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Background 1,4-Dioxane (1,4-D) is a byproduct of the synthesis of surfactants, typically found in some cosmetics products such as shampoo, toothpaste, and soap. The presence of 1,4-D in cosmetics products is limited to a certain amount since 1,4-D is classified as a probable human carcinogen. Objective This present study was intended to validate static headspace gas chromatography-mass spectrometry (HS GC-MS) for the determination of 1,4-D in cosmetics products. Methods The condition of HS and GC-MS was optimized to get the best condition for analysis of 1,4-D using 1,4-dioxane-d8 (1,4-D-d8) as internal standard (IS). The developed method was validated by evaluating the key performance characteristics, including specificity, linearity, limit of detection (LoD), limit of quantification (LoQ), accuracy, and precision. Results The results showed that HS GC-MS was specific since the peaks of the selected ion monitoring (SIM) mode could be separated and confirmed at m/z 88 and m/z 96 for 1,4-D and 1,4-D-d8, respectively. The method was linear over the concentration range of 0.1287–1.2875 µg/mL, with R2 > 0.999 and RSD residuals <2.0. A collaborative study was conducted on this method, with 10 participating laboratories from four countries. The outcome of this study was found to be accurate and precise, as evidenced by the excellent recoveries ranging from 94.6% to 102.1%, and with good reproducibility with RSD values ranging from 0.2 to 1.1%. The collaborative studies exhibited that all data reported by 10 participating laboratories in four countries were inliers without any extreme values observed either in mean or RSD values Conclusions HS GC-MS is found to be fit and suitable for the determination of trace level of 1,4-D in cosmetics products. Highlights The HS GC-MS method could be proposed as a standard method for quantitative analysis of 1,4-D in cosmetics products since the collaborative studies indicated that the developed method meet the requirement in "Guidelines for Collaborative Study Procedures to Validate Characteristics of a Method of Analysis." [ABSTRACT FROM AUTHOR]

Background Lead (Pb) content in lipsticks and potential life-long exposure of which might cause severe effects in consumers are an important concern for public. Thus, studies emphasize that lead exposure has no safe levels. Methods From 10 different brands, in total, 25 solid, gloss and creamy lipsticks are deployed from Turkish markets that are also categorized in two different price ranges. In order to evaluate the blood Pb levels in children, the United States Environmental Protection Agency's 'Exposure Uptake Biokinetic Model' is utilized. To assess the health risk of chronic usage both for children and adults, oral daily systemic exposure levels are calculated with the worst-case scenario and are compared with Maximum Allowable Dose Level for lipsticks. For lifetime risk assessment, exposure is assumed to start by age 7, and four different exposure scenarios have been deployed. Results The mean lead content of lipsticks shows significant statistical differences between the high- and low-priced lipstick groups. Daily level and total risk for lifetime Pb exposure from deployed lipsticks are below the acceptable risk levels but long-worn usage of products with routine monitoring of metal content is crucial for sensitive and unintended exposure groups. [ABSTRACT FROM AUTHOR]

Most breast cancer deaths are caused by malignant estrogen receptor–positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as a factor promoting breast cancer development and metastasis. We therefore developed superactive prolactin receptor (PRLR) antagonists aimed at blocking PRL action. We purified 12 novel mutants to homogeneity as monomers, and the most potent antagonist was over 95-fold more active than the previously reported weak antagonist, the mutant Del 1-9 human PRL G129R. This enhanced antagonistic activity resulted mostly from prolonged interaction with the extracellular domain (ECD) of PRLR. All mutants were properly refolded, as indicated by interaction with human PRLR-ECD and by circular dichroism analysis. We then prepared monopegylated variants of the most active mutants to extend their biological half-life in vivo. [ABSTRACT FROM AUTHOR]

Background Incidence of early-onset colorectal cancer (CRC) has increased globally in recent decades. We examined early-onset CRC incidence trends worldwide for potential cohort effects, defined as changes associated with time of birth (eg, early-life exposure to carcinogens), and period effects, defined as changes associated with calendar periods (eg, screening programs). Methods We obtained long-term incidence data for early-onset CRC diagnosed in patients aged 20 to 49 years through the year 2012 for 35 countries in the Cancer Incidence in Five Continents database. We used a smoothing method to help compare cohort and period trends of early-onset CRC and used an age-period-cohort model to estimate cohort and period effects. Results Cohort effects had a more dominant role than period effects in the early-onset CRC incidence in Shanghai (China), the United Kingdom, Australia, New Zealand, Canada, the United States, and Osaka (Japan). The smoothed trends show the specific birth cohorts when early-onset CRC began to increase: the 1940s-1950s birth cohorts in the United States; the 1950s-1960s birth cohorts in other Western countries; the 1960s birth cohorts in Osaka; and the 1970s-1980s birth cohorts in Shanghai. Such increases occurred earlier for early-onset cancers of the rectum than of the colon. For the other countries, the results were less clear. Conclusions Recent birth cohorts may have been exposed to risk factors different from earlier cohorts, contributing to increased early-onset CRC incidence in several developed countries or regions in the West and Asia. Such increases began in earlier birth cohorts in Western countries than in developed regions of Asia. [ABSTRACT FROM AUTHOR]

Background Industrial facilities are not located uniformly across communities in the United States, but how the burden of exposure to carcinogenic air emissions may vary across population characteristics is unclear. We evaluated differences in carcinogenic industrial pollution among major sociodemographic groups in the United States and Puerto Rico. Methods We evaluated cross-sectional associations of population characteristics including race and ethnicity, educational attainment, and poverty at the census tract level with point-source industrial emissions of 21 known human carcinogens using regulatory data from the US Environmental Protection Agency. Odds ratios and 95% confidence intervals comparing the highest emissions (tertile or quintile) to the referent group (zero emissions [ie, nonexposed]) for all sociodemographic characteristics were estimated using multinomial, population density–adjusted logistic regression models. Results In 2018, approximately 7.4 million people lived in census tracts with nearly 12 million pounds of carcinogenic air releases. The odds of tracts having the greatest burden of benzene, 1,3-butadiene, ethylene oxide, formaldehyde, trichloroethylene, and nickel emissions compared with nonexposed were 10%-20% higher for African American populations, whereas White populations were up to 18% less likely to live in tracts with the highest emissions. Among Hispanic and Latino populations, odds were 16%-21% higher for benzene, 1,3-butadiene, and ethylene oxide. Populations experiencing poverty or with less than high school education were associated with up to 51% higher burden, irrespective of race and ethnicity. Conclusions Carcinogenic industrial emissions disproportionately impact African American and Hispanic and Latino populations and people with limited education or experiencing poverty thus representing a source of pollution that may contribute to observed cancer disparities. [ABSTRACT FROM AUTHOR]

N-nitrosamine pollutants are probable carcinogens. Regulatory agencies declared their presence in the drugs unsafe for human consumption and demanded their recall. Using ultra-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (UPLC-APCI-MS/MS) in tablet dosage form based on International Conference on Harmonization (ICH) tripartite guideline criteria, we aim to develop and test a new approach for identifying and validating nitrosamine-contaminants, N -nitrosodimethylamine (NDMA) and N -nitrosodiethylamine (NDEA) in irbesartan, olmesartan and metformin. The column was Phenomenex Luna-C18, 100 × 3.0 mm and 3.0 μm. A mobile gradient phase of formic acid in either water or methanol separated the impurities. NDMA and NDEA had retention times of 0.85 and 2.55 min, respectively. The detector's linearity was established at concentrations ranging from 0.6 to 100 ng/mL. R2 for NDMA and NDEA were 0.9996 and 0.9998, respectively, with a linear response function established at 0.6–100 ng/mL. Limit of detection and limit of quantification for NDMA and NDEA were 0.35, 0.29 and 0.55, 0.37 ng/mL, respectively. On average, recovery rates for NDMA and NDEA ranged from 96.0 to 98.4 and 96.2 to 98.0%, respectively. The relative standard deviation for NDMA and NDEA was 3.46 and 2.69, respectively. According to the ICH guidelines, the developed method was quick, sensitive and valid. The pharmaceutical formulations of irbesartan, olmesartan and metformin may be regularly examined using the approach provided here. [ABSTRACT FROM AUTHOR]

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo , this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing. [ABSTRACT FROM AUTHOR]

Objectives Industry- and occupation-based carcinogen exposure matrices play a pivotal role in preventing occupational cancer. While the Korean CARcinogen EXposure (K-CAREX) has been developed in recent years to assess exposure prevalence and intensity by industry, the feasibility of constructing an occupation-based exposure matrix remains unexplored. Hence, the objective of this study is to explore the potential of combining the nationwide work environment measurement database (WEMD) and the special health examination database (SHED) to develop a comprehensive occupation-based exposure matrix. Methods The WEMD provides information on airborne lead measurements, including industry codes, but it does not include data related to occupations. In contrast, the SHED contains information on both occupation and blood lead levels. By integrating these 2 databases, we attempted to assess airborne lead exposure levels by occupation. Additionally, we performed a rank correlation analysis to compare the airborne exposure levels with corresponding blood lead levels according to occupation. Results A total of 35 425 workers who both wore air samplers for lead and underwent special health examinations for lead were extracted between 2019 and 2021. An occupation-based exposure matrix was developed to evaluate the intensity of lead exposure across a range of occupations, encompassing 51 minor occupations and 70-unit occupations. Rank correlation analyses showed strong positive correlations between airborne lead and blood lead measurements according to occupation. Conclusions Our study findings suggest that combining 2 nationwide surveillance databases can be an effective approach for creating an occupation-based exposure matrix. However, our results also highlight several limitations that need to be addressed in future studies to improve the accuracy and reliability of such matrices. [ABSTRACT FROM AUTHOR]

Systematic review and evaluation of mechanistic evidence using the Key Characteristics approach was proposed by the International Agency for Research on Cancer (IARC) in 2012 and used by the IARC Monographs Working Groups since 2015. Key Characteristics are 10 features of agents known to cause cancer in humans. From 2015 to 2022, a total of 19 Monographs (73 agents combined) used Key Characteristics for cancer hazard classification. We hypothesized that a retrospective analysis of applications of the Key Characteristics approach to cancer hazard classification using heterogenous mechanistic data on diverse agents would be informative for systematic reviews in decision-making. We extracted information on the conclusions, data types, and the role mechanistic data played in the cancer hazard classification from each Monograph. Statistical analyses identified patterns in the use of Key Characteristics, as well as trends and correlations among Key Characteristics, data types, and ultimate decisions. Despite gaps in data for many agents and Key Characteristics, several significant results emerged. Mechanistic data from in vivo animal, in vitro animal, and in vitro human studies were most impactful in concluding that an agent could cause cancer via a Key Characteristic. To exclude the involvement of a Key Characteristic, data from large-scale systematic in vitro testing programs such as ToxCast, were most informative. Overall, increased availability of systemized data streams, such as human in vitro data, would provide the basis for more confident and informed conclusions about both positive and negative associations and inform expert judgments on cancer hazard. [ABSTRACT FROM AUTHOR]

Background Studying carcinogens in tobacco and nontobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. Methods The Golestan Cohort Study has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma. For this nested study, the cases comprised of all incident cases by January 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for associations between the 90th vs the 10th percentiles of the biomarker concentrations and incident esophageal squamous cell carcinoma. Results Among individuals who did not currently use tobacco (148 cases and 163 controls), 2 acrolein metabolites, 2 acrylonitrile metabolites, 1 propylene oxide metabolite, and one 1,3-butadiene metabolite were significantly associated with incident esophageal squamous cell carcinoma (adjusted odds ratios between 1.8 and 4.3). Among tobacco users (57 cases and 63 controls), metabolites of 2 other volatile organic compounds (styrene and xylene) were associated with esophageal squamous cell carcinoma (OR = 6.2 and 9.0, respectively). In tobacco users, 2 tobacco-specific nitrosamines (NNN and N' -Nitrosoanatabine) were also associated with esophageal squamous cell carcinoma. Suggestive associations were seen with some polycyclic aromatic hydrocarbons (especially 2-hydroxynaphthalene) in nonusers of tobacco products and other tobacco-specific nitrosamines in tobacco users. Conclusion These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications. [ABSTRACT FROM AUTHOR]

Objectives Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. Methods Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. Results ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. Conclusions Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects. [ABSTRACT FROM AUTHOR]

A main function of dose-response assessment is to estimate a "safe" dose in the target population to support chemical risk assessment. Typically, a "safe" dose is developed differently for cancer and noncancer effects based on a 2-step procedure, ie, point of departure (POD) derivation and low-dose extrapolation. However, the current dose-response assessment framework is criticized for its dichotomized strategy without integrating the mode of action (MOA) information. The objective of this study was, based on our previous work, to develop a MOA-based probabilistic dose-response framework that quantitatively synthesizes a biological pathway in a dose-response modeling process to estimate the risk of chemicals that have carcinogenic potential. 3,3′,4,4′,5-Pentachlorobiphenyl (PCB-126) was exemplified to demonstrate our proposed approach. There were 4 major steps in the new modeling framework, including (1) key quantifiable events (KQEs) identification and extraction, (2) essential dose calculation, (3) MOA-based POD derivation, and (4) MOA-based probabilistic reference dose (RfD) estimation. Compared with reported PODs and traditional RfDs, the MOA-based estimates derived from our approach were comparable and plausible. One key feature of our approach was the use of overall MOA information to build the dose-response relationship on the entire dose continuum including the low-dose region. On the other hand, by adjusting uncertainty and variability in a probabilistic manner, the MOA-based probabilistic RfDs can provide useful insights of health protection for the specific proportion of population. Moreover, the proposed framework had important potential to be generalized to assess different types of chemicals other than nonmutagenic carcinogens, highlighting its utility to improve current chemical risk assessment. [ABSTRACT FROM AUTHOR]

Heterocyclic aromatic amines (HAAs) are potent carcinogenic agents found in charred meats and cigarette smoke. However, few eukaryotic resistance genes have been identified. We used Saccharomyces cerevisiae (budding yeast) to identify genes that confer resistance to 2-amino-3-methylimidazo[4,5-f] quinoline (IQ). CYP1A2 and NAT2 activate IQ to become a mutagenic nitrenium compound. Deletion libraries expressing human CYP1A2 and NAT2 or no human genes were exposed to either 400 or 800 µM IQ for 5 or 10 generations. DNA barcodes were sequenced using the Illumina HiSeq 2500 platform and statistical significance was determined for exactly matched barcodes. We identified 424 ORFs, including 337 genes of known function, in duplicate screens of the "humanized" collection for IQ resistance; resistance was further validated for a select group of 51 genes by growth curves, competitive growth, or trypan blue assays. Screens of the library not expressing human genes identified 143 ORFs conferring resistance to IQ per se. Ribosomal protein and protein modification genes were identified as IQ resistance genes in both the original and "humanized" libraries, while nitrogen metabolism, DNA repair, and growth control genes were also prominent in the "humanized" library. Protein complexes identified included the casein kinase 2 (CK2) and histone chaperone (HIR) complex. Among DNA Repair and checkpoint genes, we identified those that function in postreplication repair (RAD18, UBC13, REV7), base excision repair (NTG1), and checkpoint signaling (CHK1, PSY2). These studies underscore the role of ribosomal protein genes in conferring IQ resistance, and illuminate DNA repair pathways for conferring resistance to activated IQ. [ABSTRACT FROM AUTHOR]

Glyphosate is a systemic, non-selective, pre and post-emergence wide range herbicide. In 2015, IARC classified Glyphosate as "a probable carcinogenic agent for humans". The aim of this study was to evaluate the cytotoxicity and genotoxicity of the commercial formulation of glyphosate (Roundup® Control Max) at environmentally relevant concentrations and measure the potential effect of this herbicide over the cell capacity to repair DNA damage. HEK293 cells were exposed to 5 concentrations of Roundup® Control Max equivalent to 0.7; 7; 70; 700 and 3,500 μg/L glyphosate acid, for 1, 4 and 24 h. Cytotoxicity was quantified by the Trypan Blue staining method and by the MTT assay, while genotoxicity and evaluation of DNA damage repair kinetics were analyzed through the alkaline comet assay. In all treatments, cell viability was higher than 80%. The three highest glyphosate concentrations—70 μg/L, 700 μg/L, and 3,500 μg/L—increased levels of DNA damage compared to the control at the three exposure times tested. Finally, concerning the kinetics of DNA damage repair, cells initially exposed to 3,500 μg/L of glyphosate for 24 h were unable to repair the breaks in DNA strands even after 4 h of incubation in culture medium. The present study demonstrated for the first time that Roundup® Control Max may induce genetic damage and cause alterations in the DNA repair system in human embryonic kidney cells even at concentrations found in blood and breast milk of people exposed through residues of the herbicide in food, which values have been poorly assessed or not studied yet according to the existent literature. [ABSTRACT FROM AUTHOR]

Objective Many occupations and industries use wood as a raw material and wood dust is a well-known carcinogen. This study presents trends in occupational exposure to wood dust for all workers (employees and self-employed workers) in France between 1982 and 2017 and focuses on the exposed workers in 2017. Methods Exposures to this carcinogen were assessed using the Matgéné job-exposure matrix. Trends in the prevalence and proportion of exposure over the study period were estimated by linking the matrix with population data from the 1982, 1990, 1999, 2007, and 2017 censuses and are described for selected industry groups. Results The number of exposed workers to wood dust has decreased significantly over the last 40 years, from 466,900 potentially exposed workers in 1982 to 305,000 workers in 2017. The proportion of exposed workers has also decreased over time, although not uniformly across industries. Increases in the proportion of exposed workers are observed in certain industries, such as "Sawmilling and logging" (from 61.2% to 73.6% over the period for men) and "Finishing of sale premises" (from 3.3% to 6.2% for women). Conclusion This article is the first to describe occupational exposure to wood dust in France for all workers and to follow its evolution over the last 40 years. Occupations and industries still at risk in 2017 are also described with the aim of helping to improve prevention policies. [ABSTRACT FROM AUTHOR]

While e-cigarette and combustible cigarette use remains more common among youth, herbal smoking products are gaining interest and popularity among children and adolescents. Herbal smoking products are often touted as a safer alternative to tobacco smoking or nicotine vaping; however, research suggests that they emit significant levels of toxicants and carcinogens posing risks to child and adolescent health. The low perceived risk coupled with youth-friendly flavours and easy access may entice youth to use herbal smoking products and increase the risk of subsequent tobacco and substance use. We discuss what is known about the use, health effects, and regulations of herbal smoking products and present strategies for policymakers and paediatric providers to reduce the risks associated with these products for Canadian youth. [ABSTRACT FROM AUTHOR]

Primary aromatic amines (PAAs) are a class of hazardous substances where many compounds are classified as carcinogen, mutagen, and reproduction toxin (CMR). PAAs can be taken up by dermal exposure. In the polyurethane industry, a valid and trustworthy method for the quantification of PAAs in the presence of isocyanates that could interfere is of great interest, especially on workplaces where a regular contact to PAAs cannot be excluded. The aim of this work is the development, validation, and verification of a novel sampling device to quantify selectively the PAA load on work surfaces. We describe the synthesis of Cell-ßALA-PEMSA analytical papers and their characterization by infrared spectroscopy and thermogravimetric analysis. The recovery of TDA and MDA spiked on these filters is satisfactory. An excellent selectivity of Cell-ßALA-PEMSA papers towards PAAs in the presence of isocyanates of almost 100% was found by wipe tests of amine/isocyanate contaminated surfaces. First positive field tests were achieved at certain areas in a Polyurethane Technical Application Department where surface contamination with PAAs was expected, and the Cell-ßALA-PEMSA analytical papers were superior to an established method of surface sampling. However, recovery of these amines from surfaces shows a large variability, and more work is required to address influencing surface properties. [ABSTRACT FROM AUTHOR]

Background Areca nut (AN) is a proven human carcinogen and a global public health menace. There is yet no review providing comprehensive information on the determinants and interventions available for cessation of AN. This systematic review was aimed at summarizing the available literature on drivers and interventions for cessation of AN chewing habit and to highlight the research lacunae. Methods A systematic literature search (from 1990 till March 2021) was conducted for studies on AN cessation. Relevant data were extracted independently by two authors. Results A total of 16 studies were included, which highlighted the influence of socio-cultural factors, addictive nature of AN and withdrawal symptoms as barriers to quitting. However, the knowledge of ill-effects of AN use on health, absence of concurrent alcohol use or smoking and family pressure were associated with likelihood of AN cessation. The interventions utilized for AN cessation have been behavioural in majority of the studies except for one where antidepressants were used for this purpose. Conclusions The current review emphasizes the imperative need of appropriate cessation strategies for AN chewing habit including enhancing awareness of the harmful effects and research into additional behavioural and pharmacologic cessation therapies to control this significant public health problem. [ABSTRACT FROM AUTHOR]

The article discusses the role of apolipoprotein b mRNA editing enzyme catalytic-polypeptide-like proteins 3 (APOBEC3) enzymes in autoimmune diseases. Topics include possible involvement of hA3 enzymes in disorders, genetic variants and methylation CpG sites linking APOBEC3 enzymes to autoimmune diseases, and how integrated dissection of data on genetic, epigenetic and gene expression levels would facilitate the elucidation of the underlying mechanisms.

Cigarette smoking-induced chronic inflammation has been considered a vital driver of lung tumorigenesis. The compounds 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, and lipopolysaccharide (LPS), an inflammatory inducer, are important components of tobacco smoke which have been implicated in inflammation-driven carcinogenesis. However, the biological effects and underlying mechanisms of LPS-mediated inflammation on NNK-induced tumorigenesis are still unclear. In this study, BEAS-2B human bronchial epithelial cells were exposed to NNK, LPS or both, for short- or long-term periods. We found that acute LPS exposure promoted the secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-6 in NNK-treated BEAS-2B cells. In addition, chronic LPS exposure facilitated the NNK-induced malignant transformation process by promoting cell proliferation, cell cycle alteration, migration, and clonal formation. Previously, we determined that circular RNA circ_0035266 enhanced cellular inflammation in response to NNK + LPS by sponging miR-181d-5p and regulating expression of its downstream target DEAD-Box Helicase 3 X-Linked (DDX3X). Here, we found that knockdown of circ_0035266 or DDX3X led to a remarkable inhibition of the proliferation, cell cycle progression, and migration of NNK + LPS-transformed BEAS-2B cells, whereas overexpression of these genes produced the opposite effects, indicating the oncogenic roles of circ_0035266 and DDX3X in the malignant progression of chronic inflammation-driven malignant transformed cells. Moreover, the regulatory relationships among circ_0035266, miR-181d-5p, and DDX3X were further confirmed using a group of lung cancer tissues. Conclusively, our findings provide novel insights into our understanding of inflammation-driven tumorigenesis using a cellular malignant transformation model, and indicate a novel tumor-promoting role for circ_0035266 in chemical carcinogenesis. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are recognized as potential etiological agents in the development of oral cancer in smokers. In particular, benzo[ a ]pyrene (B[ a ]P) and dibenzo[ def,p ]chrysene (DB[ a,l ]P) are detected in cigarette smoke and the environment and can induce DNA damage, mutagenesis and carcinogenesis in the oral cavity of rodents. Consequently, DNA adducts are regarded as the most direct markers of genotoxicity and can be used as biomarkers of cancer risk. Thus, this study used LC-MS/MS analysis with isotope labeled internal standard to detect and quantify DNA adducts derived from B[ a ]P and DB[ a,l ]P in buccal cells of cigarette smokers and non-smokers. Participants in this study include 21 smokers and 16 non-smokers. Our data are the first to report that levels (mean ± SD) of BPDE-N2-dG were significantly (P < 0.001) higher in smokers (20.18 ± 8.40 adducts/108 dG) than in non-smokers (0.84 ± 1.02 adducts/108 dG). Likewise, levels of DBPDE-N6-dA in smokers (5.49 ± 3.41 adducts/108 dA) were significantly higher (P = 0.019) than non-smokers (2.76 ± 2.29 adducts/108 dA). Collectively, the results of this clinical study support that PAHs in tobacco smoke can contribute to the development of oral cancer in humans. [ABSTRACT FROM AUTHOR]

Background Poultry plant workers are exposed to chemical carcinogens and oncogenic viruses in their work environment. Our objective was to identify jobs and workplaces related to poultries that could increase the pancreatic cancer risk. Methods We conducted a case–control study within a defined cohort of poultry workers. We used a random forest algorithm to identify features that could increase pancreatic cancer in the poultry plant workers. Results The mean age of participants was 59.49 years. The majority of the study participants were females (51.30%) and Whites (71.0%). The following workplaces and job tasks had an association with increased pancreatic cancer mortality: working in chicken and turkey plants, working in plants where food products were processed and canned, working in a place where poultry and animals where present, working as a hunter for game animals, working as a veterinarian in places had animals and different poultry birds, working in pet houses and working in places where birds were handled and killed. The accuracy and the area under the curve of the model were 72.3 and 71.50%. Conclusion Chicken and turkey plant workers could be at risk for pancreatic cancer mortality. We need to confirm the results in future studies. [ABSTRACT FROM AUTHOR]

Microbes play important roles in cancer from direct carcinogenic effects to their use in treatment. Cancers caused by microorganisms account for approximately 15% of cancers, primarily in low- and middle-income countries. Unique features of infectious carcinogens include their transmissibility, mutability, and specific immune interactions, which provide challenges and opportunities for cancer prevention and treatment. For these agents, infection control through exposure reduction, antivirals, antibiotics, and vaccines is cancer control. In addition, developing evidence suggests that microorganisms including the human microbiome can indirectly modulate cancer formation and influence the effectiveness and toxicity of cancer treatments. Finally, microorganisms themselves can be used to prevent or treat cancer. The convergence of these factors signals the emergence of a new field, cancer microbiology. Recognition of cancer microbiology will spur research, stimulate cross-disciplinary training, inform drug development, and improve public health. [ABSTRACT FROM AUTHOR]

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as endogenous inhibitors of matrixin and adamalysin endopeptidase activity. The matrixins and adamalysins are the major mediators of extracellular matrix (ECM) turnover, thus making TIMPs important regulators of ECM structure and composition. Despite their high sequence identity and relative redundancy in inhibitory profiles, each TIMP possesses unique biological characteristics that are independent of their regulation of metalloproteinase activity. As our understanding of TIMP biology has evolved, distinct roles have been assigned to individual TIMPs in cancer progression. In this respect, data regarding TIMP2's role in cancer have borne conflicting reports of both tumor suppressor and, to a lesser extent, tumor promoter functions. TIMP2 is the most abundant TIMP family member, prevalent in normal and diseased mammalian tissues as a constitutively expressed protein. Despite its apparent stable expression, recent work highlights how TIMP2 is a cell stress-induced gene product and that its biological activity can be dictated by extracellular posttranslational modifications. Hence an understanding of TIMP2 molecular targets, and how its biological functions evolve in the progressing tumor microenvironment may reveal new therapeutic opportunities. In this review, we discuss the continually evolving functions of TIMP proteins, future perspectives in TIMP research, and the therapeutic utility of this family, with a particular focus on TIMP2. [ABSTRACT FROM AUTHOR]

Background To explore trends in social and occupational inequalities in terms of exposures to physically demanding working conditions for French employees. Methods Our study assessed data from the French national cross-sectional survey of occupational hazards (SUMER) that was conducted in 2003, 2010 and 2017. Trends in the prevalence of several types of physically demanding working conditions (lifting of heavy loads, awkward postures, vibrations, harmful noise, extreme temperatures, and carcinogenic, mutagenic and reprotoxic agents) were explored. Temporal changes in associations of individual and job characteristics with these factors of hardship at work were examined using multilevel logistic regressions. Results We estimated that 53.5% of French workers from all industries in the private sector and in public hospitals were exposed to at least one of the adverse physical working conditions considered in 2017. While the prevalence of exposure to severe physical constraints increased between 2003 and 2017 (+4.2 pp), the exposure associated with a hazardous physical environment decreased sharply (−6.3 pp). These observed trends did not occur similarly for all workers. Several inequalities in exposure increased over the period, particularly to the detriment of blue-collar workers. The situation of shift workers deteriorated in terms of the exposure to vibrations and awkward postures. Conclusion Our study indicates that more stringent interventions are needed to reduce the prevalence of pronounced physical constraints that contribute to MSDs. Future prevention strategies, in addition to seeking to achieve a general reduction in exposure to all physically demanding working conditions, should aim to reduce disparities that adversely affect vulnerable populations. [ABSTRACT FROM AUTHOR]

Early detection of biomarkers in lung cancer is one of the best preventive strategies. Although many attempts have been made to understand the early events of lung carcinogenesis including cigarette smoking (CS) induced lung carcinogenesis, the integrative metabolomics and next-generation sequencing approaches are lacking. In this study, we treated the female A/J mice with CS carcinogen 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone (NNK) and naturally occurring organosulphur compound, diallyl sulphide (DAS) for 2 and 4 weeks after NNK injection and examined the metabolomic and DNA CpG methylomic and RNA transcriptomic profiles in the lung tissues. NNK drives metabolic changes including mitochondrial tricarboxylic acid (TCA) metabolites and pathways including Nicotine and its derivatives like nicotinamide and nicotinic acid. RNA-seq analysis and Reactome pathway analysis demonstrated metabolism pathways including Phase I and II drug metabolizing enzymes, mitochondrial oxidation and signaling kinase activation pathways modulated in a sequential manner. DNA CpG methyl-seq analyses showed differential global methylation patterns of lung tissues from week 2 versus week 4 in A/J mice including Adenylate Cyclase 6 (ADCY6), Ras-related C3 botulinum toxin substrate 3 (Rac3). Oral DAS treatment partially reversed some of the mitochondrial metabolic pathways, global methylation and transcriptomic changes during this early lung carcinogenesis stage. In summary, our result provides insights into CS carcinogen NNK's effects on driving alterations of metabolomics, epigenomics and transcriptomics and the chemopreventive effect of DAS in early stages of sequential lung carcinogenesis in A/J mouse model. [ABSTRACT FROM AUTHOR]

BlueScreen HC is a mammalian cell-based assay for measuring the genotoxicity and cytotoxicity of chemical compounds and mixtures. The BlueScreen HC assay has been utilized at the Research Institute for Fragrance Materials in a safety assessment program as a screening tool to prioritize fragrance materials for higher-tier testing, as supporting evidence when using a read-across approach, and as evidence to adjust the threshold of toxicological concern. Predictive values for the BlueScreen HC assay were evaluated based on the ability of the assay to predict the outcome of in vitro and in vivo mutagenicity and chromosomal damage genotoxicity assays. A set of 371 fragrance materials was assessed in the BlueScreen HC assay along with existing or newly generated in vitro and in vivo genotoxicity data. Based on a weight-of-evidence approach, the majority of materials in the data set were deemed negative and concluded not to have the potential to be genotoxic, while only a small proportion of materials were determined to show genotoxic effects in these assays. Analysis of the data set showed a combination of high positive agreement but low negative agreement between BlueScreen HC results, in vitro regulatory genotoxicity assays, and higher-tier test results. The BlueScreen HC assay did not generate any false negatives, thereby providing robustness when utilizing it as a high-throughput screening tool to evaluate the large inventory of fragrance materials. From the perspective of protecting public health, it is desirable to have no or minimal false negatives, as a false-negative result may incorrectly indicate the lack of a genotoxicity hazard. However, the assay did have a high percentage of false-positive results, resulting in poor positive predictivity of the in vitro genotoxicity test battery outcome. Overall, the assay generated 100% negative predictivity and 3.9% positive predictivity. In addition to the data set of 371 fragrance materials, 30 natural complex substances were evaluated for BlueScreen HC, Ames, and in vitro micronucleus assay, and a good correlation in all three assays was observed. Overall, while a positive result may have to be further investigated, these findings suggest that the BlueScreen HC assay can be a valuable screening tool to detect the genotoxic potential of fragrance materials and mixtures. [ABSTRACT FROM AUTHOR]

Aberrant dopamine system function is thought to contribute to the positive symptoms of schizophrenia. Clinical imaging studies have demonstrated that the largest dopamine abnormality in patients appears to be an increase in presynaptic dopamine activity. Indeed, studies utilizing [ 18 F]DOPA positive emission tomography reliably report increases in presynaptic dopamine bioavailability in patients and may serve as a biomarker for treatment response. The mechanisms contributing to this increased presynaptic activity in human patients is not yet fully understood, which necessitates the use of preclinical models. Dopamine system function can be directly examined in experimental animals using in vivo electrophysiology. One consistent finding from preclinical studies in rodent models used to study schizophrenia-like neuropathology is a 2-fold increase in the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), termed population activity. We posit that increased striatal dopamine synthesis capacity is attributed to an augmented VTA dopamine neuron population activity. Here, we directly test this hypothesis using [3H]DOPA ex vivo autoradiography, to quantify striatal dopamine synthesis capacity, in the methylazoxymethanol acetate (MAM) model, a validated rodent model displaying neurophysiological and behavioral alterations consistent with schizophrenia-like symptomatologies. Consistent with human imaging studies, dopamine synthesis capacity was significantly increased in dorsal and ventral striatal subregionis, including the caudate putamen and nucleus accumbens, of MAM-treated rats and associated with specific increases in dopamine neuron population activity. Taken together, these data provide a link between mechanistic studies in rodent models and clinical studies of increased presynaptic dopamine function in human subjects. [ABSTRACT FROM AUTHOR]

Chemicals in commerce or under development must be assessed for genotoxicity; assessment is generally conducted using validated assays (e.g. Tk mouse lymphoma assay) as part of a regulatory process. Currently, the MutaMouse FE1 cell mutagenicity assay is undergoing validation for eventual use as a standard in vitro mammalian mutagenicity assay. FE1 cells have been shown to be metabolically competent with respect to some cytochrome P450 (CYP) isozymes; for instance, they can convert the human carcinogen benzo[a]pyrene into its proximate mutagenic metabolite. However, some contradictory results have been noted for other genotoxic carcinogens that require two-step metabolic activation (e.g. 2-acetylaminofluorene and 2-amino-3-methylimidazo[4,5-f]quinoxaline). Here, we examined three known or suspected human carcinogens, namely acrylamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4-aminobiphenyl (4-ABP), together with their proximate metabolites (i.e. glycidamide, N-OH-PhIP and N-OH-4-ABP), to aid in the validation of the FE1 cell mutagenicity assay. Assessments of the parent compounds were conducted both in the presence and absence of an exogenous metabolic activation mixture S9; assessments of the metabolites were in the absence of S9. The most potent compound was N-OH-PhIP -S9, which elicited a mutant frequency (MF) level 5.3-fold over background at 5 µM. There was a 4.3-fold increase for PhIP +S9 at 5 µM, a 1.7-fold increase for glycidamide −S9 at 3.5 mM and a 1.5-fold increase for acrylamide +S9 at 4 mM. Acrylamide −S9 elicited a marginal 1.4-fold MF increase at 8 mM. Treatment with PhIP −S9, 4-ABP ±S9 and N-OH-4-ABP −S9 failed to elicit significant increases in lacZ MF with any of the treatment conditions tested. Gene expression of key CYP isozymes was quantified by RT-qPCR. Cyp1a1, 1a2 and 1b1 are required to metabolise PhIP and 4-ABP. Results showed that treatment with both compounds induced expression of Cyp1a1 and Cyp1b1 but not Cyp1a2. Cyp2e1, which catalyses the bioactivation of acrylamide to glycidamide, was not induced after acrylamide treatment. Overall, our results confirm that the FE1 cell mutagenicity assay has the potential for use alongside other, more traditional in vitro mutagenicity assays. [ABSTRACT FROM AUTHOR]

Background We examined the effect of dexamethasone prescribed in the initial 3 postoperative weeks on survival, steroid dependency, and infection in glioblastoma patients. Methods In this single-center retrospective cohort analysis, we electronically retrieved inpatient administration and outpatient prescriptions of dexamethasone and laboratory values from the medical record of 360 glioblastoma patients. We correlated total dexamethasone prescribed from postoperative day (POD) 0 to 21 with survival, dexamethasone prescription from POD30 to POD90, and diagnosis of an infection by POD90. These analyses were adjusted for age, Karnofsky performance status score, tumor volume, extent of resection, IDH1/2 tumor mutation, tumor MGMT promoter methylation, temozolomide and radiotherapy initiation, and maximum blood glucose level. Results Patients were prescribed a median of 159 mg [109-190] of dexamethasone cumulatively by POD21. Every 16-mg increment (4 mg every 6 hours/day) of total dexamethasone associated with a 4% increase in mortality (95% confidence interval [CI] 1%-7%, P <.01), 12% increase in the odds of being prescribed dexamethasone from POD30 to POD90 (95% CI 6%-19%, P <.01), and 10% increase in the odds of being diagnosed with an infection (95% CI, 4%-17%, P <.01). Of the 175 patients who had their absolute lymphocyte count measured in the preoperative week, 80 (45.7%) had a value indicative of lymphopenia. In the POD1-POD28 period, this proportion was 82/167 (49.1%). Conclusions Lower survival, steroid dependency, and higher infection rate in glioblastoma patients associated with higher dexamethasone administration in the initial 3 postoperative weeks. Nearly half of the glioblastoma patients are lymphopenic preoperatively and up to 1 month postoperatively. [ABSTRACT FROM AUTHOR]

Background Since May 2017, standardized packaging has been mandatory in the UK, with packs required to display an 'information message' explaining that there are more than 70 carcinogens in tobacco smoke. Methods Three waves of a longitudinal online survey in the UK with smokers pre-standardized packaging (Wave 1: April–May 2016) and followed up post-standardized packaging (Wave 2: September–November 2017, Wave 3: May–July 2019). Of the 6233 smokers at Wave 1, 4293 responded at Wave 2 and 3175 at Wave 3. We explored knowledge of the number of carcinogens in smoke, and whether knowing that smoke contains more than 70 carcinogens mediated change in the belief that the dangers of smoking are exaggerated (risk perception), stubbing out cigarettes, quit intentions and quitting. As the information message is larger on roll-your-own packs than on cigarette packs, as the packs are larger, we also explored whether there was any difference in knowing that smoke contains more than 70 carcinogens between exclusive cigarette smokers and exclusive roll-your-own smokers. Results Knowledge that there are over 70 carcinogens in smoke increased among smokers across waves, with the increase from Waves 1 to 3 greater for exclusive roll-your-own smokers than exclusive cigarette smokers (adjusted odds ratio=1.44; 95% CI 1.03–2.03). Knowledge that there are over 70 carcinogens in smoke mediated higher risk perception but not stubbing cigarettes out, quit intentions or quitting. Conclusions The information message improved knowledge of how many carcinogens are in smoke, particularly among exclusive roll-your-own smokers, and this was linked to higher risk perception. [ABSTRACT FROM AUTHOR]

Summary: Cancer is a prominent cause of morbidity and mortality worldwide, in spite of advances in therapeutic interventions and supportive care. In 2018 alone, there were 18·1 million new cancer cases and 9·6 million deaths indicating the need for novel anticancer agents. Plant‐based products have often been linked with protective effects against communicable and non‐communicable diseases. Recently, we have shown that animals such as crocodiles thrive in polluted environments and are often exposed to carcinogenic agents, but still benefit from prolonged lifespan. The protective mechanisms shielding them from cancer could be attributed to the immune system, and/or it is possible that their gut microbiota produce anticancer molecules. In support, several lines of evidence suggest that gut microbiota plays a critical role in the physiology of its host. Here, we reviewed the available literature to assess whether the gut microbiota of animals thriving in polluted environment possess anticancer molecules. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most prevalent cancers and severely endangers human health. Due to the low rate of diagnosis, most patients with GC are diagnosed as advanced. CDC42 effector protein 3 (CDC42EP3) has been revealed to be involved in several types of human cancers' development and progression. However, the function of CDC42EP3 in GC is not yet clear. CDC42EP3 expression was detected by immunohistochemistry, quantitative real-time PCR and Western blot assay in tumor tissues and cell lines of GC. CDC42EP3 knockdown cell models were constructed by lentivirus transfection. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound-healing assay and the transwell assay were utilized to assess the cell migration. Also, the cell apoptosis and the cell cycle were evaluated by flow cytometry. Moreover, the mechanism was investigated by Human Apoptosis Antibody Array. The in vivo experiments were conducted to verify the effects of CDC42EP3 knockdown on the tumor growth of GC. The expression level of CDC42EP3 was up-regulated in tumor tissues. High CDC42EP3 expression was positively related to more advanced tumor grade. CDC42EP3 knockdown inhibited cell proliferation and migration, promoted cell apoptosis and suppressed the tumor growth. On the other hand, it was also found that the silencing of CDC42EP3 inhibited HSP27 and IGF-1sR expression as well as promoted Caspase3, p53, TNF-α, TNF-β, TRAILR-1 and TRAILR-2 expression. CDC42EP3 was revealed to work as a tumor promoter in the development and progression of GC, which could be a promising therapeutic target for the therapy of GC. [ABSTRACT FROM AUTHOR]

Mycotoxins are naturally produced hazards that result from molds grown on cereal grains and other commodities. These molds may produce carcinogenic mycotoxins, which can be harmful to humans and animals. Removing broken kernels has been demonstrated to reduce mycotoxin concentration, but with high variability. Therefore, two experiments were conducted to quantify the magnitude of natural mycotoxin concentration that may be reduced by cleaning corn. Two loads of corn that were naturally contaminated with mycotoxins were procured. Corn for Experiment 1 was contaminated with aflatoxin (1,074 parts per billion; ppb), fumonisin (8.3 parts per million; ppm), and ochratoxin A (206 ppb), while corn for Experiment 2 was contaminated with only fumonisin (5.5 ppm). Corn was cleaned by mechanical sieving. For each experiment, corn was divided into twenty 150 kg runs. Runs were randomly assigned to 1 of 4 experimental treatments: 1) no screen 2) 12.7 mm screen, 3) 4.8 mm screen, and 4) 12.7 + 4.8-mm screen. The corn cleaner was sanitized between runs. Three 5 kg corn samples were collected from each run, and analyzed for mycotoxin concentration. In Experiment 1, cleaning reduced (P < 0.05) aflatoxin and fumonisin concentration by an average of 26% and 45%, respectively, compared to the original uncleaned corn level, but did not impact (P > 0.10) ochratoxin A. The resultant screenings had nearly four times the aflatoxin (4,224 ppb) and 7.5 times the fumonisin concentration (60.4 ppm) as the uncleaned corn. In Experiment 2, cleaning reduced (P < 0.05) fumonisin concentration by 32%. The resultant screenings had 19.6 times the fumonisin concentration (65.4 ppm) as the uncleaned corn. To determine the effect that cleaning corn may have on nursery pig growth performance, 360 nursery pigs were used in Experiment 3 to evaluate the impact of cleaning or pelleting on growth performance. Treatments were arranged in a 2 × 3 factorial with corn type (uncleaned vs. cleaned) and feed form (mash vs. pelleted from either mill A or B). Neither cleaning corn nor pellet mill type affected (P > 0.19) nursery pig growth performance. Pelleting improved (P < 0.0001) gain to feed ratio (G:F) by 7.6% compared to mash diets. These data suggest that cleaning is an effective method to legally reduce aflatoxin and fumonisin concentration, but does not impact animal growth performance. Screenings should be used cautiously when feeding to animals. [ABSTRACT FROM AUTHOR]

Objective To prevent occupational cancers, carcinogen exposure surveillance systems have been developed in many countries. This study aimed to develop a carcinogen exposure database specific to South Korea. Methods Twenty known human carcinogens were selected for this study. The International Standard Classification of Industry was used for a classification scheme of industries. Three nationwide occupational exposure databases, the Work Environment Measurement Database, the Special Health Examination Database, and the Work Environment Condition Survey, were used to calculate reference exposure prevalence estimates by carcinogen and industry. Then, 37 professional industrial hygienists with at least 19 years of field experience provided their own exposure prevalence estimates, after reviewing the abovementioned reference estimates derived from three data sources. The median value of the experts' estimates was used as the final exposure prevalence. Finally, the number of exposed workers was computed by multiplying the final exposure prevalence by the number of workers extracted from the 2010 national census data by carcinogen and industry. Results The exposure prevalence and the number of exposed workers were calculated according to 20 carcinogen and 228 minor industrial groups, assuming year 2010 circumstances. The largest population was exposed to welding fumes (326 822 workers), followed by ultraviolet radiation (238 937 workers), ionizing radiation (168 712 workers), and mineral oil mist (146 798 workers). Conclusions Our results provide critical data on carcinogen exposure for the prevention of occupational cancers. [ABSTRACT FROM AUTHOR]

Objectives Certain pesticides have been associated with adverse health outcomes including cancer and reproductive harms. However, little is known about the prevalence of occupational pesticide exposure among agricultural workers in Canada. The purpose of this study was to estimate the prevalence and likelihood of occupational exposure to pesticides in Canada's agricultural industry, using three commonly used, potentially carcinogenic pesticides [chlorothalonil, 2,4-dichlorophenoxyacetic acid (2,4-D), and glyphosate] as an example. Methods Estimates were calculated using the Canadian Census of Population and the Census of Agriculture. The number of workers and the proportion of farms applying 'herbicides' or 'fungicides' by farm type was estimated using survey data from the Census of Agriculture. These values were multiplied to yield the potential number of workers at risk of exposure. Likelihood of exposure (i.e. exposed, probably exposed, and possibly exposed) was then qualitatively assigned using information on crop type, primary expected tasks, crop production practices, and residue transfer data. Additional agricultural workers who are at risk of exposure but not captured by the Census of Agriculture were identified using the 2016 Census of Population. Results An estimated range of 37 700–55 800 workers (11–13% of agricultural workers) were exposed to glyphosate in Canada while 30 800–43 600 workers (9–11%) and 9000–14 100 (2.9–3.2%) were exposed to 2,4-D and chlorothalonil, respectively. Approximately 70–75% of workers at risk of exposure were considered probably or possibly exposed to any of the pesticides. Glyphosate exposure was most common among workers in oilseed (29% of oilseed farm workers exposed) and dry pea/bean farms (28%), along with those providing support activities for farms (31%). 2,4-D exposure was most common in corn (28%), other grain (28%), and soybean farms (27%), while chlorothalonil exposure was more likely among greenhouse, nursery, and floriculture workers (42%), workers on farms (28%, for occupations not captured by the Census of Agriculture, specifically), and those providing support activities for farms (20%). Regional variations broadly reflected differences in farm types by province. Conclusions This study estimated the prevalence of occupational exposure to three pesticides in Canada. Seasonal and temporary agricultural workers, which were captured by the Census of Agriculture, contributed to many additionally exposed workers. A large percent of the workers who were considered at risk of exposure were considered probably or possibly exposed, indicating a need for enhanced data collection and availability on pesticide use data in Canada. The study's methods can be applied to estimate workers' exposures to other pesticides within the agricultural industry. [ABSTRACT FROM AUTHOR]

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical. [ABSTRACT FROM AUTHOR]

Benzo [a] pyrene (B[a]P) is a potent mutagen and carcinogen, considered one of the commonest concomitants in the environment. The study aimed to evaluate the effect of catechin hydrate on benzo pyrene-induced kidney toxicity. Thirty-six adult male albino rats were divided into six groups: group I untreated control, group II received 10 mL/kg of corn oil (solvent of benzo [a] pyrene) twice a week, group III received 1 mL/kg 0.5% dimethyl sulfoxide (DMSO) (solvent of catechin) once per day, group IV received 50 mg/kg body weight of benzo[a]pyrene twice a week, group V received 20 mg/kg body weight of catechin in 1 mL/kg 0.5% DMSO once daily, and group VI received both catechin+benzo [a] pyrene with the same doses. All treatment was given by oral gavage for four weeks. At the end of the experiment, blood samples were collected for biochemical investigations, tissues were obtained for genotoxicity, RT-PCR, and histopathological studies. B[a]P exposure induced an increase in serum urea and creatinine levels along with severe renal histopathological changes. Our results showed a subsequent decrease in the antioxidant enzyme activities (catalase and superoxide dismutase), and conversely, (malondialdehyde) levels markedly elevated. Also, B[a]P induced DNA damage as well as activated an apoptotic pathway confirmed by upregulation of Bax, caspase-3, and downregulation of Bcl-2 expression. However, treatment with catechin-corrected kidney functions and antioxidant enzymes as well as regulated apoptosis. Histological results also supported the protective effects of catechin. These findings suggested that catechin hydrate is an effective natural product that attenuates benzo pyrene-induced kidney toxicity. [ABSTRACT FROM AUTHOR]

Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumours in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumours. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/− and −/− mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/− and −/− mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signalling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells. [ABSTRACT FROM AUTHOR]

Oral exposure to hexavalent chromium (Cr[VI]) induces intestinal tumors in mice. Mutagenic and nonmutagenic modes of action (MOAs) have been accepted by different regulatory bodies globally, the latter involving cytotoxicity-induced regenerative cell proliferation. However, concerns persist that all possible MOAs have not been fully considered. To address the potential for alternative MOAs, mechanistic data not represented in the existing two MOAs were evaluated. Relevant data were identified and organized by key characteristics of carcinogens (KCCs); literature related to epigenetics, immunosuppression, receptor-mediated effects, and immortalization were reviewed to identify potential key events associated with an alternative MOA. Over 200 references were screened for these four KCCs and further prioritized based on relevance to the research objective (ie, in vivo , oral exposure, gastrointestinal tissue). Minimal data were available specific to the intestine for these KCCs, and there was no evidence of any underlying mechanisms or key events that are not already represented in the two proposed MOAs. For example, while epigenetic dysregulation of DNA repair genes has been demonstrated, epigenetic effects were not measured in intestinal tissue, and it has been shown that Cr(VI) does not cause DNA damage in intestinal tissue. High-throughput screening data related to the KCCs were also evaluated, with activity generally limited to the two recognized MOAs. Collectively, no plausible alternative MOAs (or key events) were identified in addition to those previously proposed for Cr(VI) small intestine tumors. [ABSTRACT FROM AUTHOR]

Tumor progression and metastasis are still major burdens for head and neck squamous cell carcinoma (HNSCC). Runt-related transcription factor 1 (RUNX1) is involved in aggressive phenotypes in several cancers, while the molecular role of RUNX1 underlying cancer progression and metastasis of HNSCC remains largely unknown. In our study, RUNX1 expression was increased with disease progression in patients with HNSCC. The silencing of RUNX1 significantly decelerated the malignant progression of HNSCC cells, reduced osteopontin (OPN) expression in vitro and weakened the tumorigenicity of HNSCC cells in vivo. Moreover, we demonstrated that RUNX1 activated the mitogen-activated protein kinase signaling by directly binding to the promoter of OPN in tumor progression and metastasis of HNSCC. Our results may provide new insight into the mechanisms underlying the role of RUNX1 in tumor progression and metastasis and reveal the potential therapeutic target in HNSCC. [ABSTRACT FROM AUTHOR]

Apelin acts as a tumor promoter in multiple malignant tumors; however, its regulatory mechanism remains unclear. Previous studies have indicated that exosomes are pivotal to mediating tumor progression and metastasis. This study examined whether apelin enhances proliferation and invasion ability of lung cancer cells via exosomal microRNA (miRNA). Lung cancer A549 cells overexpressing apelin and control vector were generated by lentiviral transfection. Exosomes were isolated from the culture supernatant of each cell group and characterized. A-exo and V-exo were, respectively, cocultured with A549 cells, and assays of proliferation, apoptosis, colony formation and invasion were conducted. Exosomal miRNA sequencing (miRNA-seq) was performed on A-exo and V-exo to select a candidate miRNA. It was found that A549 cells absorbed more A-exo than V-exo, and A-exo could promote proliferation, colony formation, migration and invasion of A549 cells more than V-exo. Exosomal miRNA-seq data revealed that miR-15a-5p was markedly lower in A-exo compared with V-exo. Low expression of miR-15a-5p was also found in lung cancer tissues and cell lines, suggesting that miR-15a-5p may have an anti-tumor role. Overexpression of miR-15a-5p in A549 cells was associated with less cell proliferation, migration, invasion and suppressed cell cycle, and lower amounts of CDCA4 (cell division cycle-associated protein 4) indicated that it may be a potential target for miR-15a-5p. This study elucidated a novel regulatory mechanism that apelin may promote proliferation and invasion of lung cancer cells by inhibiting miR-15a-5p encapsulated in exosomes. [ABSTRACT FROM AUTHOR]

The NOTCH1 gene encodes a transmembrane receptor protein with activating mutations observed in many T‐cell acute lymphoblastic leukemias (T‐ALLs) and lymphomas, as well as in other tumor types, which has led to interest in inhibiting NOTCH1 signaling as a therapeutic target in cancer. Several classes of Notch inhibitors have been developed, including monoclonal antibodies against NOTCH receptors or ligands, decoys, blocking peptides, and γ‐secretase inhibitors (GSIs). GSIs block a critical proteolytic step in NOTCH activation and are the most widely studied. Current treatments with GSIs have not successfully passed clinical trials because of side effects that limit the maximum tolerable dose. Multiple γ‐secretase–cleavage substrates may be involved in carcinogenesis, indicating that there may be other targets for GSIs. Resistance mechanisms may include PTEN inactivation, mutations involving FBXW7, or constitutive MYC expression conferring independence from NOTCH1 inactivation. Recent studies have suggested that selective targeting γ‐secretase may offer an improved efficacy and toxicity profile over the effects caused by broad‐spectrum GSIs. Understanding the mechanism of GSI‐induced cell death and the ability to accurately identify patients based on the activity of the pathway will improve the response to GSI and support further investigation of such compounds for the rational design of anti‐NOTCH1 therapies for the treatment of T‐ALL. Implications for Practice: γ‐secretase has been proposed as a therapeutic target in numerous human conditions, including cancer. A better understanding of the structure and function of the γ‐secretase inhibitor (GSI) would help to develop safe and effective γ‐secretase–based therapies. The ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. Toward these ends, this study focused on γ‐secretase inhibitors as a potential therapeutic target for the design of anti‐NOTCH1 therapies for the treatment of T‐cell acute lymphoblastic leukemias and lymphomas. Understanding the mechanism of γ‐secretase inhibitor (GSI)–induced cell death and the ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. This article focuses on γ‐secretase inhibitors as a potential therapeutic target to treat T‐cell acute lymphoblastic leukemias and lymphomas. [ABSTRACT FROM AUTHOR]

10-Methyl-aplog-1 (1), a simplified analog of debromoaplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes and potent antiproliferative activity against several cancer cells with few adverse effects. A recent study has suggested that its phenol group in the side chain is involved in hydrogen bonding and CH/π interactions with the binding cleft-forming loops in the PKCδ-C1B domain. To clarify the effects of the side chain length on these interactions, four analogs of 1 with various lengths of side chains (2-5) were prepared. The maximal PKC binding affinity and antiproliferative activity were observed in 1. Remarkably, the introduction of a bromine atom into the phenol group of 2 increased not only these activities but also proinflammatory activity. These results indicated that 1 has the optimal side chain length as an anticancer seed. This conclusion was supported by docking simulations of 1-5 to the PKCδ-C1B domain. [ABSTRACT FROM AUTHOR]

Inflammation is now known to play a significant role in tumour growth and progression. It is also difficult to adequately quantify systemic inflammation and the resulting localized effects in cancer. Here, we use experimental data to infer the possible contributions of inflammation in a mouse model of cancer. The model is validated by predicting tumour growth under anti-inflammatory treatments, and combination cancer therapies are explored. We then extend the model to consider simultaneous tumour implants at two distinct sites, which experimentally was shown to result in one large and one small tumour. We use this model to examine the role inflammation may play in the growth rate separation. Finally, we use this predictive two-tumour model to explore implications of inflammation on metastases, surgical removal of the primary and adjuvant anti-inflammatory treatments. This work suggests that improved tumour control can be obtained by targeting both the cancer and host, through anti-inflammatory treatments, including reduced metastatic burden post-surgical removal of primary tumours. [ABSTRACT FROM AUTHOR]

Antihypertensive drugs namely angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, and diuretics are among the most clearly documented regimens worldwide with an overall cardioprotective benefit. Given that malignancy is the second leading cause of mortality, numerous observational studies aimed to investigate the carcinogenic potential of these agents with conflicting results. The purpose of this review was to summarize current data in an effort to explore rare side effects and new mechanisms linking antihypertensive drugs with the risk of developing cancer. [ABSTRACT FROM AUTHOR]

Chemicals in commerce or under development must be assessed for genotoxicity; assessment is generally conducted using validated assays (e.g. Tk mouse lymphoma assay) as part of a regulatory process. Currently, the MutaMouse FE1 cell mutagenicity assay is undergoing validation for eventual use as a standard in vitro mammalian mutagenicity assay. FE1 cells have been shown to be metabolically competent with respect to some cytochrome P450 (CYP) isozymes; for instance, they can convert the human carcinogen benzo[ a ]pyrene into its proximate mutagenic metabolite. However, some contradictory results have been noted for other genotoxic carcinogens that require two-step metabolic activation (e.g. 2-acetylaminofluorene and 2-amino-3-methylimidazo[4,5- f ]quinoxaline). Here, we examined three known or suspected human carcinogens, namely acrylamide, 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP) and 4-aminobiphenyl (4-ABP), together with their proximate metabolites (i.e. glycidamide, N -OH-PhIP and N -OH-4-ABP), to aid in the validation of the FE1 cell mutagenicity assay. Assessments of the parent compounds were conducted both in the presence and absence of an exogenous metabolic activation mixture S9; assessments of the metabolites were in the absence of S9. The most potent compound was N -OH-PhIP -S9, which elicited a mutant frequency (MF) level 5.3-fold over background at 5 µM. There was a 4.3-fold increase for PhIP +S9 at 5 µM, a 1.7-fold increase for glycidamide −S9 at 3.5 mM and a 1.5-fold increase for acrylamide +S9 at 4 mM. Acrylamide −S9 elicited a marginal 1.4-fold MF increase at 8 mM. Treatment with PhIP −S9, 4-ABP ±S9 and N -OH-4-ABP −S9 failed to elicit significant increases in lacZ MF with any of the treatment conditions tested. Gene expression of key CYP isozymes was quantified by RT-qPCR. Cyp1a1, 1a2 and 1b1 are required to metabolise PhIP and 4-ABP. Results showed that treatment with both compounds induced expression of Cyp1a1 and Cyp1b1 but not Cyp1a2. Cyp2e1 , which catalyses the bioactivation of acrylamide to glycidamide, was not induced after acrylamide treatment. Overall, our results confirm that the FE1 cell mutagenicity assay has the potential for use alongside other, more traditional in vitro mutagenicity assays. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma- in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (m Kras) (K+) and/or loss of Pten (P−/−), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K−) failed to cause premalignant changes, while m Kras alone (P+/+E−K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and m Kras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P−/−E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7 -independent cancer development occurred in the P−/−E−K+ genotype. In the P−/−E+K− genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not well understood. This study aimed to investigate whether long noncoding RNA (LncRNA)–ENST00000446135 could serve as a novel biomarker of Cd toxicity in cells, animals, and Cd-exposed workers and regulate DNA damage and repair. LncRNA–ENST00000446135 expression increased gradually in cadmium chloride-transformed 16HBE cells. Small interfering RNA-mediated knockdown of LncRNA–ENST00000446135 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA damage-related genes (ATM, ATR, and ATRIP), whereas increased the expressions of DNA repair-related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, XRCC1, and BARD1). Chromatin immunoprecipitation-sequencing showed that MSH2 is a direct transcriptional target of lncRNA–ENST00000446135. Cadmium increased lncRNA–ENST00000446135 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000446135 expression and urinary/blood Cd concentrations, and there were significant correlations of LncRNA–ENST00000446135 expression with the DNA damage cell and the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd-exposed workers and significantly correlated with liver and renal function in Cd-exposed workers. These results indicate that the expression of LncRNA–ENST00000446135 is upregulated and may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity. [ABSTRACT FROM AUTHOR]

Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant Kras G12C in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRAS G12D mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human LADC and portended poor survival. In response to two different smoke carcinogens, Spp1 -deficient mice developed fewer and smaller LADC with decreased cellular survival and angiogenesis. Both lung epithelial- and macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS -mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRAS G12D-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target. [ABSTRACT FROM AUTHOR]