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Journal For Immunotherapy of Cancer Jun 2024How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
BACKGROUND
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
METHODS
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
RESULTS
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
CONCLUSIONS
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
Topics: Animals; Th17 Cells; Mice; Mice, Inbred C57BL; Immunotherapy, Adoptive; Whole-Body Irradiation; Melanoma, Experimental; Cyclophosphamide; Adoptive Transfer; Female; Melanoma
PubMed: 38945552
DOI: 10.1136/jitc-2023-008715 -
Mutation Research Jun 2024Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion... (Review)
Review
Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.
PubMed: 38944932
DOI: 10.1016/j.mrfmmm.2024.111870 -
Journal of Medical Case Reports Jun 2024Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest...
BACKGROUND
Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies).
CASE PRESENTATION
We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process.
CONCLUSION
The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy.
Topics: Humans; Female; Pregnancy; Lung Neoplasms; Choriocarcinoma; Uterine Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Methotrexate; Vincristine; Dactinomycin; Etoposide; Chorionic Gonadotropin, beta Subunit, Human; Cyclophosphamide; Dyspnea; Pregnancy Complications, Neoplastic
PubMed: 38944668
DOI: 10.1186/s13256-024-04615-y -
PDA Journal of Pharmaceutical Science... Jun 2024This article describes the development of a representative dataset of extractables and leachables (E&L) from the combined Extractables and Leachables Safety Information...
This article describes the development of a representative dataset of extractables and leachables (E&L) from the combined Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the Product Quality Research Institute (PQRI) published datasets, representing a total of 783 chemicals. A chemical structure-based clustering of the combined dataset identified 142 distinct chemical classes with two or more chemicals across the combined dataset. The majority of these classes (105 chemical classes out of 142) contained chemicals from both datasets, whereas 8 classes contained only chemicals from the ELSIE dataset and 29 classes contain only chemicals from the PQRI dataset. This evaluation also identified classes containing chemicals that were flagged as potentially mutagenic as well as potent (strong or extreme) dermal sensitizers by tools. The prevalence of alerting structures in the E&L datasets was approximately 9% (69 examples) for mutagens and 3% (25 examples) for potent sensitizers. This analysis showed that most (80%; 20 of 25) E&L predicted to be strong or extreme dermal sensitizers were also flagged as potential mutagens. Only two chemical classes, each containing three chemicals (alkyl bromides and isothiocyanates), were uniquely identified in the PQRI dataset and contained chemicals predicted to be potential mutagens and/or potent dermal sensitizers.
Topics: Risk Assessment; Computer Simulation; Mutagens; Humans; Drug Contamination; Pharmaceutical Preparations; Drug Packaging
PubMed: 38942479
DOI: 10.5731/pdajpst.2022.012819 -
Journal of Hazardous Materials Jun 2024Nitrogenous disinfection byproducts (N-DBPs) in water are carcinogenic, teratogenic, and mutagenic. In this work, we developed a biomimetic reduction approach based on...
Nitrogenous disinfection byproducts (N-DBPs) in water are carcinogenic, teratogenic, and mutagenic. In this work, we developed a biomimetic reduction approach based on the cysteine thiol that destructed the highly toxic, select nitrogenous haloacetamides (HAMs) and haloacetonitriles (HANs) while effectively controlling the cytotoxicity of the degradation products to serve as a basis for further technological applications (e.g. immobilized contact bed for terminal users). Mechanisms on toxicity control were elucidated. Results showed the degradation and cytotoxicity control of HAMs as more efficient than that of the HANs. The cytotoxicity of the chlorinated, brominated, and iodinated HAMs and HANs was reduced to 25 %- 0.25 % of the original after biomimetic reduction using a reasonable concentration ratio. Through a combination of thiol-specific reactivity, dehalogenation, and quantitative structure-activity relationship analyses, the major toxicity control mechanisms were found to be the reductive dehalogenation of the N-DBPs. The halogenated functional groups on the N-DBPs had a more pronounced effect than the amide and nitrile groups on the cytotoxicity and detoxification effect. Patterns of toxicity interaction variations with DBPs concentrations were identified to detect possible synergistic cytotoxicity interactions under various combinations of HAMs and HANs in the presence of the cysteine thiol. Results could benefit future N-DBPs control efforts.
PubMed: 38941836
DOI: 10.1016/j.jhazmat.2024.134983 -
Chemical Science Jun 2024Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There...
Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant ; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in . This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.
PubMed: 38939155
DOI: 10.1039/d4sc00995a -
The Canadian Journal of Infectious... 2024SARS-CoV-2 is a virus that affects the human immune system. It was observed to be on the rise since the beginning of 2020 and turned into a life-threatening pandemic.... (Review)
Review
SARS-CoV-2 is a virus that affects the human immune system. It was observed to be on the rise since the beginning of 2020 and turned into a life-threatening pandemic. Scientists have tried to develop a possible preventive and therapeutic drug against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and other related coronaviruses by assessing COVID-19-recovered persons' immunity. This study aims to review immunization against SARS-CoV-2, along with exploring the interventions that have been developed for the prevention of SARS-CoV-2. This study also highlighted the role of phototherapy in treating SARS-CoV infection. The study adopted a review approach to gathering the information available and the progress that has been made in the treatment and prevention of COVID-19. Various vaccinations, including nucleotide, subunit, and vector-based vaccines, as well as attenuated and inactivated forms that have already been shown to have prophylactic efficacy against the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, have been summarized. Neutralizing and non-neutralizing antibodies are all associated with viral infections. Because there is no specific antiviral vaccine or therapies for coronaviruses, the main treatment strategy is supportive care, which is reinforced by combining broad-spectrum antivirals, convalescent plasma, and corticosteroids. COVID-19 has been a challenge to keep reconsidering the usual approaches to regulatory evaluation as a result of getting mixed and complicated findings on the vaccines, as well as licensing procedures. However, it is observed that medicinal herbs also play an important role in treating infection of the upper respiratory tract, the principal symptom of SARS-CoV due to their natural bioactive composite. However, some Traditional Chinese Medicines contain mutagens and nephrotoxins and the toxicological properties of the majority of Chinese herbal remedies are unknown. Therefore, to treat the COVID-19 infection along with conventional treatment, it is recommended that herb-drug interaction be examined thoroughly.
PubMed: 38938549
DOI: 10.1155/2024/9952803 -
Regulatory Toxicology and Pharmacology... Jun 2024Given the widespread applications in industrial and agricultural production, the health effects of rare earth elements (REEs) have garnered public attention, and the...
Given the widespread applications in industrial and agricultural production, the health effects of rare earth elements (REEs) have garnered public attention, and the genotoxicity of REEs remains unclear. In this study, we evaluated the genetic effects of lanthanum nitrate, a typical representative of REEs,with guideline-compliant in vivo and in vitro methods. Genotoxicity assays, including the Ames test, comet assay, mice bone marrow erythrocyte micronucleus test, spermatogonial chromosomal aberration test, and sperm malformation assay were conducted to assess mutagenicity, chromosomal damage, DNA damage, and sperm malformation. In the Ames test, no statistically significant increase in bacterial reverse mutation frequencies was found as compared with the negative control. Mice exposed to lanthanum nitrate did not exhibit a statistically significant increase in bone marrow erythrocyte micronucleus frequencies, spermatogonial chromosomal aberration frequencies, or sperm malformation frequencies compared to the negative control ( P > 0.05). Additionally, after a 24-hour treatment with lanthanum nitrate at concentrations of 1.25, 5, and 20 μg/ml, no cytotoxicity was observed in CHL cells. Furthermore, the comet assay results indicate no significant DNA damage was observed even after exposure to high doses of lanthanum nitrate (20 μg/ml). In conclusion, our findings suggest that lanthanum nitrate does not exhibit genotoxicity.
PubMed: 38936798
DOI: 10.1016/j.yrtph.2024.105670 -
Regulatory Toxicology and Pharmacology... Jun 2024Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The...
Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.
PubMed: 38936796
DOI: 10.1016/j.yrtph.2024.105669 -
Chemosphere Jun 2024Pesticides are significant environmental pollutants, and many of them possess mutagenic potential, which is closely linked to carcinogenesis. Here we tested the...
Pesticides are significant environmental pollutants, and many of them possess mutagenic potential, which is closely linked to carcinogenesis. Here we tested the mutagenicity of all six pesticides classified probably carcinogenic (Group 2A) by the International Agency of Research on Cancer: 4,4'-DDT, captafol, dieldrin, diazinon, glyphosate and malathion. Whole genome sequencing of TK6 human lymphoblastoid cell clones following 30-day exposure at subtoxic concentrations revealed a clear mutagenic effect of treatment with captafol or malathion when added at 200 nM or 100 μM initial concentrations, respectively. Each pesticide induced a specific base substitution mutational signature: captafol increased C to A mutations primarily, while malathion induced mostly C to T mutations. 4,4'-DDT, dieldrin, diazinon and glyphosate were not mutagenic. Whereas captafol induced chromosomal instability, H2A.X phosphorylation and cell cycle arrest in G2/M phase, all indicating DNA damage, malathion did not induce DNA damage markers or cell cycle alterations despite its mutagenic effect. Hypersensitivity of REV1 and XPA mutant DT40 chicken cell lines suggests that captafol induces DNA adducts that are bypassed by translesion DNA synthesis and are targets for nucleotide excision repair. The experimentally identified mutational signatures of captafol and malathion could shed light on the mechanism of action of these compounds. The signatures are potentially suitable for detecting past exposure in tumour samples, but the reanalysis of large cancer genome databases did not reveal any evidence of captafol or malathion exposure.
PubMed: 38936485
DOI: 10.1016/j.chemosphere.2024.142700