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Per- and polyfluoroalkyl substances (PFAS), known as "forever chemicals," are synthetic chemicals which have been used since the 1940s. Given their remarkable thermostability and chemical stability, PFAS have been widely utilized in commercial products, including textiles, surfactants, food packages, nonstick coatings, and fire-fighting foams. Thus, PFAS are widely distributed worldwide and have been detected in human urine, blood, breast milk, tissues and other substances. Growing concerns over the risks of PFAS, including their toxicity and carcinogenicity, have attracted people's attention. Recent reviews have predominantly emphasized advancements in the detection, adsorption, and degradation of PFAS through their chemical structures and toxic properties; however, further examination of the literature is needed to determine the link between PFAS exposure and cancer risk. Here, we introduced different PFAS detection methods based on sensors and liquid chromatography-mass spectrometry (LC-MS). Then, we discussed epidemiological investigations on PFAS levels and cancer risks in recent years, as well as the mechanisms underlying the carcinogenesis. Finally, we proposed the "4C principles" for ongoing exploration and refinement in this field. This review highlights PFAS-cancer associations to fill knowledge gaps and provide evidence-based strategies for future research., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest or potential competing interests associated with this research. The authors have no financial or commercial interests that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Developing a multifunctional material that can detect and remove carcinogens in water environments, simultaneously monitor their toxic metabolites in living organisms is significant for environmental remediation and human health. However, most research only focused on detection or adsorption carcinogens due to the difficulty of integrating multiple functions into one material, let alone monitoring their toxic metabolites. Here, a multifunctional Tb/Eu@TATB-HOF (1) is first developed to monitor two carcinogens, malachite green (MG) and its metabolites leucomalachite green (LMG), and simultaneously remove MG from the contaminated water. 1, as the dual-emission fluorescence sensor, can achieve ultrasensitive and highly visualized sensing for MG and LMG with different response modes. Even in actual samples, 1 still exhibits satisfactory sensing performances. As the adsorbent, 1 displays good recyclability and high adsorption capacity for MG. The sensing and adsorption mechanisms are explored through experiments and theoretical calculations. This work not only provides a novel insight for environmental remediation and human health through detection and removal of carcinogens, simultaneously monitoring their toxic metabolites, but first reveals the enormous potential of HOFs as multifunctional materials simultaneously for fluorescence sensing and adsorption., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endocrine disrupting chemicals or carcinogens have been known for decades for their endocrine signal disruption. Endocrine disrupting chemicals are a serious concern and they have been included in the top priority toxicants and persistent organic pollutants. Therefore, researchers have been working for a long time to understand their mechanisms of interaction in different human organs. Several reports are available about the carcinogen potential of these chemicals. The presented review is an endeavor to understand the hazard identification associated with endocrine disrupting carcinogens in relation to the human body. The paper discusses the major endocrine disrupting carcinogens and their potency for carcinogenesis. It discusses human exposure, route of entry, carcinogenicity and mechanisms. In addition, the paper discusses the research gaps and bottlenecks associated with the research. Moreover, it discusses the limitations associated with the analytical techniques for detection of endocrine disrupting carcinogens., Competing Interests: Declaration of Competing Interest It is declared that all the authors mutually agreeing to submit this manuscript to the journal. It is also declared that co-authors do not hold any conflict of interest that may affect the publication of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We have found recently that two-step intrinsic hydroxyl radical ( · OH)-dependent chemiluminescence (CL) could be produced by carcinogenic tetrahaloquinone and H 2 O 2 . However, the first-step CL was too fast to clearly detect the stepwise generation of · OH and CL, and to distinguish the exact dividing point between the first-step and second-step CL. Here we found that, extremely clear two-step intrinsic CL could be produced by the relative slow reaction of tetrabromohydroquinone (TBHQ) with H 2 O 2 , which was directly dependent on the two-step · OH generation. Interestingly, the second-step, but not the first-step CL production of TBHQ/H 2 O 2 (CRET donor) was markedly enhanced by fluorescein (a typical xanthene dye, CRET acceptor) through a unique chemiluminescence resonance energy transfer (CRET) process. The novel CRET system of TBHQ/H 2 O 2 /fluorescein was successfully applied for the sensitive detection of TBHQ with the detection limit as low as 2.5 µmol/L. These findings will help to develop more sensitive and highly efficient CL or CRET systems and specific CL sensor to detect the carcinogenic haloquinones, which may have broad environmental applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Microplastics are routinely ingested and inhaled by humans and other organisms. Despite the frequency of plastic exposure, little is known about its health consequences. Of particular concern are plastic additives─chemical compounds that are intentionally or unintentionally added to plastics to improve functionality or as residual components of plastic production. Additives are often loosely bound to the plastic polymer and may be released during plastic exposures. To better understand the health effects of plastic additives, we performed a comprehensive literature search to compile a list of 2,712 known plastic additives. Then, we performed an integrated toxicogenomic analysis of these additives, utilizing cancer classifications and carcinogenic expression pathways as a primary focus. Screening these substances across two chemical databases revealed two key observations: (1) over 150 plastic additives have known carcinogenicity and (2) the majority (∼90%) of plastic additives lack data on carcinogenic end points. Analyses of additive usage patterns pinpointed specific polymers, functions, and products in which carcinogenic additives reside. Based on published chemical-gene interactions, both carcinogenic additives and additives with unknown carcinogenicity impacted similar biological pathways. The predominant pathways involved DNA damage, apoptosis, the immune response, viral diseases, and cancer. This study underscores the urgent need for a systematic and comprehensive carcinogenicity assessment of plastic additives and regulatory responses to mitigate the potential health risks of plastic exposure.

The aim of this study was to identify biomarkers associated with the initiation and prognosis of thyroid cancer and elucidate the underlying pathogenic mechanisms. We obtained expression profiles and clinical information from the Cancer Genome Atlas (TCGA)-THCA and three datasets (GSE53157, GSE82208, and GSE76039). The three microarray datasets were combined using Perl and the sva package in R and termed 'merged dataset'. Weighted gene co-expression network analysis (WGCNA) identified 15 gene co-expression modules in the merged dataset and 235 hub genes. Venn diagram analysis revealed 232 overlapping genes between the merged and THCA datasets. Overlapping genes were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The least absolute shrinkage and selection operator (LASSO) regression identified THEMIS2 as a candidate hub gene. Cox, Kaplan-Meier (K-M) survival and gene set enrichment analysis (GSEA) confirmed the correlation of THEMIS2 with overall survival, its enrichment in immunologic processes, and its association with the p53 and JAK-STAT signaling pathways. Its expression was positively correlated with those of immune checkpoints and the infiltration level of immune cells. Receiver operating characteristic curve (ROC) analysis confirmed that THEMIS2, a diagnostic biomarker, could distinguish between tumor and normal specimens. The nomogram (ROC or DCA) model containing THEMIS2, age, and stage predicted favourable prognoses. Thus, THEMIS2 was a biomarker of immune infiltration and prognosis in thyroid cancer., (© 2024. The Author(s).)

Concerns have recently arisen regarding the formation of carcinogenic and genotoxic iodinated haloacetic acids (HAAs), such as monoiodoacetic acid (MIAA), during the disinfection of iodine-containing water with chloramine. Existing detection methods for MIAA rely on either labor-intensive derivatization operations or expensive instruments, making analysis challenging. To bypass these issues, this study proposed a novel two-step liquid-liquid extraction strategy to enrich MIAA and then pioneered the integration of common ion chromatography (IC) with an ultraviolet detector to measure trace MIAA precisely. This novel approach achieved a remarkable 155.6-fold enrichment of MIAA and significantly reduced the need for water and chemicals, hence enhancing its efficiency and environmental friendliness. Besides, this method effectively removed coexisting anions and separated MIAA from other interferents by adjusting IC column and eluent conditions. The method detection limit of MIAA is an impressive 21.44 ng/L, and the recoveries in synthetic and real water samples ranged from 85 to 113%, with maximum deviations of 7.59%. We validated the reliability of our approach by comparing it with the USEPA 552.3 method. In conclusion, this IC-based method proves to be a robust and environment-benign solution for detecting trace MIAA in complex water components., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aminocarboxylic acid (monoamine-based) chelating agents such as GLDA, MGDA, NTA, and EDG are widely used in a variety of products and processes. In the European Union, based on the Green Deal and the Chemicals Strategy for Sustainability (CSS), there is an increasing tendency to speed up chemical hazard evaluation and to regulate chemicals by grouping substances based on molecular structure similarity. Recently, it was proposed to group polycarboxylic acid monoamines, hydroxy derivatives and their salts with monovalent cations , and to consider all group members as potential carcinogens based on the official CLP classification of one group member, viz. NTA, which is classified as suspected carcinogen Cat. 2. In this review, we show that a grouping approach for harmonized classification and labeling based on molecular structure alone, disregarding existing animal test data as well as current scientific and regulatory knowledge, would result in incorrect classification. Using such a simplistic, although considered pragmatic approach, classification of all group members upfront would not improve protection of human health. Instead, it could not only lead to unnecessary additional vertebrate animal testing but also to onerous and disproportionate restrictions being placed on the use of these valuable substances; some of these even being considered as green chemicals.

Background: Central register of data on exposure to carcinogenic or mutagenic chemical substances, their mixtures, agents or technological processes (CRCR) conducted by Nofer Institute of Occupational Medicine (NIOM) enables monitoring of such agents occurrence in working environment in Poland. The NIOM conducts CRCR based on the provisions of the Regulation of the Minister of Health of 24 July 2012 on chemical substances, their mixtures, agents or technological processes with carcinogenic or mutagenic effects in the work environment. The work summarizes the information reported to CRCR in 2018-2021., Material and Methods: The data were extracted from CRCR, to which it was transferred by sanitary inspections. The data were extracted from CRCR. Data in this register is gathered based on employers' notifications to sanitary inspection. The study includes the number of reported agents (chemical substances and technological processes), the number of enterprises and the number of persons exposed to particular groups of agents (chemical substances, technological processes, ionizing radiation)., Results: The number of substances notified to the CRCR increases, from 382 reported substances in 2018 to 444 in 2021. Significant increase in the number of enterprises reporting technological processes (from 981 in 2018 to 5422 in 2021) and the number of exposed persons results from the law amendments extending the list of carcinogenic or mutagenic processes., Conclusions: The CRCR is a unique database on the occurrence and exposure to occupational carcinogens and mutagens, in which data from over 20 years has been collected. The increase in the number of reports to the register was mainly influenced by legislative changes regarding carcinogenic or mutagenic agents. Due to amount and complexity of data, they can be used for analysis in projects and programs aimed at raising awareness and reducing risk of occupational exposure to carcinogens and also during legislative works in Poland and in the EU. Med Pr Work Health Saf. 2023;74(5):399-407., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Nowadays, veterinary medicine residues have been viewed as a major threat to food safety worldwide, especially when dealing with carcinogenic residues. Herein, we present the first differential pulse voltammetric method for the quantification of lignocaine and its carcinogenic metabolite 2,6-xylidine residues in bovine food samples, aided by five greenness and whiteness assessment tools, including NEMI, ESA, ComplexGAPI, AGREE, and RGB12. The method depends on the electrochemical oxidation after modification of the carbon paste sensor with recycled Al 2 O 3 -NPs functionalized multi-walled carbon nanoparticles. The produced sensor (Al 2 O 3 -NPs/MWCNTs/CPE) was characterized using XRD, FT-IR, EDX, SEM, and TEM. As expected, the active surface area and electron transfer processes were accelerated by the modification, resulting in ultra-sensitive quantification with detection limits of 19.00 and 13.94 nM for lignocaine and 2,6-xylidine, respectively. In terms of greenness, whiteness, sustainability, analytical effectiveness, and economic and practical considerations, the proposed method outperforms the reported methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Here, we explored a low-cost, rapid, sensitive, and selective practical approach to manifest carcinogenic anilines by using oxone as an oxidant to mitigate its presence in wastewater. The calibration curves for OAP & PAP indicate reasonable sensitivity, percent recovery & correlation in the range 2.18-9.28 μg/mL. The Sandell's sensitivity for OAP & PAP was found to be 0.010-0.018 & 0.009-0.018 μg/mL, respectively. The range of correlation coefficient 0.979 to 0.998 shows the involvement of high precision and perfect correlation of the data. Values of coefficient of determination (r 2 ) denote the change in absorbance or (dA/dt)i or k obs by 95.8-99.6%. The percent recovery was found to be 98.05-99.91% for six parallel determinations. Furthermore, we also analyzed some wastewater samples to further validate the proposed method. The reproducible results, good percent recovery, and reasonable sensitivity proposed a feasible approach for the estimation of aminophenol in wastewater., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Manila reports equipment, drugs, or supplies was provided by Gurukul Kangri (Deemed to be University)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here, we show that a macropinocytosis activator, the tumor promoter phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the Xenopus embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers., Competing Interests: NT, YA, JM, GB, AD, RA, NO, ED No competing interests declared, (© 2023, Tejeda-Munoz, Azbazdar et al.)

Non-coding RNAs (ncRNAs) act as important modulators of gene expression and they have been confirmed to play critical roles in the physiology and development of malignant tumors. Understanding the synergism of multiple ncRNAs in competing endogenous RNA (ceRNA) regulation can provide important insights into the mechanisms of malignant tumors caused by ncRNA regulation. In this work, we present a framework, SCOM, for identifying ncRNA synergistic competition. We systematically construct the landscape of ncRNA synergistic competition across 31 malignant tumors, and reveal that malignant tumors tend to share hub ncRNAs rather than the ncRNA interactions involved in the synergistic competition. In addition, the synergistic competition ncRNAs (i.e. ncRNAs involved in the synergistic competition) are likely to be involved in drug resistance, contribute to distinguishing molecular subtypes of malignant tumors, and participate in immune regulation. Furthermore, SCOM can help to infer ncRNA synergistic competition across malignant tumors and uncover potential diagnostic and prognostic biomarkers of malignant tumors. Altogether, the SCOM framework (https://github.com/zhangjunpeng411/SCOM/) and the resulting web-based database SCOMdb (https://comblab.cn/SCOMdb/) serve as a useful resource for exploring ncRNA regulation and to accelerate the identification of carcinogenic biomarkers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although ethylene oxide (EtO) gas is designated as a human carcinogen, extant literature reports mixed findings on the health effects of exposure. The disparate findings may reflect industry bias as many studies were funded by a large chemical industry lobby., Objective: To conduct an integrative review of studies free from industry bias to facilitate compilation of a comprehensive list of reported signs and symptoms of EtO exposure., Methods: We reviewed 1887 papers of which 42 articles met inclusion criteria. The authors conducted this review in accordance with PRISMA guidelines. The presence of bias was assessed using Joanna Briggs Institute checklists., Results: Non-industry biased literature confirmed serious adverse health effects associated with EtO exposure at the occupational, hospital, and community level. EtO represents a carcinogen, neurotoxin, and respiratory irritant., Conclusion: After removal of industry-biased studies, EtO was unequivocally found to pose a threat to human health. There remains a gap in the number of studies examining community-level exposure, which is essential to understanding the impact of EtO. Given that EtO-emitting facilities are concentrated in diverse and disadvantaged communities, further study of EtO exposure health effects is warranted to inform public policy on toxic air emissions., (© 2023 Wiley Periodicals LLC.)

The cell nuclear damage is mainly caused by the radiation and various carcinogenic compounds, the essence of the damage is molecular adhesion fracture and chemical modification. After nuclear damage, the cells whose nuclei may be abnormal in morphology, structure and function, then become a kind of morbid cells or defective cells. The cell nuclear damage can affect gene expression and regulation, leading to dysfunctions or abnormalities of transcription and protein synthesis, which results in aging and induces various chronic refractory diseases, such as hypertension, atherosclerosis, diabetes, Alzheimer's disease, autoimmune diseases, and so on. The cell nuclear damage can also affect the state of cell differentiation and lead to restart of genes related to division and proliferation, thus inducing cancer. The cancer cells are derived from the cells with nuclear abnormalities, and the biological behavior or characteristics of cancer cells (shedding and metastasis, immune tolerance, uncontrolled, loss of contact inhibition, etc.) are derived from cells with nuclear abnormalities. This article reviewed the chronic refractory diseases caused by nuclear damage and their mechanisms, which provided a new idea for occupational health and toxicology research, as well as a new method and strategy for occupational disease prevention and treatment.

The drastic initial carcinogenic changes that induce single hepatocytes and minifoci positive for GST-P (a specific biomarker of foci and nodules) identified previously in rat livers (K. Satoh, Life Sci. 2018) require elucidation. Notably, after animals were administered benzyl isothiocyanate (BITC, anti-cancer phytochemical, 0.5% by wt) in their basal diet, immunocytochemical staining of vibratome-prepared liver specimens for GST-P revealed that the canalicular networks and bile ducts of the animal livers were heavily and finely stained for GST-P even though the biomarker is a cytosolic enzyme. In addition, the mean diameter of the canaliculi was greatly enlarged. The results thus indicate that GST-P was rapidly synthesized in all hepatocytes but rapidly excreted into bile. Similar results were obtained with animals administered dietary AAF carcinogen (0.04%). The biliary excretion of GST-P was detectable not only in all hepatocytes but also within minifoci, foci and nodules. A new initiation model was therefore proposed assuming that GST-P + single hepatocytes are formed after injury to canaliculi by carcinogens to decrease the excretion of GST-P from hepatocytes. The key findings from this study and the biomarker analysis using a vibratome technique might help elucidate the 'unknowable' mechanism of cancer initiation in rat chemical carcinogenesis., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Objective: This study was performed to assessment the health and carcinogenic risk of exposure to by-products of photocatalytic degradation of toluene in a spouted bed reactor Equipped with porous and non-porous draft tube., Methods: For this purpose, titanium dioxide nanoparticles were used as photocatalysts and UV lamps as radiation sources. Degradation efficiency and CO2 selectivity were compared. By-products were also detected in three spouted bed reactors with and without a porous and non-porous draft tube., Result: The results revealed that the degradation efficiency of toluene in the spouted bed reactor without a draft tube was 30.75%. The insertion of porous and non-porous draft tubes in the spouted bed reactor increased the degradation efficiency up to 54.88% and 47.63%, respectively. Meantime, CO2 selectivity decreased from 100% to 50.8% within 180 min irradiation time in the spouted bed reactor without draft tube, while in the spouted bed reactors with porous and non-porous draft tube maintained at 89.85% and 84.35%, respectively. Toluene and four by-products with carcinogenic and non-carcinogenic risk of 0.002176 and 182.2, respectively, were detected in the spouted bed reactors without draft tube. However, no by-products with carcinogenic risk were found in the spouted bed reactor with porous and non-porous draft tube., Conclusion: photocatalytic degradation of toluene in a spouted bed reactor without a draft tube produces by-products with health and carcinogenic risks. The insertion of a porous and non-porous draft tube in spouted bed reactors provided mineralization more complete than spouted bed reactor without a draft tube by reducing the dead zone and providing appropriate contact between the toluene, photocatalyst, and UV. Therefore, prevent the formation of dangerous and carcinogenic by-products.

Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLT 1 R) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLT 1 R in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLT 1 R/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLT 1 R, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLT 1 R with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLT 1 R, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLT 1 R antagonist in cells (Apc mut or CTNNB1 mut ) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APC mut ) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLT 1 R mRNA levels. These results elucidate a previously underappreciated CysLT 1 R/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients. Video Abstract., (© 2023. The Author(s).)

Okadaic acid (OA), a lipophilic phycotoxin distributed worldwide, causes diarrheic shellfish poisoning and even leads to tumor formation. Currently, the consumption of contaminated seafood is the most likely cause of chronic OA exposure, but there is a serious lack of relevant data. Here, the Sprague-Dawley rats were exposure to OA by oral administration at 100 µg/kg body weight, and the tissues were collected and analyzed to assess the effect of subchronic OA exposure. The results showed that subchronic OA administration disturbed colonic mucosal integrity and induced colitis. The colonic tight junction proteins were disrupted and the cell cycle of colonic epithelial cells was accelerated. It is inferred that disruption of the colonic tight junction proteins might be related to the development of chronic diarrhea by affecting water and ion transport. Moreover, the accelerated proliferation of colonic epithelial cells indicated that subchronic OA exposure might promote the restitution process of gut barrier or induce tumor promoter activity in rat colon., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The induction of vasculature formation is proposed to be a significant mechanism behind the non-genotoxic carcinogenicity of a chemical. The vasculature formation model used in this study is based on the coculture of human primary HUVECs and hASCs. This model was used to develop an assay to assess the induction of vasculature formation. Three assay protocols, based on different conditions, were developed and compared in order to identify the optimal conditions required. Some serum supplements and growth factors were observed to be essential for initiating vasculature formation. Of the studied putative positive reference chemicals, aspartame, sodium nitrite, bisphenol A and nicotine treatment led to a clear induction of vasculature formation, but arsenic and cadmium treatment only led to a slight increase. This human cell-based assay has the potential to be used as one test within a next generation testing battery, to assess the non-genotoxic carcinogenicity of a chemical through the mechanism of vasculature formation induction.

More than 80,000 new cases of bladder cancer are estimated to be diagnosed in 2023. However, the 5-year survival rate for bladder cancer has not changed in decades, highlighting the need for prevention. Numerous cancer-causing mutations are present in the urothelium long before signs of cancer arise. Mutation hotspots in cancer-driving genes were identified in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) tumor samples. Mutation burden within the hotspot regions was measured in normal urothelium with a low and high risk of cancer. A significant correlation was found between the mutation burden in normal urothelium and bladder cancer tissue within the hotspot regions. A combination of measured hotspot burden and personal risk factors was used to fit machine learning classification models. The efficacy of each model to differentiate between adjacent benign urothelium from bladder cancer patients and normal urothelium from healthy donors was measured. A random forest model using a combination of personal risk factors and mutations within MIBC hotspots yielded the highest AUC of 0.9286 for the prediction of high- vs. low-risk normal urothelium. Currently, there are no effective biomarkers to assess subclinical field disease and early carcinogenic progression in the bladder. Our findings demonstrate novel differences in mutation hotspots in NMIBC and MIBC and provide the first evidence for mutation hotspots to aid in the assessment of cancer risk in the normal urothelium. Early risk assessment and identification of patients at high risk of bladder cancer before the clinical presentation of the disease can pave the way for targeted personalized preventative therapy.

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 ( CDK13 ) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.

The Prevention Technician in the Environment and Workplaces (PTEW) is a health professional who works in the identification, assessment, and management of risk in living and working places. The PTEW implements specific corrective actions at reducing exposure levels to chemicals such as formaldehyde. The aim of this report was to update the formaldehyde risk assessment document (RAD). The risk assessment process was divided into three steps as follows: (1) preliminary data collection, (2) an on-site visit to identify the use patterns and process, and (3) application of the algorithm to calculate the exposure levels of healthcare workers. In addition, with the introduction of closed-circuit systems, 23 devices were evaluated to identify possible airborne dispersion of formaldehyde. The algorithm was applied in 31 hospital units and the results allowed us to classify the staff in two levels of exposure for each hospital unit; healthcare workers were classified as "exposed" or "potentially exposed." Most of the HCWs are categorized as potentially exposed, and only workers working in laboratories are considered to be exposed. The results showed that devices must be used properly according to the user manual. To increase the level of worker safety, we have proposed to introduce closed-circuit safe handling systems and keeping the duration and intensity of exposure at the lowest possible levels according to the "ALARA" principle. The assignment of the Italian PTEW is to achieve excellence in the levels of health and safety of patients and hospital workers by pursuing a shared mission: improving the quality of public health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pattavina, Wachocka, Tuti, Boninti, Santi, Grossi and Laurenti.)

Facial makeup cosmetics are commonly used products that are applied to the skin, and their ingredients come into contact with it for many years. Consequently, they should only contain substances that are considered safe or used within an allowable range of established concentrations. According to current European laws, all cosmetics approved for use should be entirely safe for their users, and the responsibility for this lies with manufacturers, distributors, and importers. However, the use of cosmetics can be associated with undesirable effects due to the presence of certain chemical substances. An analysis of 50 random facial makeup cosmetics commercially available on the European Union market and manufactured in six European countries was carried out, concerning the presence of substances with potential carcinogenic properties, as described in recent years in the literature. Nine types of facial makeup cosmetics were selected, and their compositions, as declared on the labels, were analyzed. The carcinogens were identified with information present in the European CosIng database and according to the Insecticide Resistance Action Committee's (IRAC) classification. As a result, the following potential carcinogens were identified: parabens (methylparaben, propylparaben, butylparaben, and ethylparaben), ethoxylated compounds (laureth-4, lautreth-7, or ethylene glycol polymers known as PEG), formaldehyde donors (imidazolidinyl urea, quaternium 15, and DMDM hydantoin), and ethanolamine and their derivatives (triethanolamine and diazolidinyl urea), as well as carbon and silica. In conclusion, all of the analyzed face makeup cosmetics contain potential carcinogenic substances. The literature review confirmed the suppositions regarding the potential carcinogenic effects of selected cosmetic ingredients. Therefore, it seems necessary to carry out studies on the long-term exposure of compounds present in cosmetics and perhaps introduce stricter standards and laws regulating the potential presence of carcinogens and their activity in cosmetics.

Loss-of-function mutations in SPOP E3 ubiquitin ligase drive multiple cancers. However, carcinogenic gain-of-function SPOP mutations have been a major puzzle. In this issue of Molecular Cell, Cuneo et al. 1 show that several mutations map to SPOP oligomerization interfaces. Additional questions remain about SPOP mutations in malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Utilizing the atto-zeptomole sensitivity of UPLC-accelerator mass spectrometry (UPLC-AMS), we previously demonstrated significant first-pass metabolism following escalating (25-250 ng) oral micro-dosing in humans of [ 14 C]-benzo[a]pyrene ([ 14 C]-BaP). The present study examines the potential for supplementation with Brussels sprouts (BS) or 3,3'-diindolylmethane (DIM) to alter plasma levels of [ 14 C]-BaP and metabolites over a 48-h period following micro-dosing with 50 ng (5.4 nCi) [ 14 C]-BaP. Volunteers were dosed with [ 14 C]-BaP following fourteen days on a cruciferous vegetable restricted diet, or the same diet supplemented for seven days with 50 g of BS or 300 mg of BR-DIM® prior to dosing. BS or DIM reduced total [ 14 C] recovered from plasma by 56-67% relative to non-intervention. Dietary supplementation with DIM markedly increased T max and reduced C max for [ 14 C]-BaP indicative of slower absorption. Both dietary treatments significantly reduced C max values of four downstream BaP metabolites, consistent with delaying BaP absorption. Dietary treatments also appeared to reduce the T 1/2 and the plasma AUC( 0,∞ ) for Unknown Metabolite C, indicating some effect in accelerating clearance of this metabolite. Toxicokinetic constants for other metabolites followed the pattern for [ 14 C]-BaP (metabolite profiles remained relatively consistent) and non-compartmental analysis did not indicate other significant alterations. Significant amounts of metabolites in plasma were at the bay region of [ 14 C]-BaP irrespective of treatment. Although the number of subjects and large interindividual variation are limitations of this study, it represents the first human trial showing dietary intervention altering toxicokinetics of a defined dose of a known human carcinogen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hexavalent chromium [Cr(VI)], a Group I carcinogen classified by the International Agency for Research on Cancer (IARC), represents one of the most common occupational and environmental pollutants. The findings from human epidemiological and laboratory animal studies show that long-term exposure to Cr(VI) causes lung cancer and other cancer. Although Cr(VI) is a well-recognized carcinogen, the mechanism of Cr(VI) carcinogenesis has not been well understood. Due to the fact that Cr(VI) undergoes a series of metabolic reductions once entering cells to generate reactive Cr metabolites and reactive oxygen species (ROS) causing genotoxicity, Cr(VI) is generally considered as a genotoxic carcinogen. However, more and more studies have demonstrated that acute or chronic Cr(VI) exposure also causes epigenetic dysregulations including changing DNA methylation, histone posttranslational modifications and regulatory non-coding RNA (microRNA and long non-coding RNA) expressions. Moreover, emerging evidence shows that Cr(VI) exposure is also capable of altering cellular epitranscriptome. Given the increasingly recognized importance of epigenetic and epitranscriptomic dysregulations in cancer initiation and progression, it is believed that Cr(VI) exposure-caused epigenetic and epitranscriptomic changes could play important roles in Cr(VI) carcinogenesis. The goal of this chapter is to review the epigenetic and epitranscriptomic effects of Cr(VI) exposure and discuss their roles in Cr(VI) carcinogenesis. Better understanding the mechanism of Cr(VI) carcinogenesis may identify new molecular targets for more efficient prevention and treatment of cancer resulting from Cr(VI) exposure., Competing Interests: Conflict of interest statement The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1, and thereby increasing epithelial-tomesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and are of clinical significance in breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hexavalent chromium is a firmly established human carcinogen with documented exposures in many professional groups. Environmental exposure to Cr(VI) is also a significant public health concern. Cr(VI) exists in aqueous solutions as chromate anion that is unreactive with DNA and requires reductive activation inside the cells to produce genotoxic and mutagenic effects. Reduction of Cr(VI) in cells is nonenzymatic and in vivo principally driven by ascorbate with a secondary contribution from nonprotein thiols glutathione and cysteine. In addition to its much faster rate of reduction, ascorbate-driven metabolism avoids the formation of Cr(V) which is the first intermediate in Cr(VI) reduction by thiols. The end-product of Cr(VI) reduction is Cr(III) which forms several types of Cr-DNA adducts that are collectively responsible for all mutagenic and genotoxic effects in Cr(VI) reactions with ascorbate and thiols. Some Cr(V) forms can react with H 2 O 2 to produce DNA-oxidizing peroxo species although this genotoxic pathway is suppressed in cells with physiological levels of ascorbate. Chemical reactions of Cr(VI) with ascorbate or thiols lack directly DNA-oxidizing metabolites. The formation of oxidative DNA breaks in early studies of these reactions was caused by iron contamination. Production of Cr(III)-DNA adducts in cells showed linear dose-dependence irrespective of the predominant reduction pathway and their processing by mismatch repair generated more toxic secondary genetic lesions in euchromatin. Overall, Cr(III)-DNA adduction is the dominant pathway for the formation of genotoxic and mutagenic DNA damage by carcinogenic Cr(VI)., Competing Interests: Conflict of interest statement The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bee pollen, known as a natural super-food with valuable nutritional ingredients, is regarded as a good indicator of ecotoxic substances, such as potentially toxic elements (PTEs). Therefore, this study aims to examine the concentrations of selected PTEs (Al, As, Ba, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Mo, Ni, Pb, Se, Sn, Sr, V, Zn) in bee pollen purchased from online markets in Turkey and perform a health risk assessment to identify the potential risk to consumers., Methods: The quantitative analyses were conducted by inductively coupled plasma optical emission spectrometry (ICP-OES)., Results: The mean values of essential PTEs in decreasing content order were Mg > Fe > Zn > Mn > Cu > Ni > Se > Cr > Mo >Co = V. Regarding the results of the study, daily consumption (40 g for adult or 20 g for children) of commercial bee pollen can recompense 20-35 % of daily Cu, Mn, Se requirements for children, adults, pregnant, and breastfeeding women. The decreasing content order of non-essential elements was Al > Sn > Sr > Ba > Pb > As. Cadmium and Hg concentrations were below the detection limits in all the samples. In terms of food and public health; detection of the PTEs concentrations is necessary to assess the quality and safety of bee pollen before consumption. According to the carcinogenic and non-carcinogenic risk assessments; commercial pollen consumption does not pose a health risk to either children or adults for the PTEs monitored in this study., Conclusion: We conclude that bee pollen is an ideal indicator for the monitoring of environmental pollution of PTEs and also a valuable source of essential elements. This study highlights the need to develop standards that regulate acceptable concentrations of PTEs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Epyrifenacil (trademark name: Rapidicil®), a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide, induces hepatocellular adenomas and carcinomas in male CD-1 mice after 78 weeks treatment. The mode of action (MOA) of these mouse liver tumors and their relevance to humans was assessed based on the 2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework. Epyrifenacil is not genotoxic and induced liver tumors via the postulated porphyria-mediated cytotoxicity MOA with the following key events: (#1) PPO inhibition; (#2) porphyrin accumulation; (#3) hepatocellular injury; with (#4) subsequent regenerative cell proliferation; and ultimately (#5) development of liver tumors. This article evaluates the weight of evidence for this MOA based on the modified Bradford Hill criteria. The MOA data were aligned with the dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a porphyria-mediated cytotoxicity MOA while excluding other alternative MOAs. Although the postulated MOA could qualitatively potentially occur in humans, we demonstrate that it is unlikely to occur in humans because of quantitative toxicodynamic and toxicokinetic differences between mice and humans. Therefore, this MOA is considered not relevant to humans, utilizing the IPCS Human Relevance Framework; consequently, a nonlinear, threshold dose response would be appropriate for human risk assessment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors reports financial support was provided by Sumitomo Chemical Co Ltd. Satoki Fukunaga reports a relationship with Sumitomo Chemical Co Ltd that includes: employment. Keiko Ogata, Ayumi Eguchi, Kohei Matsunaga, Kengo Sakurai, Jun Abe and Hiroyuki Asano reports a relationship with Sumitomo Chemical Co Ltd that includes: employment. Samuel M Cohen reports a relationship with Sumitomo Chemical Co Ltd that includes: consulting or advisory., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The Metabokiller platform was developed to allow for identification of carcinogenic human metabolites., (©2022 American Association for Cancer Research.)

Ecdysoneless (ECD) protein is essential for embryogenesis, cell-cycle progression, and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer and ECD overexpression predicts shorter survival in patients with breast cancer. However, the genetic evidence for an oncogenic role of ECD has not been established. Here, we generated transgenic mice with mammary epithelium-targeted overexpression of an inducible human ECD transgene (ECDTg). Significantly, ECDTg mice develop mammary hyperplasia, preneoplastic lesions, and heterogeneous tumors with occasional lung metastasis. ECDTg tumors exhibit epithelial to mesenchymal transition and cancer stem cell characteristics. Organoid cultures of ECDTg tumors showed ECD dependency for in vitro oncogenic phenotype and in vivo growth when implanted in mice. RNA sequencing (RNA-seq) analysis of ECDTg tumors showed a c-MYC signature, and alterations in ECD levels regulated c-MYC mRNA and protein levels as well as glucose metabolism. ECD knockdown-induced decrease in glucose uptake was rescued by overexpression of mouse ECD as well as c-MYC. Publicly available expression data analyses showed a significant correlation of ECD and c-MYC overexpression in breast cancer, and ECD and c-MYC coexpression exhibits worse survival in patients with breast cancer. Taken together, we establish a novel role of overexpressed ECD as an oncogenesis driver in the mouse mammary gland through upregulation of c-MYC-mediated glucose metabolism., Implications: We demonstrate ECD overexpression in the mammary gland of mice led to the development of a tumor progression model through upregulation of c-MYC signaling and glucose metabolism., (©2022 The Authors; Published by the American Association for Cancer Research.)

Based on a publication of Tomasetti and Vogelstein in 2015, in which the risk of cancer development is postulated to be just one-third caused by genetic predisposition and environmental factors, it seemed worth focusing again on the value of test systems for screening chemicals for their carcinogenicity. This review aims to firstly summarize data on a host-mediated in vivo/in vitro assay developed by our working group to screen the tumorigenic potential of chemicals. Subsequently, in this article the importance and advantages of host-mediated in vivo/in vitro assays in general have been compared with in vivo and in vitro tests. The applicability of the host-mediated in vivo/in vitro assay system within broad screening strategies is discussed. The main intention of this review is to stimulate developments of newer approaches in the field of carcinogenic testing., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Meat is a rich source of various nutrients. However, it needs processing before consumption, what in turn generates formation of carcinogenic compounds, i.a., polycyclic aromatic hydrocarbons (PAH), nitrosamines (NOCs), and the most mutagenic heterocyclic aromatic amines (HAAs). It was widely found that many factors affect the content of carcinogens in processed meat. However, it has recently been discovered that after digestion free HAAs are released, which are not detectable before enzymatic treatment. It was established that the highest percentage of carcinogens is released in the small intestine and that its amount can be increased up to 6.6-fold. The change in free HAAs content in analyzed samples was dependent on many factors such as meat type, doneness, particle size of meat, and the enzyme concentration used for digestion. In turn, introduction of bacteria naturally occurring in the human digestive tract into the model significantly decreases total amount of HAAs. Contrary, the addition of food ingredients rich in polyphenols, fiber, and water (pepper powder, onions, apples) increases free HAAs' release up to 56.06%. Results suggests that in vitro digestion should be an integral step of sample preparation. Artificial digestion introduced before chromatographic analysis will allow to estimate accurately the content of carcinogens in processed meat.

European directives stipulate that French employers take all available measures to reduce the use of carcinogenic agents. Our study explores the links between regulations on chemicals and the effective implementation of collective protection measures in France to occupational exposure to carcinogenic chemicals. Individual data from the French national cross-sectional survey of occupational hazards, conducted in 2017, were analysed. We investigated whether stricter regulations and longer exposures were associated with a higher level of collective protection using multivariate logistic regressions. In 2017, any collective protection measures were implemented for 35% of occupational situations involving exposure to a carcinogen. A total of 21% of exposure situations benefited from source-based controls (e.g., isolation chamber and local exhaust ventilation) and 26% from general ventilation, for which the effect is limited as collective protection. Our regressions showed that longer exposure durations were associated with more collective protection. Exposure situations to chemicals classified as proven carcinogens by the European Union (category 1A) benefited more from collective protections, which is not the case for products only classified as suspected carcinogens (category 1B). Exposures to products with a Binding Occupational Exposure Limit Value benefited more from source-based controls. Nonetheless, the time spent on the IARC list of carcinogens did not appear to influence the implementation of collective protection measures, except for local exhaust ventilation. At a time when efforts to improve the implementation of protective measures in order to drastically reduce the risks of occupational cancers are still necessary, stricter European and national regulations, but above all, better coordination with the work of the IARC and its classification, are avenues to pursue.

Objectives: This study aimed to provide an assessment of chlorothalonil's possible carcinogenic risk posed to the public. In combination and comparison with the non-carcinogenic risk, the results hopefully could provide useful insights, early warning, and references for policy formulation., Methods: This study firstly investigated the occurrence of chlorothalonil on selected key vegetables for different scenarios, and then conducted an exposure assessment with officially published data. Lastly, both the non-carcinogenic and carcinogenic risk of chlorothalonil were calculated by using Monte-Carlo simulation., Results: Even though mean non-carcinogenic risks of chlorothalonil for all scenarios were below threshold value, the mean carcinogenic risks for maximum-risk scenario and most-likely risk scenario were mostly above threshold value. High probabilities of exceedance of threshold value existed for carcinogenic risk under all scenarios., Conclusion: Potential threat to public health existed for conventionally 'safe' pesticide if considering the possible carcinogenicity. Extra caution should be taken and the potential carcinogenic effects should be included into consideration for better protection of public health during the policy formulation process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Liu, Wang, Yuan and Wu.)

Background: To explore the expression and carcinogenic mechanism of RIPK2 in human tumours, and to provide the theoretical basis for the further study of RIPK2., Methods: We used the TCGA, CPTAC, HPA databases to analyse the expression, mutation, and prognosis of RIPK2 in human tumours. Through the Cbioportal, Ualcan, TIMER2.0, and STRING websites, We understand the genetic variation, immune infiltration and enrichment analysis of RIPK2 related genes., Results: RIPK2 was highly expressed in most tumours (such as BRCA, COAD and LUSC, etc.), and the high expression of RIPK2 was correlated with tumour stage and prognosis. In addition, Amplification was the main type of RIPK2 in tumour mutation state, and the amplification rate was about 8.5%. In addition, RIPK2 was positively associated with tumour-infiltrating immune cells (such as CD8+ T, Tregs, and cancer-associated fibroblasts). According to the KEGG analysis, RIPK2 may play a role in tumour mainly through NOD-like signaling pathway and NF-kappaB signaling pathway. GO enrichment analysis showed that the RIPK2 is mainly related to I-kappaB kinase/NF-kappaB signaling, Ribonucleoprotein granule and Ubiquitin-like protein ligase binding., Conclusion: RIPK2 plays an important role in the occurrence, development and prognosis of malignant tumours. Our pancancer study provided a relatively comprehensive description of the carcinogenic effects of RIPK2 in different tumours, and provided useful information for further study of RIPK2., (© 2022. The Author(s).)

This commentary is written in response to a recent commentary in Carcinogenesis that provides several viewpoints on the International Agency for Research on Cancer's (IARC) Monographs program on cancer hazard identification. This commentary offers an alternative viewpoint of the role of cancer hazard identification derived from cancer epidemiology studies in risk characterization, as well as clarification on the previous commentary's interpretation of the purpose of the Monographs and other programs of cancer hazard identification and how IARC communicates the findings of the Monographs., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This study was designed to visualize the pan-cancer prognostic significance of PReferentially expressed Antigen in Melanoma (PRAME) and investigate the relationship between PRAME expression and tumor immunity., Material and Methods: We explored the expression patterns and prognostic value of PRAME across multiple cancers using data from the Cancer Genome Atlas, Genotype-Tissue Expression, and Cancer Cell Line Encyclopedia databases. Spearman's correlation test was used to evaluate correlations between PRAME expression and the tumor immune microenvironment, mutation indicators, and DNA methylation. Finally, the functions of PRAME and potential signaling pathway mechanisms were explored through Gene Set Enrichment Analysis (GSEA)., Results: Pan-cancer survival analysis indicated that PRAME was widely up-regulated in most tumors, and its high expression was indicative of poor overall survival in different cancer types. In addition, PRAME expression levels were strongly linked to immune infiltration, immune score, immune checkpoint, immune neoantigens, tumor mutation burden, microsatellite instability, mismatch repair, and DNA methyltransferase in a variety of cancers. GSEA analysis revealed that PRAME was related to the regulation of numerous signaling pathways implicated in tumor immunity and tumorigenicity., Conclusions: PRAME has the potential to serve as a prognostic pan-cancer biomarker and is correlated with tumor immunity. Its use may help shed light on optimum cancer therapies., (© 2022 by the Association of Clinical Scientists, Inc.)

Public knowledge about the risk factors of cancer is essential to ensure an effective prevention program. This study aims to explore the knowledge of the general Saudi population about cancer and carcinogens and to determine the misconceptions about carcinogens to help create appropriate evidence-based prevention awareness programs. A questionnaire of 63 questions related to biographic data, source of knowledge, risk factors, and the burden of cancer was distributed online. The internet was the most sought source for cancer-related information (75.2%). The inclusion of cancer-related subjects in the educational curriculum was believed to be the best way to educate children about cancer (48.4%). Knowledge about cancer risk factors was good overall for 10 out of the 27 risk factors assessed in the study, with cigarette smoking being the most well-known risk factor (91.5%), followed by hookah smoking (85.6%), and nuclear waste exposure (80%). However, only 16.3% of participants were aware of the risk associated with Oral Contraceptive Pills (OCPs), and less than half of the participants knew the risk associated with poor physical activity. About 45% (44.9%) believed that envy and spiritual causes are associated with cancer. Most of the study participants (70%) considered cancer to be a significant health issue in Saudi, mainly due to the increasing incidence rate (44%). Conclusion: This study showed a good level of awareness regarding cancer risk factors and environmental carcinogens, which could serve as a roadmap for future awareness programs and studies targeted at the knowledge of other risk factors for cancer.

Introduction: Alcohol use increases cancer risk, yet awareness of this association is low. Alcohol control policies have the potential to reduce alcohol-caused cancer morbidity and mortality. Research outside the U.S. has found awareness of the alcohol-cancer link to be associated with support for alcohol control policies. The purpose of this study is to estimate the prevalence of support for 3 communication-focused alcohol policies and examine how awareness of the alcohol-cancer link and drinking status are associated with policy support among U.S. residents., Methods: Investigators analyzed data from the 2020 Health Information National Trends Survey 5 Cycle 4. Analyses were performed in 2021. The proportion of Americans who supported banning outdoor alcohol advertising and adding warning labels and drinking guidelines to alcohol containers was estimated. Weighted multivariable logistic regression was used to examine how awareness of the alcohol-cancer link and drinking status were associated with policy support., Results: Most Americans supported adding warning labels (65.1%) and drinking guidelines (63.9%), whereas only 34.4% supported banning outdoor alcohol advertising. Americans reporting that alcohol had no effect/decreased cancer risk had lower odds of support for advertising ban (OR=0.56), warning labels (OR=0.43), and guidelines (OR=0.46) than Americans aware of the alcohol-cancer link. Moreover, heavier drinkers had lower odds of support for advertising ban (OR=0.41), warning labels (OR=0.59), and guidelines (OR=0.60) than nondrinkers., Conclusions: Awareness of the alcohol-cancer link was associated with policy support. Increasing public awareness of the alcohol-cancer link may increase support for alcohol control policies., (Published by Elsevier Inc.)

CYP1B1 activates many chemical carcinogens into potent genotoxins, and allelic variants are risk factors in lung, breast, and prostate cancer. However, few eukaryotic genetic instability endpoints have been directly measured for CYP1B1-activated metabolites. In this study, we expressed human CYP1B1 in yeast strains that measure DNA damage-associated toxicity and frequencies of chromosomal translocations. DNA damage-associated toxicity was measured in a rad4 rad51 strain, defective in both DNA excision and recombinational repair. Frequencies of chromosomal translocations were measured in diploid yeast strains containing two his3 fragments. These strains were exposed to benzo[a]pyrene-7,8-dihydrodiol (BaP-DHD), aflatoxin B 1 (AFB 1 ), and the heterocyclic aromatic amines, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). We observed that AFB 1 , BaP-DHD, IQ, and MeIQx conferred toxicity in the DNA repair mutant expressing CYP1B1. Translocation frequencies increased eight-fold and three-fold after exposure to 50 μM AFB 1 and 33 μM BaP-DHD respectively. A DNA damage response was observed after AFB 1 exposure, as measured by the induction of the small subunit of ribonucleotide reductase, Rnr3. While CYP1B1-mediated activation of BaP-DHD and heterocyclic aromatic amines was expected, activation of AFB 1 to become a potent recombinagen was not expected. These studies demonstrate that chromosomal rearrangement is a useful genotoxic endpoint for CYP1B1-mediated carcinogen activation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Benzo[a]pyrene (BaP) is formed by incomplete combustion of organic materials (petroleum, coal, tobacco, etc.). BaP is designated by the International Agency for Research on Cancer as a group 1 known human carcinogen; a classification supported by numerous studies in preclinical models and epidemiology studies of exposed populations. Risk assessment relies on toxicokinetic and cancer studies in rodents at doses 5-6 orders of magnitude greater than average human uptake. Using a dose-response design at environmentally relevant concentrations, this study follows uptake, metabolism, and elimination of [ 14 C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250 ng (2.7-27 nCi) of [ 14 C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [ 14 C]-BaP and metabolites in plasma measured over 48 h. [ 14 C]-BaP median T max was 30 min with C max and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250 ng dose was seen with 7 volunteers as measured by the C max (8.99 ± 7.08 ng × mL -1 ) and AUC 0-48hr (68.6 ± 64.0 fg × hr -1  × mL -1 ). Approximately 3-6% of the [ 14 C] recovered (AUC 0-48 hr ) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30 min), a substantial percentage of [ 14 C] in plasma was polar BaP metabolites. The best fit modeling approach identified non-compartmental apparent volume of distribution of BaP as significantly increasing as a function of dose (p = 0.004). Bay region tetrols and dihydrodiols predominated, suggesting not only was there extensive first pass metabolism but also potentially bioactivation. AMS enables the study of environmental carcinogens in humans with de minimus risk, allowing for important testing and validation of physiologically based pharmacokinetic models derived from animal data, risk assessment, and the interpretation of data from high-risk occupationally exposed populations., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)