations. These studies show that a tumor-targeted oral formulation of PAC (FA-ExoPAC) significantly improved the overall efficacy and safety profile while providing a user-friendly, cost-effective alternative to bolus i.v. PAC and i.v. Abraxane.

Aflatoxin B1 (AFB1), ochratoxin A (OTA), and deoxynivalenol (DON) are the three mycotoxins that have received the most scholarly attention and have been tested most routinely in clinics. These mycotoxins not only suppress immune responses but also induce inflammation and even increase susceptibility to pathogens. Here, we comprehensively reviewed the determining factors for the bidirectional immunotoxicity of the three mycotoxins, their effects on pathogens, and their action mechanisms. The determining factors include mycotoxin exposure doses and times, as well as species, sex, and some immunologic stimulants. Moreover, mycotoxin exposure can affect the infection severity of some pathogens, including bacteria, viruses, and parasites. Their specific action mechanisms include three aspects: (1) mycotoxin exposure directly promotes the proliferation of pathogenic microorganisms; (2) mycotoxins produce toxicity, destroy the integrity of the mucosal barrier, and promote inflammatory response, thereby improving the susceptibility of the host; (3) mycotoxins reduce the activity of some specific immune cells and induce immune suppression, resulting in reduced host resistance. The present review will provide a scientific basis for the control of these three mycotoxins and also provide a reference for research on the causes of increased subclinical infections.

Due to their unique chemical properties, per- and polyfluoroalkyl substances (PFAS) have been used extensively as industrial surfactants and processing aids. While several types of PFAS have been voluntarily phased out by their manufacturers, these chemicals continue to be of ecological and public health concern due to their persistence in the environment and their presence in living organisms. Moreover, while the compounds referred to as “legacy” PFAS remain in the environment, alternative compounds have emerged as replacements for their legacy predecessors and are now detected in numerous matrices. In this review, we discuss the historical uses of PFAS, recent advances in analytical techniques for analysis of these compounds, and the fate of PFAS in the environment. In addition, we evaluate current biomonitoring studies of human exposure to legacy and emerging PFAS and examine the associations of PFAS exposure with human health impacts, including cancer- and non-cancer-related outcomes. Special focus is given to short-chain perfluoroalkyl acids (PFAAs) and ether-substituted, polyfluoroalkyl alternatives including hexafluoropropylene oxide dimer acid (HFPO-DA; tradename GenX), 4,8-dioxa-3H-perfluorononanoic acid (DONA), and 6:2 chlorinated polyfluoroethersulfonic acid (6:2 Cl-PFESA; tradename F-53B).

Summary Wheat immunotoxicity is associated with abnormal reaction to gluten‐derived peptides. Attempts to reduce immunotoxicity using breeding and biotechnology often affect dough quality. Here, the multiplexed CRISPR‐Cas9 editing of cultivar Fielder was used to modify gluten‐encoding genes, specifically focusing on ω‐ and γ‐gliadin gene copies, which were identified to be abundant in immunoreactive peptides based on the analysis of wheat genomes assembled using the long‐read sequencing technologies. The whole‐genome sequencing of an edited line showed mutation or deletion of nearly all ω‐gliadin and half of the γ‐gliadin gene copies and confirmed the lack of editing in the α/β‐gliadin genes. The estimated 75% and 64% reduction in ω‐ and γ‐gliadin content, respectively, had no negative impact on the end‐use quality characteristics of grain protein and dough. A 47‐fold immunoreactivity reduction compared to a non‐edited line was demonstrated using antibodies against immunotoxic peptides. Our results indicate that the targeted CRISPR‐based modification of the ω‐ and γ‐gliadin gene copies determined to be abundant in immunoreactive peptides by analysing high‐quality genome assemblies is an effective mean for reducing immunotoxicity of wheat cultivars while minimizing the impact of editing on protein quality.

Background Together with poor biodegradability and insufficient recycling, the massive production and use of plastics have led to widespread environmental contamination by nano- and microplastics. These particles accumulate across ecosystems - even in the most remote habitats - and are transferred through food chains, leading to inevitable human ingestion, that adds to the highest one due to food processes and packaging. Objective The present review aimed at providing a comprehensive overview of current knowledge regarding the effects of nano- and microplastics on intestinal homeostasis. Methods We conducted a literature search focused on the in vivo effects of nano- and microplastics on gut epithelium and microbiota, as well as on immune response. Results Numerous animal studies have shown that exposure to nano- and microplastics leads to impairments in oxidative and inflammatory intestinal balance, and disruption of the gut’s epithelial permeability. Other notable effects of nano- and microplastic exposure include dysbiosis (changes in the gut microbiota) and immune cell toxicity. Moreover, microplastics contain additives, adsorb contaminants, and may promote the growth of bacterial pathogens on their surfaces: they are potential carriers of intestinal toxicants and pathogens that can potentially lead to further adverse effects. Conclusion Despite the scarcity of reports directly relevant to human, this review brings together a growing body of evidence showing that nano- and microplastic exposure disturbs the gut microbiota and critical intestinal functions. Such effects may promote the development of chronic immune disorders. Further investigation of this threat to human health is warranted.

Our understanding of how the microbiota affects the balance between response to and failure of cancer treatment by modulating the tumour microenvironment and systemic immune system has advanced rapidly in recent years. Microbiota-targeting interventions in patients with cancer are an area of intensive investigation. Promisingly, phase I–II clinical trials have shown that interventions such as faecal microbiota transplantation can overcome resistance to immune checkpoint blockade in patients with melanoma, improve therapeutic outcomes in treatment-naive patients and reduce therapy-induced immunotoxicities. Here, we synthesize the evidence showing that the microbiota is an important determinant of both cancer treatment efficacy and treatment-induced acute and long-term toxicity, and we discuss the complex and inter-related mechanisms involved. We also assess the potential of microbiota-targeting interventions, including bacterial engineering and phage therapy, to optimize the response to and recovery from cancer therapy.This Review outlines the mechanisms by which the microbiota alters the efficacy and immunotoxicity of established and emerging cancer treatments, and discusses the benefits and limitations of microbiota-targeting interventions that are being investigated to improve patient outcomes.

The expanding uses of carbon nanotubes (CNTs) in industry and medicine have raised concerns about their toxicity on human and animal health. CNTs, including multi-walled nanotubes (MWCNTs), have been reported to induce immunotoxic, inflammatory, and oxidative effects. Quercetin is a natural flavonoid present in many vegetables and fruits and has immunomodulatory, anti-inflammatory, and antioxidant properties. Herein, we investigated the protective effects of quercetin on pristine MWCNTs-induced immunotoxicity in mice. In comparison with two doses of MWCNTs, high doses [0.5 mg/kg body weight (BW), once intraperitoneally (IP)] caused higher immunotoxic, inflammatory, and oxidative effects than low doses (0.25 mg/kg BW, once IP). Administration of quercetin (30 mg/kg BW, IP for 2 weeks) relieved these deleterious effects as evidenced by (1) reduced spleen weight, (2) increased number of total leukocytes, lymphocytes, and neutrophils, (3) elevated serum levels of IgM, IgG, and IgA, (4) decreased lipid peroxide malondialdehyde levels and increased levels of antioxidant markers reduced glutathione, superoxide dismutase, and catalase in the spleen, (5) decreased concentrations and mRNA levels of inflammatory markers tumor necrosis factor-alpha (TNFα), interleukin 1 beta (IL1ß), and IL6 in the spleen, (6) downregulated expression of immunomodulatory genes transforming growth factor-beta (TGFß), cyclooxygenase2 (COX2), and IL10, and (7) regenerative histological changes as indicated by decreased mononuclear cell infiltration, minimized degenerative changes and restored lymphocytes depletion in the spleen. These results infer that quercetin can ameliorate MWCNTs-induced immunotoxic, inflammatory, and oxidative effects.

Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan–dextran-based magnetic nanomedicine (IO@FuDex3) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti-CD28). IO@FuDex3 can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex3 and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy.

Background Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature. Objective The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system. Methods A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed. Conclusions Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life.

In this Perspective, June, Bluestone and Warshauer discuss potential cellular and molecular explanations for the autoimmunity often associated with immunotherapy, and propose additional research and changes to reporting practices to aid efforts to understand and minimize these toxic side effects. The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies—and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.