key: cord-0871991-b4y9d0jh
authors: Fishbein, Anna; Hammock, Bruce D.; Serhan, Charles N.; Panigrahy, Dipak
title: Carcinogenesis: Failure of resolution of inflammation?
date: 2020-09-03
journal: Pharmacol Ther
DOI: 10.1016/j.pharmthera.2020.107670
sha: 9a3da3150cb6730284172ac3350af4ab5df905f3
doc_id: 871991
cord_uid: b4y9d0jh

Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

Carcinogens induce inflammation, an established hallmark of cancer (Greten & Grivennikov, 2019; Hanahan & Weinberg, 2011; Mantovani, Allavena, Sica, & Balkwill, 2008) .

With potential exposure to greater than 15 million environmental chemicals worldwide, controlling inflammation and its resolution will be a critical component of the successful prevention and treatment of cancer (Gilligan et al., 2019; Panigrahy et al., 2019; . Uncontrolled local and systemic hyperinflammation is an underlying driving force of diseases including cardiovascular disease (e.g. atherosclerosis and myocardial infarction), abdominal aortic aneurysm, heart arrhythmias, arthritis, central nervous system disorders, periodontal disease, inflammatory bowel disease, gallstones, sepsis, infection, stroke/epilepsy, infection, acute respiratory distress syndrome (ARDS), fibrosis (e.g. liver, kidney and lung), portal hypertension, fatty liver, neurodegenerative diseases (e.g. Alzheimer"s disease), traumatic brain injury, asthma, obesity, diabetes, pain, severe coronavirus disease (e.g. , and autoimmune diseases (Chelko et al., 2019; Chiang et al., 2012; Espinoza et al., 2016; Imig & Hammock, 2009; Libby, 2002; Mehta et al., 2020; Serhan, 2014; Spite et al., 2009 ). Over the past century, the study of anti-inflammatory mechanisms has focused on the suppression of pro-inflammatory mediators, such as cytokines, eicosanoids, and enzymes (D.

Wang & Dubois, 2010) . In recent years, a new direction has emerged to "turn off" inflammation with the discovery of a new superfamily of endogenous specialized pro-resolving lipid-autacoid mediators (SPMs), such as resolvins, which have potent novel inflammation clearing ("proresolution") activity without being immunosuppressive (Serhan, 2014; Serhan et al., 2002; . Virchow studied the four signs of inflammation (redness, swelling, heat and pain) and hypothesized a link between microinflammation and subsequent tumor progression (Heidland, Klassen, Rutkowski, & Bahner, 2006) . Experimental studies have indeed confirmed that inflammation can stimulate or induce tumor initiation, growth, and metastasis (Bogen, 2019; Chang et al., 2019; Coussens & Werb, 2002; Fishbein et al., 2020; Gartung et al., 2019; Gilligan et al., 2019; Guerra et al., 2007; Mantovani et al., 2008; Panigrahy et al., 2019; D. Wang & Dubois, 2010) . Cancers arise frequently at sites of chronic inflammation and injury as the observation that secondary tumors occur at the points of injury (e.g. tumor growth next to surgical placement of glass rods) was noted in 1914 (F. S. Jones & Rous, 1914) . The wound inflammatory response stimulates the growth of preneoplastic cells and cancer progression (Antonio et al., 2015) . Experimental evidence demonstrates that cancer therapies including chemotherapy, radiation, and surgery can stimulate tumor growth via a pro-tumorigenic host response including a eicosanoid/cytokine storm of pro-inflammatory and pro-angiogenic mediators (Camphausen et al., 2001; Filippou & Karagiannis, 2020; Fishbein et al., 2020; Gartung et al., 2019; Karagiannis et al., 2017; Shaked, 2019; Volk-Draper et al., 2014) . Wounding including surgery or biopsy can stimulate cancer growth via inflammation and angiogenesis (Alieva et al., 2017; Forget, Simonet, & De Kock, 2013; Hobson et al., 2013; Krall et al., 2018; with an average of four characteristics per agent (Krewski, Bird, et al., 2019) . These characteristics of carcinogens help to create the necessary tumor microenvironment for tumor initiation and progression via mechanisms distinct from the hallmarks of cancer (Guyton, Rieswijk, et al., 2018; M. T. Smith et al., 2016; M. T. Smith et al., 2020) . These key characteristics may also lead to the development of human-based assays and biomarkers for assessing cancer risk (Fielden et al., 2018) . At low concentrations, a chemical mixture has synergistic pro-tumorigenic activity on benign and malignant cells at a significantly lower concentration than as single chemicals (Dairkee, Luciani-Torres, Moore, Jaffee, & Goodson, 2018) . Carcinogens may not directly be genotoxic but cause DNA damage by stimulating inflammation. Chronic inflammation triggers oxidative stress via the release of pro-inflammatory cytokines and stimulation of cell proliferation, leading to DNA damage (Krewski, Bird, et al., 2019) . Heavy metals such as arsenic, aluminum, nickel, cadmium, chromium, cobalt, palladium, and titanium induce severe damage triggering pro-inflammatory cytokines and oxidative stress (Jomova & Valko, 2011; Magrone, Russo, & Jirillo, 2019) . Carcinogens such as per-and polyfluoroalkyl substances (PFAS) cause cancer in animals and increase risk of cancer in humans via several key characteristics including oxidative stress, immunosuppression, and receptor-mediated activity (Temkin, Hocevar, Andrews, Naidenko, & Kamendulis, 2020) .

Primary genotoxicity can result from carcinogen-induced particles (e.g. from polycyclic aromatic hydrocarbons) while oxidative stress-induced DNA damage can induce secondary genotoxicity (Schins & Knaapen, 2007) .

This important classification of key characteristics focused on the mechanisms of action of the cancer-causing activity of carcinogens provides a robust platform for novel chemopreventive treatment approaches to carcinogen-induced cancers. The carcinogenic potential of a compound is its ability to induce neoplasia via genotoxicity, cytotoxicity, proliferation, and inflammation depending on dose and duration of exposure (Doe et al., 2019) .

Importantly, inflammation can induces genetic changes which can cause cancer (Kay, Thadhani, Samson, & Engelward, 2019; Kiraly, Gong, Olipitz, Muthupalani, & Engelward, 2015) , . Cancer may be initiated with a mutation post-exposure to a DNA-damaging carcinogen, followed by pro-tumorigenic mechanisms such as inflammation which fuel the fire (Aggarwal et al., 2006; Cooks, Harris, & Oren, 2014) . Oxidative stress including reactive oxygen and nitrogen species (RONS) critically mediate cancer progression by carcinogens and pathogens (Kay et al., 2019; Meira et al., 2008) . While oxidative stress can induce DNA damage and inflammation, repair of DNA lesions formed by RONS during chronic inflammation can protect from carcinogen-induced cancers (Meira et al., 2008) . DNA damage also indirectly promotes inflammation through cytotoxicity (Kay et al., 2019) . Excessive DNA damage during proliferation may not be cleared by DNA repair pathways, resulting in cell death including apoptosis, necroptosis, necrosis, or senescence. Thus, DNA damage is considered essential to carcinogenesis.

Initiators of carcinogenesis include radiation, certain chemotherapeutics and chemicals such as aflatoxin, urethane, tryptophan metabolites, and nitrosamines, can cause an irreversible genetic modification in a normal cell leading to cancer (Chung & Gadupudi, 2011; Molho-Pessach & Lotem, 2007; Xie et al., 2012) . Initiators can bind to and alter the DNA to generate adducts. The initiation stage is an event in which carcinogens usually induce mutations or other modifications in critical genes, which can produce cancer stem cells (J. He, Liu, & Lubman, 2012; Tirino et al., 2013) . A compound that acts as both an initiator and a promoter is referred to as a 'complete carcinogen' because tumor development can occur without the application of another compound (Rastogi, Dogra, Khanna, & Das, 2006) . In studies of mouse skin carcinogenesis, a linear relationship has been observed between the dose of initiator and the quantity of tumors that can be produced (Gills et al., 2006) . Thus, the more exposure to the carcinogen, the higher the risk of developing tumors (D. S. Kang et al., 2018) . Cancer risk and slope factor are calculated in a linear dose-response (D. S. Kang et al., 2018) . All known human carcinogens that have been studied for carcinogenesis in experimental animals have generated positive results in one or more animal species (Tomatis, Aitio, Wilbourn, & Shuker, 1989; Wilbourn et al., 1986) . For several carcinogens, such as aflatoxins and vinyl chloride, carcinogenesis in experimental models of cancer was established before epidemiological studies confirmed their carcinogenesis in humans (Vainio et al., 1995) .

The mechanism of action of carcinogens traditionally has been simplified as genotoxic and/or nongenotoxic. A genotoxic carcinogen is defined as a chemical that causes cancer by directly altering the genetic material of target cells, while non-genotoxic carcinogens are chemicals that can induce cancer by mechanisms not related to direct genetic damage. Many genotoxic carcinogens cause cancer in carcinogenic bioassays in animals (W. J. Lee et al., 2014) . Concerning cancer risk assessment, genotoxic carcinogens exert carcinogenic potential regardless of the animal species. Thus, chemicals that are carcinogenic via genotoxicity to rodents are also presumed to be carcinogenic to humans unless proven otherwise. Because genotoxic carcinogens are mutagenic and may act through interaction with DNA to produce irreversible genetic changes in target organ cells, they may exhibit no dose threshold for their carcinogenic potential (Preussmann, 1980; Tomatis et al., 1997) . A genotoxic chemical can induce mutations (e.g. induction of DNA modifications). Carcinogens may induce a specific gene mutation frequently observed in a particular cancer increasing the risk of cancer (Moore et al., 2008) . While carcinogen-induced DNA damage can cause cancer, some studies suggest that DNA adducts alone or mutations alone may not be sufficient to cause cancer (Bogen, 2019; Johnson et al., 2014) . Non cell-autonomous mechanisms such as inflammation and angiogenesis may also be critical to tumor initiation and progression (Folkman, 2007) .

Importantly, proliferation of cells alone does not cause cancer as tumors can also develop in J o u r n a l P r e -p r o o f tissues subjected to infection, wounding, and inflammation (Coussens & Werb, 2002; Krall et al., 2018; Panigrahy et al., 2019) .

Carcinogens (e.g. aflatoxins, nitrosamines, asbestos, dioxins, tobacco, and alcohol) can initiate and stimulate cancer progression through various mechanism including inflammation, oxidative stress, DNA damage, cytotoxicity, acute or chronic injury, and subsequent regenerative proliferation via cell death (e.g. apoptosis) (Bogen, 2019; Klaunig, Hocevar, & Kamendulis, 2012; X. Yao & Zhong, 2005) . Environmental and occupational exposure to carcinogenic metals (e.g. arsenic, chromium, and vanadium) causes cancer via cell apoptosis, inflammation, DNA damage, and lipid peroxidation (F. Chen, Vallyathan, Castranova, & Shi, 2001) . There are over 8,000 compounds identified as carcinogens to date. Carcinogens can stimulate cancer via the production of critical pro-inflammatory, pro-angiogenic and protumorigenic cytokines/transcription factors, including TNF-α, IL-6, and NF-κB, as well as protooncogenes (e.g., c-Myc) (D. Chen, Yan, & Ye, 1998; .

Moreover, carcinogens may impair the host protective immune response via immunotoxicity, including increased apoptosis of leukocytes and reactive oxygen species (Iwaniuk, Jablonska, Jablonski, Ratajczak-Wrona, & Garley, 2015; Jablonski, Jablonska, & Chojnowski, 2001; Jablonski, Jablonska, & Leonik, 2011; Nowak, Ratajczak-Wrona, Garley, & Jablonska, 2018; Ratajczak-Wrona et al., 2014) . Impaired resolution of inflammation can lead to many human diseases including cancer (Gartung et al., 2019; Panigrahy et al., 2019; Serhan & Levy, 2018; . Carcinogens can disrupt inflammation resolution by impairing host-protective immune cells (e.g. neutrophil and macrophage) phagocytosis of debris (Fishbein et al., 2020; Mehrzad et al., 2011; Moon, Rhee, & Pyo, 1999) . Impaired clearance of debris fuels a pro-tumorigenic feedback loop between inflammation, DNA damage and carcinogenesis which can be aggravated by the tumor cell debris generated by cytotoxic cancer therapy including chemotherapy and radiation Gartung et al., 2019; J o u r n a l P r e -p r o o f sulfuric acid, coal emissions, nitrosamines, and other carcinogens may occur via occupations such as carpentry, plastic production, automobile manufacturing, mining and other industries (Hidajat et al., 2019; Rogers, Vaughan, Davis, & Thomas, 1995; Song, Wu, & Guan, 2015) .

People can be exposed to chemical carcinogens such as trichloroeythylene in daily routines in house cleaning compounds, benzidine which used to be used often for color dyes, or asbestos found in housing insulation (Kumagai-Takei et al., 2018) .

While exposure to certain carcinogens has declined with preventative education, other carcinogens cannot be completely avoided as they occur naturally or in the diet. Aflatoxins are mycotoxins produced by fungi which may contaminate a large portion of the world"s food supply leading to cancer progression including hepatocellular carcinoma (HCC) (Marchese et al., 2018; Xue et al., 2019; J. Zhang, O. Orang'o, et al., 2019) . Other natural carcinogens include minerals like cadmium, nickel or erionite, thorium, crystalline silica, ultraviolet light, or radon gases.

Arsenic can be found in contaminated ground water. Polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene (BaP) or dibenz[a,h]anthracene (DBA), can also be ingested in the diet or result in exposure in work environments (Luch, 2005; Poirier, 2016) .

Two of the most common human carcinogens are alcohol and tobacco, which is the leading risk factor for lung cancer with up to 80% of lung cancer deaths resulting from smoking inducing inflammation mechanisms such as increased macrophage recruitment, delayed clearance of neutrophils, and stimulation of reactive oxygen species (Walser et al., 2008) . While ethanol is not genotoxic nor mutagenic, its metabolite acetaldehyde is a potent local carcinogen (Salaspuro, 2017) . Tobacco smoke is also associated with many other carcinogens such as Abnet, 2011; Grosse et al., 2013; Johansson & Cohen, 1997) , and smokers are more than twice as likely to get bladder cancer than non-smokers. Moreover, the increased risk from smoking, although progressively decreasing after cessation, remains elevated by 62% and 50% even after 25 and 32 years, respectively (Brennan et al., 2000) . The carcinogen alcohol can lead to 4-6% of cancers (Madia et al., 2019) . Chronic consumption of alcohol stimulates inflammation due to leakage of bacteria and bacterial products, predominantly lipopolysaccharide (LPS), from the gut into the bloodstream and the liver.

Aflatoxins are a group of mycotoxins produced by Aspergillus fungi which are natural carcinogens and contaminate a large portion of the world"s food supply including grains and other food sources in tropical and subtropical climates, wetlands, and high temperatures. Up to 5 billion people exposed to aflatoxins are at increased risk for developing hepatocellular carcinoma (HCC) as the carcinogen causes up to 28% of HCC cases globally (Y. Liu & Wu, 2010; Strosnider et al., 2006; . Although aflatoxins have been primarily characterized as hepatocarcinogens, they are also carcinogenic in other tissues including mammary and lung (Eldridge, Gould, & Butterworth, 1992; X. J. Yang et al., 2012; Yi et al., 2017) . Aflatoxins have been linked to high levels of gallbladder cancers in Bolivia and Peru, as well as esophageal squamous cell carcinomas in China (Asai et al., 2012; Xue et al., 2019) .

Aflatoxins require bioactivation to reactive epoxides for genotoxic activity. The carcinogenicity of aflatoxins can result from metabolic activation of AFB 1 to a genotoxic epoxide, with a high prevalence of point mutations in the p53 gene (Chappell, Pogribny, Guyton, & Rusyn, 2016;  hepatotoxic potential and has synergistic carcinogenic effects with fumonisin B 1, another hepatocarcinogen, as well as with lipopolysaccharide (LPS), hepatitis C, and alcohol (Abbes, Ben Salah-Abbes, Jebali, Younes, & Oueslati, 2016; Barton, Ganey, & Roth, 2000; Chu et al., 2018) . Aflatoxins have demonstrated genotoxic as well as nongenotoxic mechanisms of carcinogenesis including significant numbers of DNA-adducts from AFB 1 from HCC analysis (C.

J. Chen, Zhang, Lu, & Santella, 1992; W. J. Wang, Xu, Yu, & Xu, 2017) .

Triclosan (TCS) is a chemical that is commonly used in toothpaste, cosmetics, cooking materials, and other products as an antimicrobial but has recently been identified as a possible carcinogen. Up to 75% of people in the United States have likely been exposed to the chemical (Weatherly & Gosse, 2017) . Importantly, this carcinogen exposure induces an inflammatory response even at very low doses by activating TLR4 signaling and altering gut microbiota predisposing to colon carcinogenesis (H. . TCS has been found in fluids and tissues of people of all ages and has demonstrated a wide range of effects including endocrine disruption, induction of inflammation and oxidative stress, epigenetic alterations, and carcinogenicity (Yueh & Tukey, 2016) .

The perfluorinated carboxylic acids (PFCAs) are a family of synthetic perfluorinated compounds that include perfluorooctanoic acid (PFOA, also known as C8), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA). PFOA has been used in the manufacture of items such as Teflon non-stick coating, Gore-Tex water-repellent gear, microwave popcorn bags, carpet, and fire-fighting foam (Nicole, 2013) . Most carcinogens such as PFOA frequently exhibit several modes of action in causing cancer in animals. For example, PFOA can initiate and cause cancer through promoting oxidative stress and DNA damage (Klaunig et al., 2012; X. Yao & Zhong, 2005) . PFOA can also stimulate breast and colon cancer cell invasion via matrix metalloproteinases (MMPs) (Miao et al., 2015; W. Zhang et al., 2014) .

Nitrosamines including N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) play a critical role in the initiation stage of carcinogenesis (J. Y. Hong et al., 1991; Ratajczak-Wrona, Jablonska, Garley, Jablonski, & Radziwon, 2013) . IARC has classified NDMA and NDEA as probable carcinogens to humans (Group 2A) (W. Wang, Yu, An, & Yang, 2016) .

NDMA induces cancer via a dose-response (Peto, Gray, Brantom, & Grasso, 1984) . NDMA has demonstrated highly carcinogenic, mutagenic, and teratogenic activity (Dennehy & Loeppky, 2005; Fitzgerald & Robinson, 2007; O. Zhang et al., 2016) . Nitrosamines have been associated with an increased risk of many cancers including gastric, esophageal, nasopharyngeal, and bladder cancers (Bartsch, Ohshima, Shuker, Pignatelli, & Calmels, 1990; Mirvish, 1995) . Nnitroso compounds are used as a prototype carcinogens to induce various types of cancer in animal models, including liver, lung, bile duct and pancreatic (V. Sharma & Singh, 2014) . In a large matched case-control study of pancreatic cancer, a significant positive association was found for NDEA, NDMA and pancreatic cancer (J. Zheng et al., 2018) . Moreover, extensive studies have demonstrated the cytotoxicity, genotoxicity, carcinogenicity, mutagenicity, as well as reproductive and developmental toxicity of nitrosamines (W. H. Chen & Young, 2009; Yin et al., 2019; Zhao et al., 2008; Zhou, Boyd, Qin, Hrudey, & Li, 2009) . Tumors in multiple organs have been induced by nitrosamine compounds in 39 species including higher primates (Bogovski & Bogovski, 1981) . NDMA causes cancer both as a single dose and with long-term exposure to lower quantities (Pottegard et al., 2018) . Other carcinogens such as dibenzo[a,l]pyrene (DBP) can potently transform cells, even in the absence of detected DNA adducts (Nesnow et al., 1997) .

Although epidemiology and studies with human tissues or cells are relevant to carcinogen exposure in humans, the mechanistic of action studies underlying carcinogenesis are focused in animal models for obvious ethical considerations. Laboratory animals are routinely utilized to mimic cancer in humans because there are more genetic, physiologic, biochemical, and metabolic similarities than differences to humans, large sample size, reproducibility, and feasibility to generate various cancers as well as study the mechanism of action of carcinogens (Maronpot et al., 2004) . For example, NDMA is a powerful carcinogen which induces 100% incidence of transitional cell carcinoma of the urinary bladder in the rat and the Syrian golden hamster (Lijinsky & Taylor, 1975; Reznik-Schuller, 1981 ). An example of an initiation-promotion model is a DMBA-induced, phorbol 12-myrisate 13-acetate (PMA) promoted or 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted squamous cell carcinoma (Monga et al., 2014; Muller-Decker et al., 2002) . A frequent model of colon carcinogenesis is induced by azoxymethane (AOM) and promoted with dextran sodium sulfate (DSS) (Hattori et al., 2019; Yamaguchi, Takai, Hosono, & Seki, 2014; . N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in esophagus is a model of human esophageal squamous cell carcinoma used for investigations of chemical carcinogenesis (Carlton et al., 2002; Yan et al., 2015) . Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer is commonly used to study mechanisms of lung and smoking-induced carcinogenesis (Rioux & Castonguay, 1998; H. C. Zheng & Takano, 2011) . 4-nitroquinaline 1-oxide (4-NQO) is utilized to induce tongue and oral cancers (Yanaida et al., 2002) . N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) is used to create a mouse model of human muscle invasive bladder cancer to study histological, physiological, molecular, and mutational mechanisms of carcinogenesis (Fantini et al., 2018) . Various chemically induced cancer models reflect various routes of exposure as tools to study mechanisms of carcinogens ( Figure 2 ).

J o u r n a l P r e -p r o o f risk and carcinogenesis (Moss & Blaser, 2005) . In a mouse model benzo(a)pyrene (BaP) and lipopolysaccharide (LPS) promote lung tumorigenesis (L. Huang et al., 2019) . Multiple liver infections including liver fluke and Clonorchis sinensis administered with NDMA cause experimental cholangiocarcinoma (E. M. Kim, Bae, Choi, & Hong, 2019; Laothong et al., 2013) .

Hepatitis C virus is synergistic with AFB 1 in hepatocarcinogenesis including an enhanced inflammatory response and lipid peroxidation (Jeannot et al., 2012; London et al., 1995) . (Satarug et al., 1998) . Additionally, carcinogens such as aflatoxin B 1 may promote influenza viral replication demonstrating synergy between environmental toxins and infections in causing cancer . The immune response to bacterial infection including stimulated eicosanoid production (e.g. prostaglandin E 2 (PGE 2 ) and cytokines (e.g. IL-8) shows the tight association between carcinogenesis and the immune response, particularly an inflammatory response (Biarc et al., 2004) .

sources such as heavy metals, pesticides, industrial chemicals, commercial products and solvents. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis is a powerful analytical technique utilized to detect genotoxic and non-genotoxic chemicals (e.g. in the environment and food) at very low concentrations (Escriva, Font, Manyes, & Berrada, 2017) .

One-step competitive enzyme immunoassays have been developed for monitoring carcinogen (e.g. fumonisin B1 and ochratoxin A) contamination in food such as cereals (X. Liu et al., 2015; Shu et al., 2016) . Many genotoxic carcinogens may also be detected via DNA binding assays with a new biosensor assay detecting carcinogens in contaminated food samples with a 24base guanine rich DNA segment at ranges as low as 0.0001 ppm (Sani, Heng, Marugan, & Rajab, 2018) . DNA adducts formed from genotoxic carcinogens can be identified in exposed people. Environmental carcinogens can be detected in serum, blood, and urine samples allowing for the measurement of chemicals such as tobacco and lead (Pirkle, Osterloh, Needham, & Sampson, 2005) . Detection methods including electrochemical detection, mass spectrometry, fluorescence, and immunohistochemistry, have advanced to accelerator mass spectrometry, which can detect about 1 in 10 12 nucleotides if labeled with a heavy isotope.

Importantly, this mass spectrometry technique can be used to identify DNA as well as protein adduct formation to more accurately determine chemical carcinogen exposure in human populations (Poirier, Santella, & Weston, 2000) . A metabolomics approach can predict the activity of non-genotoxic carcinogens via alterations in the levels of eicosanoids and reactive oxygen species (Ament et al., 2013) .

mutations in bacteria and mammalian cells; chromosomal aberrations, micronuclei formation, unscheduled DNA synthesis or DNA damage in mammalian cells and in rodents. Environmental mutagens such as ultraviolet light or cigarette smoke can lead to a high mutation rate in certain cancer types (e.g., skin and lung) (Srivastava, Reid, Ghosh, & Kramer, 2016 Winter et al., 2008) . Genotoxicity induced by NDMA is further demonstrated in extrahepatic tissues of rats by the persistence of DNA damage in the lung, liver, kidney and nasal cavity (Brendler, Tompa, Hutter, Preussmann, & Pool-Zobel, 1992; Pool, Brendler, Liegibel, Tompa, & Schmezer, 1990; Pool-Zobel et al., 1992) . Also, Nnitroso compounds such as NDMA activate ras oncogenes, which play a pro-tumorigenic role in the development of various cancers (e.g., colon) (Tricker & Preussmann, 1991) . DNA damage induced by NDEA increases micronuclei due to DNA breakage that could not be repaired, J o u r n a l P r e -p r o o f leading to an increase in chromosomal aberrations, and apoptotic cell death which can lead to cancer (Aiub et al., 2011; Fishbein et al., 2020) . Thus, carcinogens can initiate tumor growth via genotoxic mechanisms in synergy with nongenotoxic processes including cell death, inflammation, oxidative stress, angiogenesis and tissue injury.

Non-cell-autonomous contribution to tumorigenesis from the non-transformed "host-tissue", et al., 2015) . However, many chemicals considered to be nongenotoxic carcinogens actually possess certain genotoxic activities (Melnick, Kohn, & Portier, 1996) . Importantly, chronic inflammation can lead to genetic instability and DNA damage without direct DNA adduct mechanisms of genotoxic carcinogens, which along with the ability to dysregulate DNA repair pathways potently promotes carcinogenesis (Colotta, Allavena, Sica, Garlanda, & Mantovani, 2009 ). Interestingly, both genotoxic, and non-genotoxic carcinogens generate oxidative stress J o u r n a l P r e -p r o o f as an underlying cause for carcinogenesis (Deferme, Wolters, Claessen, Briede, & Kleinjans, 2015) . A new highly innovative model of carcinogenesis has been proposed as the Inflammation Somatic Model (ISM) based off the 2-stage somatic mutation model suggesting genotoxic effects are not sufficient to promote carcinogenesis and that inflammation as well as oxidative stress can prime tissues for cancer growth (Bogen, 2019) . Importantly, AFB 1 -induced hepatocarcinogenesis was prevented in rats with systemic administration of an antiinflammatory and antioxidant CDDO-Im despite significant DNA adduct burden suggesting a protective effect and a DNA damage threshold (Eaton & Schaupp, 2014; Johnson et al., 2014) .

Thus, carcinogens can generate a feedforward cycle of tissue damage, inflammation, oxidative stress, mutagenesis, cell death, and subsequent regeneration and carcinogenesis ( Figure 3 ).

Inflammation generated from carcinogens, such as crystalline silica, can be a critical underlying mechanism promoting genotoxicity (Borm et al., 2011) . Inflammation-induced cell proliferation potently stimulates carcinogen-induced mutations (Kiraly et al., 2015) . These elegant studies demonstrate a key mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer progression and cancer recurrence (Kiraly et al., 2015) . Inflammation enhances the production of reactive chemical species that damage DNA which may stimulate mutations (Kay et al., 2019) . Inflammation and cholangiocarcinoma (bile duct tumors) can be induced by NDMA combined with infections (Wongsena et al., 2018; Yothaisong et al., 2014) . Infection and NDMA-induced tumor tissue exhibit significantly higher numbers of inflammatory cells (especially eosinophils), bile duct proliferation, and IL-17+ cell infiltration compared to normal livers (Wongsena et al., 2018) . NDMA activates the PI3K-Akt/PKB pathway in human neutrophils which activates pro-J o u r n a l P r e -p r o o f inflammatory transcription factors NF-κB, c-Jun, and FosB involved in nitric oxide (NO) production (through modulation of inducible nitric oxide synthase (iNOS) expression) (Ratajczak-Wrona et al., 2014) . Thus, nitrosamines including NDMA stimulate inflammation via oxidative stress and an immune response (Hebels, Jennen, Kleinjans, & de Kok, 2009 ). The association between N-nitroso precursors and esophageal cancer may be modified by inflammation (Rogers et al., 1995) . NDEA stimulates inflammatory cell infiltration (e.g.

(lymphocytes, neutrophils, eosinophils, and Kupffer cells), pro-inflammatory cytokines, including the IL-1 and IL-6 signaling pathway, as well as oxidative stress and proliferation in the liver, stomach and colon including cyclooxygenase (COX-2) expression in hepatic tissues (Ding, Wu, Wei, Shu, & Peng, 2017; X. Y. Duan et al., 2014; Hebels et al., 2009; Mansour et al., 2019) .

Thus, inflammation plays a critical role in carcinogen-induced cancers.

Carcinogens such as NDMA also induce fibrosis leading to inflammation accompanied by the infiltration of lymphocytes, monocytes, granulocytes, and macrophages into the space of Disse (Koyama & Brenner, 2017) . Activation of transcription factors including NF-κB, c-Jun, and FosB in inflammatory cells underlie NDMA-induced NO synthesis/release (Ratajczak-Wrona et al., 2013) . N-nitrosamines are activated by inflammatory cells, such as macrophages (Sheweita, El-Shahat, Bazeed, Abu El-Maati, & O'Connor, 2004) . NDMA increases the proliferation of macrophages and expression of Raf in tumor-bearing lungs. Thus, the increase of both Raf and PCNA in the lung parenchyma surrounding NDMA-induced lung tumors suggesting an important lung tumor-macrophage interaction (Ramakrishna et al., 2002) . IL-1β is also able to contribute to fibrosis while TNF-α increases anti-apoptotic signals to avoid cell death (Amicone & Marchetti, 2018) . Importantly, while carcinogens can induce inflammation, chronic inflammation can also increase carcinogen exposure and uptake within the body by weakening barrier functions (Greten & Grivennikov, 2019) .

Nuclear factor kappa B (NF-κB) is a transcription factor that plays a critical role in inflammation, cancer invasion, regulation of apoptosis, oxidative stress, tumor progression, and metastasis (Karin, 2009; Karin & Greten, 2005; Q. Shi et al., 2017) . NF-κB is activated by Tolllike receptors (TLR) signaling microbes, tissue damage, or primary cytokines and can trigger production of multiple pro-inflammatory cytokines, prostaglandin synthesis enzymes (including COX), nitric oxide (NO) synthase, angiogenic molecules, and other pro-tumorigenic mediators.

STAT3/NF-κB signaling is important in cancer-related inflammation associated with IL-6-induced chronic inflammation (Colotta et al., 2009 (Corsini et al., 2011; Miao et al., 2015) . PFOA also induces the expression of the pro- J o u r n a l P r e -p r o o f Subramanian & Arul, 2013) . In a NDEA-induced hepatocarcinogenesis model, deletion of IkB kinase Beta (IKKβ) activates NF-κB from hepatocytes demonstrating increased tumorigenesis via ROS production, JNK activation, and hepatocyte death. However, hepatocarcinogenesis was decreased with IKKβ deletion from hepatocytes and Kupffer cells via reduced compensatory proliferation of hepatocytes demonstrating not only the importance of NF-κB signaling and its reduction in tumor associated immune cells, but the importance of cellular crosstalk in carcinogen-induced cancers (Maeda, Kamata, Luo, Leffert, & Karin, 2005) . Thus, NF-κB activation can mediate carcinogen-induced inflammatory cancers.

Downstream signaling of NF-κB leads to chronic inflammation via upregulation of a series of pro-inflammatory cytokines and chemokines which promote carcinogenesis. cytokines IL-6, IL−1β, IL-2, TNF-α and modulation of the PI3K-Akt-mTOR pathway (Keshari et al., 2017; Zeng et al., 2017) . In an AOM/DSS model of colon carcinogenesis, an anti-cancer compound celastrol, reduces COX-2, TNF-α, IL-6, IL−1β and iNOS (Barker et al., 2018) .

Another natural product, flaxseed, was able to reduce lung tumorigenesis in an NNK carcinogen-induced model affected Akt/JNK/MAPK signaling pathways to reduce the carcinogen-induced pro-inflammatory IL-6, IL-8 and increase the anti-inflammatory IL-12α (Chikara et al., 2018) . Demonstrating the importance of the pro-inflammatory cytokine TNF-α, TNF-α inhibition or deletion inhibits tumorigenesis in a NDEA-induced HCC model while reducing proliferation preventing activation of progenitor cells (Jing et al., 2018) .

Other carcinogens such as asbestos have extensive changes on immune cells including expression of MMP7, CXCR5, CXCL13, and CD44 on exposed T cells and increased IL-6

initiating crosstalk between B and T cells with mesothelial and epithelial cells (Kumagai-Takei et al., 2018) . Additionally, PFOA stimulates the production of critical pro-tumorigenic cytokines in multiple tissues including TNF-α, IL-1β and IL-6 in the liver or spleen, and increases protooncogenes (e.g. c-Myc activity in the spleen and thymus), which may be another important mechanism by which carcinogens cause cancer (Son et al., 2009; J. H. Yang, 2010) . PFOA may therefore impair the host-protective immune response. Carcinogen-induced immunotoxicity also occurs in other animals such as harbor porpoises living in oceans contaminated by persistent organic pollutants, polychlorinated biphenyls, and polybrominated diphenyl ether, resulting in impaired cellular responses from atrophy of the thymus and splenic depletion (Beineke, Siebert, Stott, Muller, & Baumgartner, 2007) . enzymes. Studies on the arachidonic acid pathway initially focused on its role in inflammatory and cardiovascular diseases (Imig & Hammock, 2009; Zeldin, 2001) . Most recently, arachidonic acid-derived eicosanoids have attracted increasing attention due to the increasing evidence of their role in cancer biology (Hyde & Missailidis, 2009; . Besides epoxyeicosatrienoic acids (EETs), CYP also generate hydroxyeicosatrienoic acids (HETEs) (Zeldin, 2001 ) whose role in cancer biology is not as extensively characterized as the COX and LOX-derived eicosanoids (A. M. Guo et al., 2008; Moreno, 2009 ).

Eicosanoid dysregulation can lead to chronic inflammation and oxidative stress or prevent pro-apoptotic signals generating the accumulation of damaged cells. The ratios of eicosanoids with opposing effects can be used to predict pathology following carcinogen exposure (Jelinska, Bialek, Gielecinska, Mojska, & Tokarz, 2017) . Interestingly, NNK can interact with beta-adrenergic receptors to directly stimulate the release of arachidonic acid, which could lead to aberrant eicosanoid production (Schuller, Tithof, Williams, & Plummer, 1999) . In addition to their roles in inflammation, the eicosanoid pathways also play a role in metabolism and bioactivation of carcinogens. CYP450 enzymes are also the main activators of many environmental carcinogens as they play a large role in drug and toxin metabolism.

Interestingly, COX isoenzymes generate ROS and also may be responsible for bioactivation of multiple carcinogens via metabolism of aromatic and heterocyclic amines or polycyclic hydrocarbons which may account for the carcinogen specific activity of cyclooxygenases (Wiese, Thompson, & Kadlubar, 2001) . Additionally, LOX is a peroxidase also generating ROS and free radicles may play an important role in the bioactivation of NNK via oxidation as the CYP450 enzymes were found to be only partially responsible for its activation (T. J. Smith, Stoner, & Yang, 1995) .

The COX pathway leads to pro-tumorigenic and pro-inflammatory activity in multiple models, including carcinogen-induced cancers. COX-2 activation can sensitive tissues to genotoxic carcinogens (Muller-Decker et al., 2002) . A tobacco carcinogen upregulates COX-1 expression correlated with NF-κB activation (Rioux & Castonguay, 2000) . antioxidants (Siddiqi, Saidullah, & Sultana, 2018) . However, the role of COX-2 may be contextdependent as COX-2 overexpression and upregulated prostaglandins can suppress tumorigenesis in skin (Bol et al., 2002) . Moreover, COX-2 can also be host-protective by generating anti-inflammatory and pro-resolution lipid mediators from arachidonic acid including lipoxins and pro-resolution prostaglandins (Gilroy & Colville-Nash, 2000; Levy, Clish, Schmidt, Gronert, & Serhan, 2001 ).

The lipoxygenase (LOX) pathways also play important roles in carcinogen-induced cancers via inflammation. Interestingly, ethanol stimulates carcinogenesis in a 4-NQO oral carcinogenesis model via induction of the 5-LOX pathway (Y. Guo, Wang, Zhang, Sun, & Chen, 2011) . Similarly, use of a 5-LOX inhibitor (garcinol) or herbal extracts (zyflamend) block LTB 4 to exhibit chemopreventive activity in a DMBA-induced oral carcinogenesis model (X. Chen et al., 2012; P. Yang et al., 2008) . Interestingly, cumin, a common spice used in curries, contained curcumin which inhibited TPA-induced skin inflammation by inhibiting the LOX metabolites 5-HETE and 8-HETE, as well as multiple prostaglandins (M. T. Huang et al., 1991) . In an AOM/DSS model of colon inflammation-associated carcinogenesis, cysteinyl leukotriene receptor 1 (CysLT1R) deletion reduced pro-inflammatory cytokines leading to decreased leukocyte and macrophage infiltration via eicosanoid regulation (Osman et al., 2017) . However,

downregulates NF-κB signaling, IL-6, IL−1β, and TNF-α in AOM/DSS-induced colorectal cancerassociated inflammation (R. Tian et al., 2017) . Zileuton, a 5-LOX inhibitor, is more potent in inhibiting DMBA oral carcinogenesis than celecoxib, a selective COX-2 inhibitor, via suppression of eicosanoids. A leukotriene A 4 hydrolase (LTA 4 H) inhibitor suppresses carcinogenesis via eicosanoid regulation (Z. Sun et al., 2006) . However, as each of these eicosanoid pathways play key roles in carcinogen-associated inflammation, dual eicosanoid inhibition (e.g. dual COX-2/sEH inhibition) may exhibit more potent anti-tumor activity then targeting a single eicosanoid pathway (Fishbein et al., 2020; Gartung et al., 2019; G. Zhang et al., 2014) . Supplementation of vitamin E or selenium in NMBA-exposed esophagus inhibited carcinogenesis via downregulation of both COX and LOX pathways inhibiting proliferation and angiogenesis (H. Yang et al., 2011) .

In the context of arachidonic acid metabolism CYP450 enzymes generate monohydroxyeicosatrienoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) (Panigrahy, J o u r n a l P r e -p r o o f Greene, Pozzi, Wang, & Zeldin, 2011; Zeldin, 2001) , . CYP450-derived eicosanoids including EETs and epoxydocosapentaenoic acids (EDPs) play a key role in angiogenesis, tumor growth, and metastasis (Imig & Hammock, 2009; Panigrahy et al., 2012; G. Zhang, D. Panigrahy, et al., 2013) . Epoxygenated fatty acids (EpFA), eicosanoid metabolites generated by CYP450, were 

Oxidative stress results from an imbalance between production of free radicals and reactive oxygen or nitrogen species (RONS) and their elimination by through protective mechanisms, including antioxidants (Tu, Wang, Li, Liu, & Sha, 2019) . Inflammation can J o u r n a l P r e -p r o o f stimulate tumor-promoting and tumor-initiating reactive chemical species, which can damage DNA leading to genetic instability, a hallmark of cancer, and oxidative stress. Oxidative and endoplasmic reticulum stress is often intertwined in inflammatory processes and is also induced by environmental carcinogens to promote tumor growth (Fishbein et al., 2020; Nowsheen, Aziz, Kryston, Ferguson, & Georgakilas, 2012) . The importance of oxidative stress is demonstrated via nongenotoxic carcinogens, such as dicyclanic hepatocarcinogenesis and arsenic, and their ability to induce DNA damage indirectly via increased ROS production, mitochondrial damage, upregulation of stress genes, and biomarkers such as 8-hydroxy-deoxyguanosine (8-OHdG) (S.

X. Liu et al., 2005; Moto et al., 2006) . Inflammation, including upregulation of COX-2, recruits leukocytes including neutrophils which can trigger oxidative damage, thus anti-inflammation can also prevent oxidative insult during tumorigenesis (Murakami et al., 2000) . Interestingly, neutrophils can also generate further production of N-nitroso carcinogens during intestinal inflammation promoting colon carcinogenesis (Vermeer et al., 2004) . NDMA increases iNOS in neutrophils associated with carcinogenesis (Ratajczak-Wrona et al., 2014) . Red meat, known to contain multiple carcinogenic compounds including nitrosamines, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic aromatic amines (HAAs), increases the risk of human cancers via lipid peroxidation, inflammation, and generation of reactive oxygen species (Turesky, 2018) . N-nitroso compounds and their metabolism stimulate pro-inflammatory reactive oxygen species causing cellular injury (Aiub, Pinto, & Felzenszwalb, 2003 Akshatha, Raval, Arpitha, Raval, & Ghodasara, 2018; Bansal, Bansal, Soni, & Bhatnagar, 2005b) .

Oxidative stress-induced cell injury plays a crucial role in NDEA-induced carcinogenesis as a single necrogenic dose of NDEA enhances levels of hepatic lipid peroxidation (LPO) and

conjugated dienes as markers of oxidative stress (Bansal, Bansal, Soni, & Bhatnagar, 2005a) . Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulatory molecule of oxidative stress and a potential therapeutic agent in carcinogen-induced cancer. Inhibition of Nrf2 stimulates oxidative stress, inflammation, circulating cytokines, and proliferation leading to intestinal carcinogenesis (Cheung et al., 2014) . NDEA stimulates inflammatory and oxidative stress markers via COX-2 upregulation, yet ginger extract demonstrated protective effects via Nrf2 activation to suppress oxidation and inflammation (Mansour et al., 2019) . AFB 1 upregulates Nrf2 signaling in response to oxidative stress, although expression of the SOD antioxidant is downregulated (W. J. . In liver carcinogenesis Nrf2 activation as a result of AHR and CYP1B1 downregulation led to restoration of liver tissue and reduced oxidative damage (Bose et al., 2020) . A novel compound, CDDO-Im, with anti-inflammatory properties also activates Nrf2 to potently inhibit AFB 1 -induced carcinogenesis in 100% of animals (Eaton & J o u r n a l P r e -p r o o f Schaupp, 2014; Johnson et al., 2014) . A structurally similar compound in the family of synthetic pentacyclic oleanane triterpenoids, CDDO-Me is in clinical development. Further, a family of compounds with the same activity but simpler synthesis, tricyclic-bis-enone (TBE) compounds, is also potent in reducing oxidative stress to inhibit AFB 1 -induced carcinogenesis (Liby et al., 2008) . Thus, inhibition of oxidative stress is a potent therapeutic approach to carcinogeninduced cancers.

Clinic inflammatory scores, including neutrophil to lymphocyte ratio or platelet to leukocyte ratio, can also predict cancer patient outcome ( J o u r n a l P r e -p r o o f

Cancer therapy-generated tumor cell debris can stimulate tumor growth via a storm of pro-inflammatory cytokines and eicosanoids Gartung et al., 2019; . Cellular debris (apoptotic cells) and inflammation-induced cellular damage can induce cellular proliferation to activate a "Phoenix Rising" Pathway) to promote wound healing and tissue regeneration of the damaged tissue (F. Li et al., 2010) . Cytotoxicity-induced pro-inflammatory activity of carcinogens and tissue damage/injury may lead to inflammation as a cancer co-initiator and predict low or negligible risk at noninflammatory carcinogen doses (Bogen, 2019) . Inflammation activated-stem cells involved in tissue repair in damaged tissue and may lead to cancer if the normal termination of inflammation is suppressed by mutations (Bogen, 2019) . Non-mutagenic cytotoxic agents such as alcohol, chloroform, and ultraviolet light induce cell death triggering cytokines which stimulate hyperplasia and tumor growth Gartung et al., 2019; Trosko, 2001) . While carcinogeninduced inflammation and oxidative stress can lead to cellular damage, cell death can play a complex role in carcinogenesis by either stimulating or inhibiting tumor growth (Bonavita, Pelly, & Zelenay, 2018; . While cell death is beneficial to prevent accumulation of cells with accumulated DNA damage, it also generates stress signals leading to more inflammation and regenerative proliferation which can stimulate tumor growth.

Carcinogens in tobacco smoke, including nicotine-derived nitrosamine ketone (NNK), trigger the IKKβ/JNK1 mediated apoptotic pathway leading to a subsequent proliferation response, while other carcinogens including aflatoxins trigger cell death via ROS production (Sakurai et al., 2008; Takahashi, Ogata, Nishigaki, Broide, & Karin, 2010; J. Zhang et al., 2015) . Oxidative stress induced by carcinogens as nitric oxide induces cell death associated with COX-2 and PPARgamma signaling (Lim, Jang, & Surh, 2003) . In a naphthalene-induced nasal tumor model a dual mode of action links genotoxic and cytotoxic effects (Bogen, 2019) . Interestingly, in a via DAMPs released by dying hepatocytes demonstrating the importance of immune and nonimmune cell crosstalk in carcinogenesis (Liang et al., 2019) . In a study of three nongenotoxic carcinogens, cadmium chloride, methyl carbamate, and lithocholic acid, genome wide methylation analysis demonstrated changes in cancer and surveillance pathways, but also in autophagy pathways a mechanism by which the body clears damaged cells (Hwang, Yeom, Eom, Lee, & Lee, 2019) . Another nongenotoxic carcinogen, fumonisin B1, induces carcinogenesis via induction of apoptosis and necrosis leading to regenerative proliferation (Dragan et al., 2001) . NDMA-induced cytotoxic activity and apoptosis in various organs (e.g., large bowel) can lead to inflammation (Potten, Li, O'Connor, & Winton, 1992) . In a liver model, 

Dormancy is a stage in cancer progression where the cancer cells are not dividing but survive in a quiescent state. Dormant tumors have been identified at autopsy in normal adults who died of trauma and without prior history or clinical evidence of cancer (Folkman, 2001; Harach, Franssila, & Wasenius, 1985) . The reported incidence of these dormant tumor cells has been as high as 39% for in situ breast carcinoma, 46% for in situ prostate cancer, and 36% for thyroid carcinoma (Black & Welch, 1993) . Thus, it is highly likely that many humans exposed to 

A dysregulated immune system following carcinogen exposure can lead to chronic inflammation, but also immunosuppressive activity may further damage the host response to protect from cancer. Chronic inflammation, including signaling molecules such as PGE 2 , can lead to immunosuppression in the tumor microenvironment (D. Wang & DuBois, 2016 .

For example, pro-tumorigenic activity of NNK on alveolar macrophages modulated by PGE 2 included immunosuppression (Therriault, Proulx, Castonguay, & Bissonnette, 2003) . In a DMBA (Desjardins, Fournier, Denizeau, & Krzystyniak, 1992) .

Carcinogens, including aflatoxins and tamoxifen, disrupt inflammation resolution and the innate immune system by impairing host-protective neutrophil and macrophage phagocytosis of debris (Lukac, Kusic, Kordic, Koncar, & Bolanca, 1994; Mannerstrom, Maenpaa, Toimela, Salminen, & Tahti, 2001; Mehrzad et al., 2011; Moon et al., 1999) . In addition, NDMA can negatively impact neutrophil phagocytic activity, oxygen metabolism, and functions associated with production and release of immunologically-active molecules (Jablonski, Jablonska, & Moniuszko-Jakoniuk, 2007) , thus impairing inflammation resolution. NDMA is immunotoxic to immune cells, cell-mediated immunity and inflammation (e.g., mononuclear cells and neutrophils (PMN)) (Holsapple, Bick, & Duke, 1985; Jablonski et al., 2011) . Reduced host resistance to infectious agents (reduced response to streptococci and influenza challenge) following NDMA administration also indicate systemic toxicity on humoral immunity (Thomas et al., 1985) . NDMA also impairs the cellular immune response by altering the production and/or maturation/differentiation of bone marrow stem cells into functional macrophages (Myers, Dickens, & Schook, 1987; Myers, Pullen, & Schook, 1986; Myers, Schook, & Bick, 1987) .

Cytotoxic carcinogens can trigger cell death of lymphocytes leading to an immunosuppression without the ability to control the accumulating transformed cells (Badr, El-Reda, El-Gamal, & Farid, 2020; J. Chen et al., 2016) . NDMA may impair the host immune response and exhibit immunotoxicity, including increased apoptosis (death) of leukocytes and production of pro-tumorigenic reactive oxygen species (Iwaniuk et al., 2015; Jablonski et al., 2001; Jablonski et al., 2011; Nowak et al., 2018; Ratajczak-Wrona et al., 2014) . PFOA also exhibits immunotoxic potential in mice (Son et al., 2009) . The toxic activity of NDMA greatly influences the biological activity and lifespan of immune cells (Iwaniuk et al., 2015) , including J o u r n a l P r e -p r o o f neutrophils, by inducing a respiratory burst and subsequent release of ROS responsible for the apoptosis of these cells (Jablonski et al., 2001) . NDMA can also modulate the apoptosis of human neutrophils by regulating the expression of death receptor DR5 as well as through the release of its soluble form (sDR5) (Jablonski et al., 2007) . In a prospective clinical study the hepatocellular carcinoma tumor microenvironment exhibited pro-angiogenic and proinflammatory activity, but also a distinctly immunosuppressed environment including White . NDMA depressed T-lymphocyte function as measured by T-cell proliferation in response to T-cell mitogens (Holsapple et al., 1985) . NDMA suppresses T-celldependent antibody response (Jeong & Lee, 1998) . PFOA causes splenic and thymic atrophy with suppressed thymocyte proliferation (Q. Yang, Xie, Eriksson, Nelson, & DePierre, 2001) .

PFOA also inhibited CD4 + CD8 + populations, demonstrating impaired splenocyte and thymocyte maturation from CD4 -CD8to CD4 + CD8 + cells (Son et al., 2009 Furthermore, phagocytes utilize antibodies generated by B lymphocytes to allow them to recognize and destroy pathogens (Hansson, 1997; Stemme et al., 1995) . Carcinogens such as aflatoxins generate tumor cell death ("debris") that can trigger tumor dormancy escape via an eicosanoid and cytokine storm of pro-inflammatory as well as pro-angiogenic mediators J o u r n a l P r e -p r o o f (Fishbein et al., 2020) . Thus, carcinogen exposure may disrupt host-protective anti-tumor host immune responses and impair the resolution of inflammation.

Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin reduces the risk and incidence of cancer (Gilligan et al., 2019; D. Wang & Dubois, 2010) . However, severe toxicity including bleeding has precluded the routine application of anti-inflammatory agents in the chemoprevention and treatment of cancer.

Moreover, selective cytokine or eicosanoid blockade may not be sufficient to prevent carcinogen-induced cancers (Fishbein et al., 2020; Gartung et al., 2019) . Inflammatory transcription factors such as Nrf2 can reduce the DNA damage by neutralizing reactive chemicals with antioxidants and upregulating DNA repair pathways (Kay et al., 2019) . The triterpenoid oleanane, a highly potent anti-inflammatory agent, prevents hepatocellular carcinoma (HCC) in an experimental rat model while only partially reducing AFB 1 -DNA adducts (Johnson et al., 2014) . Other anti-inflammatory mechanisms designed to reduce cancer risk include a healthy diet, exercise, antioxidants, and spices (e.g. curcumin).

A new potentially-paradigm shifting direction of inflammation research has emerged with the discovery of the autacoid superfamily of specialized pro-resolving lipid autacoid mediators (SPMs), including resolvins, maresins, protectins, and lipoxins, as key mediators in the resolution of inflammation, possessing potent inflammation clearing activity without being immunosuppressive (Mukherjee, Marcheselli, Serhan, & Bazan, 2004; Serhan et al., 1984;  J o u r n a l P r e -p r o o f Serhan et al., 2002; Serhan et al., 2009) . The resolution of inflammation is now appreciated to be an active process regulated by SPMs, which are endogenously produced in multiple tissues throughout the human body (Serhan & Levy, 2018 

Selective COX-2 inhibitors (coxibs) and nonselective NSAIDs can reduce the incidence of cancers in humans and in experimental models (D. Wang & Dubois, 2010) . The risk for colorectal cancer is increased in patients with inflammatory bowel disease. COX-2 and PGD 2 have been identified as potential therapeutic targets for the chemoprevention of colon cancer (D. Wang & Dubois, 2010) . However, COX-2 is also a pivotal enzyme necessary to stimulate the resolution of inflammation and production of specialized pro-resolving mediators (SPMs) such as lipoxins (Wallace, 2006) . Given the important roles of COX-2 (in part through biosynthesis of PGD 2 ) in the resolution of inflammation, inhibition of COX-2 may be "resolution toxic" (Gilroy et al., 1999; Panigrahy et al., 2019; Serhan & Levy, 2018) . Inflammation (e.g. paw swelling) in COX-2 KO mice failed to resolve and exhibited significant leukocyte infiltration.

COX-2 is an important source of PGD 2 (15-deoxy-Δ 12-14 PGJ 2 ) and is also essential for driving J o u r n a l P r e -p r o o f resolution of the inflammatory response in the lung (Gilroy et al., 1999) . Human fibroblasts generate pro-resolving peroxisome proliferator-activated receptor-γ ligands in a COX-2dependent manner via pro-resolving prostaglandins (Lacy et al., 2016) . Thus, inhibition of COX-2 impairs resolution of inflammation because prostaglandins such as PGE 2 initiate a lipid mediator class switching to SPMs such as lipoxins to accelerate the resolution of inflammation (Levy et al., 2001) .

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for inflammatory diseases, pain, fever and include aspirin, celecoxib, ibuprofen, sulindac, diclofenac, and ketorolac (D. Wang & Dubois, 2010) . NSAIDs that block the enzymatic activity of COX and subsequent production of prostaglandins, are widely used to treat inflammation and pain (Marnett, 2009) While initial studies have focused on colorectal cancers, low-dose aspirin exhibits antitumor activity in other tumor-types, including lung, breast, prostate, and metastatic cancers (D.

Wang & Dubois, 2010) . Aspirin can stimulate resolution by triggering the biosynthesis of resolvins, lipoxins and protectins (Gilligan et al., 2019; Serhan, 2014) . Compelling evidence of aspirin"s anti-cancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence.

Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (Gilligan et al., 2019) . Aspirin-triggered resolvins and lipoxins may account for aspirin"s antitumor activity at least in part without the toxicity of aspirin (Claria & Serhan, 1995; Gilligan et al., 2019) . Because SPMs are not triggered by other NSAIDs besides aspirin, this may explain why aspirin"s beneficial anti-tumor activity has not been fully recapitulated with other NSAIDs (Gilligan et al., 2019) .

However, NSAIDs can down-regulate pro-tumorigenic cytokines but also generate toxic side effects and may be immunosuppressive resulting in increased risk for infections. Pretreatment of the NSAID carprofen impaired initiation of inflammatory-and overlapping resolution response and promoted cardiorenal syndrome and heart failure (V. Krishnan et al., 2019) . The classic cyclooxygenase inhibitors, celecoxib and indomethacin, that block thromboxanes and prostanoids do not inhibit production of the clot-driven SPM cluster .

Additionally, NSAIDs have been associated with gastrointestinal (GI) injury for a century (D.

Wang & Dubois, 2010) . It was the discovery by Vane in 1971 that these drugs suppress the biosynthesis of prostaglandins (PGs) that first suggested that autacoids may play a role in the maintenance of GI mucosal injury (Vane, 1971 ). Coadministration of a selective COX-2 inhibitor with aspirin inhibits pro-resolution lipoxin synthesis in the stomach increasing gastric mucosal damage (Fiorucci et al., 2002) . Administration of synthetic LXA 4 prior to aspirin resulted in a dose-dependent reduction in the extent of gastric damage. Thus, aspirin-triggered lipoxins reduce injury to the gastric mucosa (Wallace & Fiorucci, 2003) . Lidocaine impairs resolution by inhibiting efferocytosis (Serhan & Levy, 2018) . In contrast, frequently used drugs such as aspirin promote resolution through acetylation of COX-2, and triggering production of R-epimer lipoxins, resolvins, and protectins. Statins also boost SPMs and the resolution of inflammation (Serhan, 2014) . Glucocorticoids can have mixed activity While PGE 2 and LTB 4 initiate inflammation following tissue injury, PGD 2 is a proresolution prostaglandin that triggers the switch from initiation of inflammation to resolution by inducing 15-LOX and SPM production which is upregulated in colitis patients who undergo long term remission (Serhan, 2014; Vong, Ferraz, Panaccione, Beck, & Wallace, 2010) . Thus, proresolution prostaglandins inhibit IKKβ to suppress NF-κB induced chronic inflammation, may be a therapeutic approach to carcinogen-induced inflammation (Rossi et al., 2000) . Alternatively, more specific inhibition of microsomal PGE synthase (mPGES-1) suppressed carcinogeninduced colon cancer without broadly blocking prostaglandin signaling as a potential mechanism to reduce NSAID-associated toxicity (Nakanishi et al., 2011) . Thus, inhibition of eicosanoid enzyme pathways may disrupt inflammation resolution in carcinogen-induced cancers which can be restored via supplementation of pro-resolution lipid mediators.

A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins, lipoxins, protectins and maresins (Serhan, 2014) . Resolvins and other pro-resolution lipid mediators stimulate macrophage-mediated clearance of cellular debris and counter pro-inflammatory cytokine production, a process called termed the "resolvins" (short for resolution phase interaction products), "protectins," and "maresins" (short for macrophage mediators in resolving inflammation) (Mukherjee et al., 2004; Serhan et al., 2002; Serhan et al., 2009 ). Each family is structurally distinct and biosynthesized from essential fatty acid precursors eicosapentaenoic acid (EPA), docosapentaenoic acid (n-3DPA), or docosahexaenoic acid (DHA).

Aspirin stimulates the biosynthesis aspirin-triggered specialized pro-resolving mediators (AT-SPMs) from omega-3 polyunsaturated fatty acid substrates, including eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA) by acetylation of COX-2 . AT-SPMs include endogenous production of aspirin-triggered lipoxins, aspirin-triggered resolvins and aspirin-triggered neuroprotectins (Claria, Lee, & Serhan, 1996; Claria & Serhan, 1995; Petasis et al., 2012; Serhan, 2014; Serhan, Dalli, Colas, Winkler, & Chiang, 2015; Takano, Clish, Gronert, Petasis, & Serhan, 1998) . Stable analogues of lipoxin A 4, lipoxin B 4, and aspirintriggered lipoxin A 4 inhibit neutrophil infiltration more potently than aspirin and rescue resolution deficits in various inflamed tissue injury models (Clish et al., 1999; Schwab et al., 2007; Serhan, 2005; Takano et al., 1997) . Aspirin-triggered resolvin D3 are potent immunoresolvents, including blocking neutrophil transmigration as well as stimulating macrophage phagocytosis and efferocytosis (Dalli et al., 2013) . Aspirin-triggered resolvins can mediate the anti-proliferative and anti-tumor activity of aspirin (Claria et al., 1996; Gilligan et al., 2019) . Aspirin-triggered resolvins can mediate the anti-tumor activity of aspirin at >10,000 fold lower doses than aspirin without toxicity in experimental cancer models via resolution of inflammation (Gilligan et al., 2019) . Preoperative administration of the NSAID ketorolac and/or resolvins (RvD2, RvD3, and RvD4) activate endogenous resolution programs before surgery to eliminate micrometastases and reduce tumor recurrence .

Importantly, as NF-κB is central to inducing tissue injury and inflammation in carcinogenesis, SPMs have been shown to downregulate this signaling via activation of NF-κB regulators, including 15-epi-lipoxin A 4 induction of A20 and SIGIRR via its ALX/FPR2 receptor signaling following LPS-induced inflammation (Sham et al., 2018) . Resolvin D1 protects from LPS-induced inflammation in a lung injury model via inhibition of damaging oxidative stress (L. Wang et al., 2014) . Upregulation of the ALOX-15/LXA4 pathway in a PMA-induced skin inflammation model can promote the resolution of inflammation via inhibition of IFN-γ (G. Zhang, X. Liu, et al., 2013) . Resolvin D1 in colitis-associated cancer inhibits c-Myc and TNF-α in colon cancer cells (Zhong et al., 2018) . In an inflammatory intestinal model, protectin D1 n-3DPA and resolvin D5 n-3DPA protected against colitis and intestinal injury, both of which are risk factors for intestinal carcinogenesis (Gobbetti et al., 2017 ).

An important function of pro-resolution mediators or signaling pathways is the induction of macrophage phagocytosis and efferocytosis. Clearance of microbes as well as apoptotic cells is important in multiple inflammatory diseases, including carcinogen-induced cancers as dead cells or increased microbe uptake can stimulate chronic inflammatory cycles. Peroxisome proliferator-activated receptors (PPARs) stimulate macrophage phagocytosis to promote clearance of infection and inhibit pro-inflammatory mediators in macrophages, which may be key to "resolve" inflammation-driven cancers (DuBois et al., 1998; Penas et al., 2015) . As targeting specific macrophage phenotypes is crucial to the resolution of inflammation in carcinogen-induced cancers, a MerTK macrophage phenotype has been demonstrated to induce phagocytosis and prevent liver damage (Triantafyllou et al., 2018) . Additionally, LTB 4 , a potently pro-inflammatory mediator, can be detected via PPAR-α binding which signals for its metabolism and clearance in the liver to control pro-inflammatory signaling (Devchand et al., J o u r n a l P r e -p r o o f 1996). Thus, exploring multiple targets involved in the resolution of inflammation may elucidate novel therapeutics in carcinogen-induced inflammation and cancer.

SPMs also induce a macrophage phenotype switch from a generally M1 to M2 phenotype which promotes efferocytosis and phagocytosis functions (Werz et al., 2018) .

Hypoxia activates resolution metabolomes (SPM-biosynthetic circuits) which stimulate resolution including resolvins in M2-like human macrophages via interactions with erythrocytes which store omega-3 fatty acids to increase phagocytosis and efferocytosis . This clearance of dead and damaged cells would inhibit the increased inflammatory response to DAMPs and reduce the debris-induced macrophage-derived cytokine storm. SPMs, including resolvins, have functioned to clear therapy-generated dead cells to prevent their generation of tumor promoting inflammation, as well as prevent micrometastases to prolong survival in surgery-stimulated tumor dormancy escape models . In addition, phagocytosis of inflammatory microbes which may have increased in the tissue via carcinogen exposure and failed barrier function may prevent synergistic tumorigenic inflammation. Macrophage phenotype is of utmost importance in the tumor microenvironment, as M1-like macrophages produce prostaglandins and leukotrienes generating an inflammatory and pro-tumorigenic microenvironment, while M2-like macrophages translocate 5-LOX and 15-LOX-1 to produce resolvins and maresins in response to inflammatory bacteria stimuli (Werz et al., 2018) .

A critical difference between pro-resolution mediators ("resolving" inflammation) compared to anti-inflammation ("blocking" inflammation) is that while most anti-inflammatory agents can lead eventually to immunosuppression, the resolution of inflammation in an active endogenous reprogramming of the immune response to turn off inflammation without being immunosuppressive. In surgery-stimulated and chemotherapy-stimulated cancer models J o u r n a l P r e -p r o o f preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses . SPMs also promote the differentiation of B cells to be antibody-producing thus endogenously enhancing the adaptive immune system (Ramon, Gao, Serhan, & Phipps, 2012) . SPMs not only inhibit macrophage-derived pro-inflammatory cytokines but prevent activated CD8+ and CD4+ cells from releasing inflammatory cytokines without inhibiting T regulatory cells (Aoki et al., 2008; Aoki et al., 2010) . Thus, the resolution of inflammation via SPMs may be a novel approach to preventing carcinogen-induced cancers via downregulation of pro-inflammatory cytokines, suppression of neutrophil infiltration, reduced oxidative damage, and clearance of carcinogengenerated debris (Figure 4 ).

The most extensively studied SPMs in cancer biology at this time are the lipoxins (e.g.

LXA 4 ). Lipoxins suppress cancer cell proliferation in culture and in animal xenograft models inhibit tumor cell invasion (Y. Chen et al., 2010; Claria et al., 1996; Schottelius et al., 2002; X. Y. Zhou et al., 2009) . Lipoxins exhibit anti-inflammatory actions by inhibiting NF-κB signaling pathway (Gewirtz et al., 2002) . Lipoxins inhibit pro-inflammatory cytokines (IL-8) and adhesion molecule (i.e., ICAM-1) expression in human astrocytoma brain tumor cells (Decker, McBean, & Godson, 2009 Dai et al., 2019) . However, ATL-1 had no direct effect on cancer cell proliferation (Simoes et al., 2017) . Additionally, LXA 4 did not exert any direct anti-proliferative effect on liver cancer (H22 cells) (Y. Chen et al., 2010) .

Cancer progression including leukemia and colorectal cancer is associated with downregulation of lipoxins (H. Liu et al., 2019; Stenke et al., 1991) . reactive oxygen species as well as MMP9 and MMP2 (Zong et al., 2016) . In patients with pancreatic cancer, a low Lipoxin effect score (LES) has been observed. Specifically, a low LES tended to correlate with lymph node and distant metastasis. The "Lipoxin effect score" (LES) was the product of the immunohistochemistry scores of both 15-LOX and FPRL1. LES was correlated with aggressive metastatic potential in pancreatic tissue from pancreatic cancer patients (Zong et al., 2017) . In PDAC, human pancreatic stellate cells (hPSCs), the main precursors of pancreatic cancer associated fibroblasts (CAFs), become activated and induce fibrosis by secreting extracellular matrix, which presents a barrier to anti-cancer drugs (Schnittert, Heinrich, Kuninty, Storm, & Prakash, 2018) . Lipoxin A 4 can disrupt the pro-tumoral paracrine signaling of human (hPSCs) (Schnittert et al., 2018) . LXA 4 inhibited the activation of hPSCs into CAF-like myofibroblasts in vitro and inhibited hPSC-induced tumor-promoting activity (Schnittert et al., 2018) . LXA 4 can also inhibit renal and lung fibrosis (Mitchell et al., 2004; Roach, Feghali-Bostwick, Amrani, & Bradding, 2015) . Lipoxin A 4 also inhibited pancreatic tumor growth via anti-fibrotic mechanisms such as reduced collagen I expression and thus may increase the efficacy of chemotherapy and radiation in pancreatic cancer (Schnittert et al., 2018) . LXA 4 also reduced tumor angiogenesis as determined by a reduction in the endothelial marker CD31 (Schnittert et al., 2018) . In a liver metastasis model in nude mice, the LXA 4 analogue mimetic BML-111, could inhibit the metastasis of pancreatic cancer cells (Zong et al., 2017) . Lipoxin reverses mesenchymal phenotypes to attenuate invasion and metastasis via inhibition of autocrine TGF-β1 signaling in pancreatic cancer (Zong et al., 2017) . EMT is a metastasis-promoting process in which cancer cells lose epithelial phenotypes such as Ecadherin expression and acquire mesenchymal characteristics including elevated expression of N-cadherin and vimentin expression (Zong et al., 2017) .

Aspirin-triggered-lipoxin, 15-epi-LXA 4 analog, is a potent inhibitor of endothelial cell 

SPMs such as resolvins are entirely unique from traditional anti-inflammatory agents in that they actively promote resolution of inflammation via activation of macrophages to clear inflammatory cell debris and killing/clearing microbes, counter-regulate pro-inflammatory cytokines, and halt leukocyte infiltration to reduce the propagation of inflammation at piconanogram concentrations (Serhan, 2014) . Reduced resolvins have already proven to be critically involved in a number of autoimmune diseases characterized by uncontrolled inflammation (Serhan, 2014; Serhan & Levy, 2018) . S. Hong, Gronert, Devchand, Moussignac, & Serhan, 2003; Jin et al., 2009; Kasuga et al., 2008; Merched et al., 2008; Serhan et al., 2002; Spite et al., 2009; H. Tian, Lu, Sherwood, Hongqian, & Hong, 2009; Van Dyke & Serhan, 2003) . Clinical trials show increasing resolvin activity in inflammatory diseases such as dry eye inflammation and periodontal diseases can reduce local inflammation (Serhan & Levy, 2018) .

Demonstrating the importance of resolvins in cancer, the neutralization of Resolvin D1 receptor GPR32-mimics FPR1-silencing which increases angiogenesis and tumorigenesis of gastric cancer cells (Prevete et al., 2017) . Resolvins (e.g. RvE1) also inhibit the oncoprotein c-Myc expression which is overexpressed in a large variety of human cancers such as colon cancer (Zhong et al., 2018) .

attenuation of NF-κB signaling (Zhong et al., 2018) . RvD1 stimulated c-Myc degradation through direct interaction with the ALX/FPR2 receptor (Zhong et al., 2018) . RvD1 induces cytotoxic activity and elevated caspase-3 activity in natural killer (NK) cells in pancreatic ductal adenocarcinoma cells (PDAC) cells (Halder et al., 2015) . RvD1 and RvD2 also exhibited antiinflammatory activity by inhibiting LPS-interferon (IFN)-γ-induced M1 polarization as well as promoting interleukin-4 (IL-4)-mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. Thus, regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer (Shan et al., 2020) . The communication between human monocyte-derived M2-like macrophages (MDM) and cancer cells in co-incubations can strikingly modulate the biosynthetic capacities to produce bioactive LM including lipoxin A 4 , resolvin D2 and D5 were elevated after coculture with human A549 epithelial lung carcinoma cells (Werner et al., 2020) .

Current therapy for HCC and hepatoblastoma includes resection, transplantation, J o u r n a l P r e -p r o o f radiofrequency ablation, chemoembolization and sorafenib (Villanueva, Hernandez-Gea, & Llovet, 2013) . Resolvin D1 and E1 prevent liver injury and progression from hepatitis to liver cancer in murine models . Resolvins protect from acute liver injury (e.g.

carbon tetrachloride) (X. Chen et al., 2016) . Resolvin D1 and E1 prevent concanavalin A (Con A)-induced liver injury and the changes of hepatitis to liver cancer in mice by inhibition of inflammatory cytokine secretion and NF-κB/AP-1 activity . RvD1 and RvE1

inhibit Con A-induced liver injury, the production of TNF-α, IFN-γ, IL-2, IL-1β and IL-6, NF-κB and AP-1 signaling, TLR4, IκBα, IKKβ, MyD88, JNK, ERK and p38, and necrosis in mice . Resolvins (e.g. 17(R)-Resolvin D1) can regulate Toll-like receptor 4mediated inflammatory responses of human macrophages to LPS and E. coli (Palmer et al., 2011) . Resolvins (e.g. RvD1) also inhibits the proliferation of LPS-treated liver cancer cells and reduces the expression and release of TNF-α, IL-1β and IL-6 at the protein and mRNA levels in LPS-treated liver cancer cells (Lu et al., 2018) . In addition, RvD1 decreases p-ERK, p-JNK and p-p38 levels in LPS-treated liver cancer cells (Lu et al., 2018) .

Resolvins may have the potential to resolve damaging inflammation generated by tobacco smoke, one of the most widespread worldwide carcinogens. Chronic secondhand exposure to tobacco smoke stimulated the levels of pro-inflammatory cytokines IL-17A, IL-6, IL-1β, and TNF-α in the lungs and impairs bacterial clearance from the lungs (Bhat et al., 2018).

Pro-resolution mediators such as resolvins suppressed macrophage production of smokeinduced pro-inflammatory cytokines, enzymes, and lipid mediators (Croasdell et al., 2015) .

Resolvins also increased anti-inflammatory cytokines, promoted an M2 macrophage phenotype, and restored cigarette smoke-induced defects in phagocytosis (Croasdell et al., 2015) . Resolvin D1 (RvD1) suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. RvD1 administered with cigarette smoke exposure reduced J o u r n a l P r e -p r o o f neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10 in mice (Hsiao et al., 2013) .

Alarmins such as high-mobility group box 1 (HMGB1) can disrupt the resolution of inflammation by inhibiting macrophage efferocytosis induced by SPMs (G. J. Kang et al., 2015) .

HMGB1 plays an important role in maintaining inflammation and can be actively released from various immune cells such as macrophages, monocytes, NK cells, dendritic cells, and endothelial cells, as well as from dead (e.g necrotic) cells (Scaffidi, Misteli, & Bianchi, 2002) . Kang et al., 2015) . Hepatocellular carcinoma ensues in the presence of excessive hepatic apoptosis and necroptosis in the tumor microenvironment which directs lineage commitment to either hepatocellular carcinoma or intrahepatic cholangiocarcinoma (Seehawer et al., 2018) . The clearance of necroptotic cells are inefficiently taken up by macrophages in diseases characterized by impaired inflammation resolution (Gerlach et al., 2020) . Necroptotic cells are inefficiently taken up by macrophages because they have increased surface expression of CD47, a "don't eat me" signal (Gerlach et al., 2020) . Resolvin D1 enhanced the clearance of necroptotic cells in advanced murine plaques by the release of the "eat me signal" calreticulin from macrophages in a CDC42 dependent manner (Gerlach et al., 2020) .

Evidence in humans demonstrates the importance of pro-resolving lipid mediators in the cancer patients. The pro-inflammatory response in response to hepatobiliary surgery is associated with low circulating concentrations of lipoxin A 4 and resolvins of the D series which were the opposite of IL-6 and cortisol which were elevated after surgery for liver tumors (Cata et al., 2017) . The systemic inflammatory markers in the plasma C-reactive protein (CRP) and

interleukin-6 were decreased in lung cancer patients administered EPA and DHA supplementation undergoing chemotherapy in a double-blind placebo-controlled study (Finocchiaro et al., 2012) . In another study, compared with healthy volunteers, the levels of serum pro-inflammatory cytokines in colon cancer patients increase while the level of RvD1 decreased significantly associated with higher TNM stage of colon cancer (Zhuang, Meng, Xi, & Wu, 2018) . Concentrations of IL-6, IL-1β, IL-10 and TNF-α gradually increased with the advancement of TNM staging (Zhuang et al., 2018) . In stage III, concentrations of IL-6, IL-1β, and IL-10 were the highest, TNF-α concentration was the highest in stage IV. RvD1 concentration gradually decreased with the advancement of TNM staging (Zhuang et al., 2018) .

Resolvin E1 (RvE1) plays an key role in the resolution of acute inflammation when immunonutrition is supplemented with EPA in patients undergoing a severely stressful operation (Uno et al., 2016) . Pre-operative immunonutrition reduced pro-inflammatory responses and protected against the aggravation of post-operative complications in patients undergoing major hepatobiliary resection (Uno et al., 2016) . In clinical randomized trials focused on dietary interventions that can boost SPMs, omega-3 fatty acids increased resolvins (e.g. RvE1) in patients undergoing hepatobiliary surgery for liver cancer, resulting in lower rates of infections, complications, and disease progression (Uno et al., 2016) . The omega-3 fatty acid Lovaza J o u r n a l P r e -p r o o f stimulates SPM production in coronary artery disease patients (Elajami et al., 2016) . SPMs were also boosted in military personnel and in traumatic brain injury patients administered with substrate supplementation (Bisicchia et al., 2018) . Peripheral blood markers of inflammation as well as inflammation resolution markers (e.g. resolvins) have been identified in cancer patients.

ω-3 PUFAs exhibit anti-tumor activity in a variety of cancers such as breast cancer. SPMs may account for the anti-inflammatory and anti-cancer activity of ω-3 PUFA at least in part.

Maresins (e.g. MaR1) can also inhibit EMT of mouse type II alveolar epithelial cells and improve bleomycin-induced lung fibrosis (Y. Wang et al., 2015) . Protectin DX (PDX), a PD1

isomer that is a double lipoxygenation product, reverses bleomycin-induced lung fibrosis by reversing EMT and alleviates acute kidney injury (Duffield et al., 2006; .

Docosahexaenoic acid (DHA) with A549 lung cancer cells can generate maresins (e.g. MaR1 )

and protectins (e.g. PD1/NPD1 ) . The role of maresins and protectins in cancer remain of interest in the years ahead now that they are widely available.

In addition to SPMs, inflammation resolution is also controlled by a variety of endogenous mediators including protein/peptide mediators, such as annexin A1 and annexin A1-derived peptides which stimulate inflammation resolution (Perretti et al., 2002) . Interestingly, estrogen can stimulate resolution of inflammation in macrophages (Villa, Rizzi, Vegeto, Ciana, & Maggi, 2015) . Wallace, Ianaro, Flannigan, & Cirino, 2015) . Drugs that stimulate resolution include aspirin, statins, omega-3 fatty acids, annexin A1 and annexin A1-derived peptides, statins, glucocorticoids, diclofenac, α-melanocyte stimulating hormone, erythropoietin, kinase inhibitors, galectins, chemerin, adrenocorticotropic hormone, gaseous mediators (e.g. hydrogen sulfide and carbon monoxide), purine (adenosine) as well as neuromediators and pioglitazone (Serhan & Levy, 2018) . Drugs that may be resolution toxic include NSAIDs, COX-2 inhibitors, and lidocaine which impair efferocytosis (Serhan & Levy, 2018) .

Both omega-3 fatty acids and aspirin, which are known to reduce cancer risk, trigger the body"s production of resolvins (Y. P. Sun et al., 2007) . Although resolvins inhibit primary tumor growth at doses over 10,000 fold less than omega-3 fatty acids, due to their rapid metabolism in vivo, an alternative approach for clinical application of SPMs in cancer is to increase their endogenous synthesis through dietary and pharmacologic intervention (Serhan, 2014) . Omega-3 polyunsaturated fatty acids are precursors for many SPMs; for example, DHA is the substrate that aspirin-acetylated COX-2 converts to aspirin-triggered resolvins (e.g. AT-RvD1). In human subjects, dietary intake of DHA and EPA with aspirin treatment effectively increased plasma resolvin levels (Serhan, 2014) . Similarly, mice fed a high omega-3 diet exhibited high levels of resolvins and omega-3 fatty acids in their tissues, serum, and plasma.

Thus, dietary interventions have been suggested as an approach to carcinogen associated inflammation. For example, in a DMBA-induced mammary carcinogenesis model low dose EPA and DHA demonstrated chemopreventive activity (Noguchi et al., 1997) . A diet high J o u r n a l P r e -p r o o f in omega-3s opposes the western diet, high in omega-6 fatty acids, which promotes inflammatory macrophage-and colitis-associated colon carcinogenesis (I. W. Kim et al., 2010) .

Importantly, DHA supplementation may increase the efficacy of HCCA patients receiving sorafenib via increased anti-angiogenic and anti-tumorigenic lipids such as 19,20epoxydocosapentaenoic acid (EDP) (Leineweber et al., 2020; G. Zhang, D. Panigrahy, et al., 2013) . Additionally, diets, based off elite crop varieties containing anticancer effects have been demonstrated to reduce hepatocarcinogenesis from NDEA by downregulating TNF-α/IL-6, increasing antioxidants, and increasing apoptosis without stimulating regenerative proliferation (J. Zheng et al., 2019) . Additionally, EPA suppressed IL-6-induced chronic inflammation in high fat diet and carcinogen-induced HCC (Inoue-Yamauchi, Itagaki, & Oda, 2018) . In a colon cancer model EPA also reduced MMP9 cytokine production via NOTCH1 signaling to exhibit protective effects (Fazio et al., 2016) . Alternatively, caloric restriction has been suggested as a mechanism to alter metabolic pathways in NDEA-induced HCC rather than diet leading to altered inflammation, oxidative stress, cell migration, injury and oncogenesis (Ploeger, Manivel, Boatner, & Mashek, 2017) . Human plasma and serum found to consist of eicosanoids and SPMs, additional omega-3 or acetylsalicylic acid supplementation also increased plasma SPM levels inducing increased phagocytosis (Colas, Shinohara, Dalli, Chiang, & Serhan, 2014) . In a randomized double blinded placebo controlled study marine oil supplements containing fatty acid precursors increased SPM levels in blood samples and reprogramed blood cells to a proresolution phenotype (Souza et al., 2020) . Thus, the beneficial activity of diets on lipid production may depend on the pre-existing tumor lipid microenvironment (Djuric et al., 2017) . While fish oils have been suggested as an important source of antioxidants one group found environmental pollutants to outweigh the benefits of antioxidants in fish oil without proper regulation of persistent organic pollutants (M. Y. Hong et al., 2017) . In a study of women diagnosed with breast cancer omega-3 fatty acid intake did not affect overall breast cancer risk, although it did marginally reduce the risk of estrogen and progesterone receptor positive breast cancers, which was increased with omega-6 fatty acid intake (Kiyabu et al., 2015) .

Epoxyeicosatrienoic acid (EETs) are lipid signaling molecules which act as autocrine and paracrine mediators of proliferation, migration, and inflammation in several tissues (Spector & Norris, 2007) . EETs are fatty acid epoxides (EpFA) produced via the epoxidation of arachidonic acid catalyzed by cytochrome P450 (CYP) enzymes. Most CYP enzymes are general oxidases showing varying degrees of selectivity for the substrate and the product formed. In normal animals CYP2C8 or CYP2J2 appear largely responsible for production of EpFA and are metabolized by soluble epoxide hydrolase (sEH) to the corresponding 1, 2-diols.

Members of the CYP4A, CYP2C, and CYP2J families of epoxygenases are among the most extensively studied (Fleming, 2007) , however, in animals with induced cytochrome P450s other J o u r n a l P r e -p r o o f Journal Pre-proof families may dominant production of EpFA. While CYP4A enzymes produce the vasoconstrictor 20-hydroxyeicosatrienoic acid (20-HETE), the CYP2C and CYP2J enzymes convert arachidonic acid to the bioactive epoxyeicosatrienoic acids (EETs), including 5, 8, 11, and 14, EETs are metabolized by soluble epoxide hydrolase (sEH) to less active dihydroxyeicosanoic acids (DHETs). EETs, which function primarily as autocrine and paracrine mediators of arachidonic acid-induced relaxation in the cardiovascular and renal systems, are short-lived and quickly metabolized in most tissues (Campbell & Falck, 2007; Fleming, 2008) .

EETs secreted mainly by endothelial cells have critical roles in cellular proliferation, migration and inflammation; their major target cells are blood vessels (Spector & Norris, 2007) . The EET producing enzymes of the CYP2C and CYP2J subfamilies have been found in endothelial cells (ECs) in vitro and in vivo (Fleming, 2007; Pozzi et al., 2005) . Poly-unsaturated fatty acids also generate EETs which are metabolites of the omega-6 fatty acid arachidonic acid (Lopez-Vicario et al., 2015; G. Zhang, D. Panigrahy, et al., 2013) .

EETs may potently downregulate endoplasmic reticulum (ER) stress responses as demonstrated in response to cigarette smoke damage (Yu et al., 2015) . Thus, inhibition of sEH may allow for their stability and prolonged effects and has demonstrated pro-resolution activity such as stimulation of SPMs and activating anti-cytokine programs in multiple inflammatory diseases, including those which are risk factors for cancer induction (Schmelzer et al., 2005 ; W. Yu et al., 2015) . Importantly, the sEH eicosanoid pathway has been suggested to be involved in the progression of colorectal cancer, including obesityassociated cancer (J. Zhang, Sanidad, & Zhang, 2019) . Inflammatory mediators, including J o u r n a l P r e -p r o o f angiotensin, TNF-α and NF-κB can upregulate sEH expression in immune cells (Bastan et al., 2018) . sEH inhibitors (sEHI) downregulate NF-κB and other inflammatory markers leading to decreased pro-inflammatory cytokines and nitric oxide metabolites and upregulates lipoxins to generate resolution (Schmelzer et al., 2005) . In addition to downregulating a series of proinflammatory cytokines, EETs promote macrophage phagocytosis (Bystrom et al., 2013) , which may have implications for the clearance of carcinogen-generated dead cells. Importantly, inhibition of sEH also promotes the generation of SPMs such as lipoxin generation (Ono et al., 2014) . A metabolomics approach identified a critical role for cytochrome P450 (CYP)-generated epoxygenerated fatty acids and sEH-mediated eicosanoids were elevated in the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer (W. Wang et al., 2019) .

However, the role of EETs in cancer is complex as these epoxyeicosanoids may stimulate pro-angiogenic and pro-tumorigenic mechanisms (Imig & Hammock, 2009; Panigrahy et al., 2012) . The CYP3A4 produced EETs play a role in breast cancer progression, including in tamoxifen-resistant subsets via proliferation, angiogenesis, and migration (Thuy Phuong et al., 2017) . While EETs can be mildly pro-angiogenic, inhibition of sEH prevents angiogenic diseases such as diabetic retinopathy (J. Hu et al., 2017) . Interestingly, EET-induced angiogenesis is suppressed by simultaneous inhibition of COX-2 by preventing COX mediated metabolism to pro-angiogenic lipids (Rand et al., 2019) . Importantly, sEHIs may also reduce the toxicities of NSAIDs and COX-2 inhibitors via anti-inflammation and inhibition of oxidative injury as well as barrier breakdown (R. D. Jones et al., 2019) . To minimize the pro-angiogenic activity of sEH inhibitor and the GI toxicity of COX-2 inhibitors, a novel COX-2/sEH inhibitor (PTUPB) was synthesized which potently inhibits inflammation (Hwang et al., 2011) . F. Zhang et al., 2020) . Dual COX-2/sEH inhibition inhibits primary tumor growth including glioblastoma growth, metastasis and potentiates the antitumor efficacy of chemotherapeutic agents such as cisplatin (J. Li et al., 2017; F. Wang et al., 2018; G. Zhang et al., 2014) . A novel dual COX-2/sEH inhibitor (PTUPB) inhibits debris-stimulated ovarian tumor growth by preventing an eicosanoid and cytokine surge of pro-inflammatory and pro-angiogenic mediators (Gartung et al., 2019) . PTUPB inhibits high-fat diet-induced non-alcoholic fatty liver disease via inhibition of fibrosis, collagen deposition and pro-inflammatory cytokines (C. C. Sun et al., 2020) . sEH is a therapeutic target as it is upregulated in obesity-induced colonic inflammation and sEH inhibition reduces obesity-induced activation of Wnt signaling in mice (W. . Notably, carcinogen-induced cell death dose-dependently promotes tumor dormancy escape and progression by triggering oxidative stress as well as an eicosanoid/cytokine storm of pro-inflammatory mediators (Fishbein et al., 2020) . In contrast, dual COX-2/sEH inhibition prevents inflammation-initiated tumor growth by preventing the eicosanoid/cytokine storm and reducing oxidative stress, as well as by promoting macrophage-mediated efferocytosis of tumor debris (Fishbein et al., 2020) . Thus, inhibition of sEH may synergize with COX-2 inhibition while reducing the toxicity of COX-2 inhibition.

Thus, EETs may additionally be a novel approach to resolving carcinogen-induced inflammation via anti-inflammatory signaling and stimulation of macrophage phagocytosis.

Importantly, in bronchiolar cells in which oxidative stress reduced lipoxin production, sEHIs stimulated pro-resolution mechanisms by stimulating the levels of lipoxins (Ono et al., 2014) .

Stimulation of resolution of inflammation, via SPMs or EETs, may be a novel chemopreventive J o u r n a l P r e -p r o o f approach to carcinogen-induced cycles of inflammation, cell death, oxidative stress, and carcinogenesis ( Figure 4 ).

Cancer accounts for over 8 million deaths annually worldwide and presents one of the largest disease morbidity and mortality (Cortes et al., 2020) . Carcinogens continue to play a large role in the disease and social burdens of cancer globally.

However, genotoxic mechanisms alone may not be sufficient for carcinogenesis and increased tumor risk (Bogen, 2019; Johnson et al., 2014) , and more studies are required to further characterize nongenotoxic mechanisms including "failed" inflammation resolution. There is a malignant pro-tumorigenic feedback loop between apoptosis, inflammation, DNA damage, and carcinogenesis. Chronic inflammation and oxidative stress are largely intertwined processes which contribute via feedback loops to a microenvironment of stress, injury, and regeneration (Nowsheen et al., 2012) . Initial carcinogen exposure induces inflammatory pathways and signaling through NF-κB leads to cytokine production, inflammatory infiltrates, and reactive oxygen species in a pro-tumorigenic environment. Controlling the local and systemic inflammatory response will be essential to prevent carcinogen-induced cancers. Stimulation of J o u r n a l P r e -p r o o f resolution via supplementation of specifically pro-resolution lipid mediators may be a potent and less toxic non-immunosuppressive approach to reduce and prevent carcinogenesis at an early stage (Gilligan et al., 2019) . Importantly, SPMs, including resolvins, lipoxins, and protectins, as well as sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of carcinogen-induced cancers. Pro-resolution therapies can complement current anti-carcinogen strategies via debris clearance and inflammatory cytokine suppression. Further studies including human cancer trials are needed to evaluate the stimulation of resolution of inflammation to prevent and treat carcinogen-induced cancers. Represents the 10 key characteristics of carcinogens adapted from Table 1 in (M. T. Smith et al., 2016) . Aflatoxin B 1 as an example of a carcinogen which undergoes 1. Metabolic activation 2. Is genotoxic 3. Alters DNA repair 4. Leads to epigenetic alterations 5. Generates oxidative stress, 6. Chronic inflammation, and 7. Immunosuppression 8. Activates receptor mediated signaling 9. Causes cell immortalization and 10. Increases cell proliferation. Adapted from Smith et al Environmental Health Perspectives 124:6 2016.

A) Intraperitoneal injection of male Sprague-Dawley rats with 30 mg/kg Diethylnitrosamine (DEN) twice a week for 11 weeks led to hepatocellular carcinoma B) Male C57BL/6J mice or BALB/c mice injected intraperitoneally week one with 10 mg/kg azoxymethane (AOM) and one week later given 1.5% or 2% dextran sodium sulfate (DSS) in the drinking water for one week leading to colon carcinomas. C) Male F344 rats given 20 p.p.m. 4-nitroquinoline 1-oxide (4-NQO) in drinking water for 10 weeks led to tongue squamous cell carcinoma or papilloma. D) NMRI mice exposed to single epicutaneous application of 0.1 µmol 7,12dimethylbenz[a]anthracene (DMBA) in acetone and two weeks later exposed twice a week to 5nmol phorbol 12-myrisate 13-acetate (PMA) for 28 weeks leading to skin papilloma and carcinoma. E) Male A/J mice were injected intraperitoneally with 50 mg/kg 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone (NNK)) for 4 weeks led to lung adenocarcinoma. F) Male F344 rats injected subcutaneously with 1mg/kg Nnitrosomethylbenzylamine (NMBA) 5 times a week for 5 weeks and then once a week for 5 more weeks led to esophageal papilloma and carcinomas. Following carcinogen exposure inflammation is induced leading to inflammatory infiltrates at the location of exposure. With the upregulation of NF-κB, COX-2, and 5-LOX inflammatory cells are triggered to release a storm of pro-inflammatory and tissue regenerative eicosanoids, cytokines, and reactive oxygen species. The factors generate DNA mutations, cell damage, and epigenetic alterations leading to cellular transformation. In addition, the inflammation and oxidative stress leads to upregulated anti-apoptotic mechanisms, angiogenesis, and DNA damage but downregulated DNA repair, immune surveillance, and resolution. Together, these processes driven by carcinogen induced inflammation alter the microenvironment allowing for extracellular matrix remodeling, cytotoxicity and damage-associated molecular pattern (DAMP) signaling, and regenerative proliferation resulting in tumor growth.

Carcinogen (NDEA) induced inflammation causes tissue damage and cell death of normal cells (hepatocytes) generating cellular debris. These dead cells activate local macrophages (Kupffer cells) to a pro-inflammatory phenotype generating a cytokine storm. This chronic inflammation reduces pro-resolving mediators including SPMs and EETs and signals for angiogenesis, fibrosis, and inflammatory cell infiltration. Infiltrating white blood cells add to the tissue injury by producing reactive oxygen and nitrogen species triggering the upregulation of NF-κB, COX-2, 5-LOX, and MMPs in surrounding hepatocytes generating a vicious cycle leading to tumor growth. However, resolution of inflammation via SPMs or sEH inhibition may break this pro-tumorigenic J o u r n a l P r e -p r o o f cycle. Resolution promotes macrophage phagocytosis of cellular debris, inhibits the cytokine storm, suppresses inflammatory infiltration, and is not immunosuppressive leading to the downregulation of NF-κB, COX-2, 5-LOX, and MMPs and inhibition of carcinogenesis. Represents the 10 key characteristics of carcinogens adapted from Table 1 in (M. T. Smith et al., 2016) . Aflatoxin B 1 as an example of a carcinogen which undergoes 1. Metabolic activation 2. Is genotoxic 3. Alters DNA repair 4. Leads to epigenetic alterations 5. Generates oxidative stress, 6. Chronic inflammation, and 7. Immunosuppression 8. Activates receptor mediated signaling 9. Causes cell immortalization and 10. Increases cell proliferation. Adapted from Smith et al Environmental Health Perspectives 124:6 2016.

J o u r n a l P r e -p r o o f

Interaction of aflatoxin B1 and fumonisin B1 in mice causes immunotoxicity and oxidative stress: Possible protective role using lactic acid bacteria

Inflammation and cancer: how hot is the link?

Proteomic approach to identify molecular signatures during experimental hepatic fibrosis and resveratrol supplementation

N-nitrosodiethylamine genotoxicity evaluation: a cytochrome P450 induction study in rat hepatocytes

N-Nitrosodiethylamine mutagenicity at low concentrations

Standardization of conditions for the metabolic activation of N-nitrosodiethylamine in mutagenicity tests

Immunohistochemical, histopathological study and chemoprotective effect of Solanum nigrum in N-nitrosodiethylamine-induced hepatocellular carcinoma in Wistar rats

Preventing inflammation inhibits biopsy-mediated changes in tumor cell behavior

VEGF-C and VEGF-D Blockade Inhibits Inflammatory Skin Carcinogenesis

A metabolomics investigation of non-genotoxic carcinogenicity in the rat

Resolvins: Current understanding and future potential in the control of inflammation

Molecular circuits of resolution: formation and actions of resolvins and protectins

Modulation of Nnitrosodiethylamine (NDEA) induced oxidative stress by vitamin E in rat erythrocytes

Protective role of Vitamin E pretreatment on N-nitrosodiethylamine induced oxidative stress in rat liver

Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation

Lipopolysaccharide augments aflatoxin B(1)-induced liver injury through neutrophil-dependent and -independent mechanisms

Exposure of humans to endogenous N-nitroso compounds: implications in cancer etiology

Inhibition of soluble epoxide hydrolase attenuates eosinophil recruitment and food allergen-induced gastrointestinal inflammation

Hepatitis B virus. The major etiology of hepatocellular carcinoma

Inducible NO synthase: role in cellular signalling

Phenotypical characterization of changes in thymus and spleen associated with lymphoid depletion in free-ranging harbor porpoises (Phocoena phocoena)

Omega-3 fatty acidderived mediators 17(R)-hydroxy docosahexaenoic acid

Key Determinant of Liver Cancer Development

Inflammation as a Cancer Co-Initiator: New Mechanistic Model Predicts Low/Negligible Risk at Noninflammatory Carcinogen Doses

Animal Species in which N-nitroso compounds induce cancer

Cyclooxygenase-2 overexpression in the skin of transgenic mice results in suppression of tumor development

Resolving the dark side of therapy-driven cancer cell death

The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism

Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]-induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway

In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat

Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies

Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis: a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease?

MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors

Radiation therapy to a primary tumor accelerates metastatic growth in mice

The role of lipoxin A4 in endometrial biology and endometriosis

FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Piroxicam is an ineffective inhibitor of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus

Inflammation and pro-resolution inflammation after hepatobiliary surgery

ATL-1, an analogue of aspirin-triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor

EMT, cell plasticity and metastasis

Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis

Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

UVB-irradiated apoptotic cells induce accelerated growth of co-implanted viable tumor cells in immune competent mice

Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma

Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy

Aflatoxin B1 DNA adducts in smeared tumor tissue from patients with hepatocellular carcinoma

Cell apoptosis induced by carcinogenic metals

Effects of aflatoxin B1 on oxidative stress markers and apoptosis of spleens in broilers

Influence of nitrogen source on NDMA formation during chlorination of diuron

Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice

Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol

Lipoxin A4 and its analogue suppress the tumor growth of transplanted H22 in mice: the role of antiangiogenesis

Resolvin D4 attenuates the severity of pathological thrombosis in mice

Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation

Identification of resolvin D2 receptor mediating resolution of infections and organ protection

Infection regulates pro-resolving mediators that lower antibiotic requirements

Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions

Flaxseed Consumption Inhibits Chemically Induced Lung Tumorigenesis and Modulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/J Mice

Host pathogen interactions in Helicobacter pylori related gastric cancer

Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption

Possible roles of excess tryptophan metabolites in cancer

Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation

Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions

Altered biosynthesis of leukotrienes and lipoxins and host defense disorders in patients with J o u r n a l P r e -p r o o f cirrhosis and ascites

Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo

Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue

The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus)

Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Caught in the cross fire: p53 in inflammation

In vitro evaluation of the immunotoxic potential of perfluorinated compounds (PFCs)

Enhancing global access to cancer medicines

Resolvins attenuate inflammation and promote resolution in cigarette smokeexposed human macrophages

Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy

Prognostic significance of Creactive protein in urological cancers: a systematic review and meta-analysis

Lipoxin A4 Suppresses IL-1beta-Induced Cyclooxygenase-2 Expression Through Inhibition of p38 MAPK Activation in Endometriosis

A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually

Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents

Identification and Complete Stereochemical Assignments of the New Resolvin Conjugates in Tissue Regeneration in Human Tissues that Stimulate Proresolving Phagocyte Functions and Tissue Regeneration

Inflammation in prostate carcinogenesis

Altered prostanoid signaling contributes to increased skin tumorigenesis in Tpl2 knockout mice

Lipoxin A4 inhibits IL-1beta-induced IL-8 and ICAM-1 expression in 1321N1 human astrocytoma cells

Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens

Mass spectrometric methodology for the determination of glyoxaldeoxyguanosine and O6-hydroxyethyldeoxyguanosine DNA adducts produced by nitrosamine bident carcinogens

Immunosuppression by chronic exposure to N-nitrosodimethylamine (NDMA) in mice

The PPARalpha-leukotriene B4 pathway to inflammation control

Increases in levels of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EETs and DHETs) in liver and heart in vivo by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in hepatic EET:DHET ratios by cotreatment with TCDD and the soluble epoxide hydrolase inhibitor AUDA

An internally validated new clinical and inflammation-based prognostic score for patients with advanced hepatocellular carcinoma treated with sorafenib

Role of the epidermal growth factor receptor and transforming growth factor alpha in mouse skin carcinogenesis

Effect Of Dual sEH/COX-2 Inhibition on Allergen-Induced Airway Inflammation

Hepatic inflammation-fibrosiscancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine

Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible

Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B(1) as an example

High-saturate-fat diet delays initiation of diethylnitrosamine-induced hepatocellular carcinoma

A novel human anti-AXL monoclonal antibody attenuates tumour cell migration

The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers

Resolvin D series and protectin D1 mitigate acute kidney injury

Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing

Of mice, rats, and men: could Nrf2 activation protect against aflatoxin heptocarcinogenesis in humans?

Thiamethoxam induced hepatotoxicity and pro-carcinogenicity in rabbits via motivation of oxidative stress, inflammation, and anti-apoptotic pathway

Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling

Genotoxicity of environmental agents in human mammary epithelial cells

Anti-tumorpromoting activities of agaro-oligosaccharides on two-stage mouse skin carcinogenesis

Tumour-microenvironmental blood flow determines a metabolomic signature identifying lysophospholipids and resolvin D as biomarkers in endometrial cancer patients

Studies on the Presence of Mycotoxins in Biological Samples: An Overview. Toxins (Basel)

The inflammatory inception of gallbladder cancer

Profiling cytochrome P450 family 4 gene expression in human hepatocellular carcinoma

A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer

Inflammation increases NOTCH1 activity via MMP9 and is counteracted by Eicosapentaenoic Acid-free fatty acid in colon cancer cells

Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation

Modernizing Human Cancer Risk Assessment of Therapeutics

Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4)

Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study

Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage

Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammationinitiated hepatocellular cancer progression

Development of a tolerable daily intake for Nnitrosodimethylamine using a modified benchmark dose methodology

Epoxyeicosatrienoic acids, cell signaling and angiogenesis

Vascular cytochrome p450 enzymes: physiology and pathophysiology

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Harrison's Textbook of Internal Medicine

Angiogenesis: an organizing principle for drug discovery?

Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma

Cancer surgery induces inflammation, immunosuppression and neo-angiogenesis, but is it influenced by analgesics? F1000Res

An imbalance between specialized pro-resolving lipid mediators and proinflammatory leukotrienes promotes instability of atherosclerotic plaques

Association between smoking and risk of bladder cancer among men and women

The mythos of laudable pus along with an explanation for its origin

Tumor promoters: from chemicals to inflammatory proteins

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Molecular mechanisms in the pathogenesis of N-nitrosodimethylamine induced hepatic fibrosis

Alteration of Trace Elements during Pathogenesis of N-Nitrosodimethylamine Induced Hepatic Fibrosis

Resolvin D1 promotes the targeting and clearance of necroptotic cells

Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfateinduced colitis

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion

New insights into the role of COX 2 in inflammation

Inducible cyclooxygenase may have anti-inflammatory properties

Inflammatory resolution: new opportunities for drug discovery

Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection

Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins

Regulation of inflammation in cancer by eicosanoids

Inflammation and Cancer: Triggers, Mechanisms, and Consequences

International Agency for Research on Cancer Monograph Working

Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence

Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice

Evidence for induction of a tumor metastasis-receptive microenvironment for ovarian cancer cells in bone marrow and other organs as an unwanted and underestimated side effect of chemotherapy/radiotherapy

Expression of CYP4A1 in U251 human glioma cell induces hyperproliferative phenotype in vitro and rapidly growing tumors in vivo

Ethanol promotes chemically induced oral cancer in mice through activation of the 5-lipoxygenase pathway of arachidonic acid metabolism

Key Characteristics Approach to Carcinogenic Hazard Identification

Application of the key characteristics of carcinogens in cancer hazard identification

HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis

Lifetime exposure to rubber dusts, fumes and N-nitrosamines and cancer mortality in a cohort of British rubber workers with 49 years follow-up

Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis

Effects of N-nitrosodimethylamine on cellmediated immunity

Suppression of humoral antibody production by exposure to 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin

Effects of Nnitrosodimethylamine on humoral immunity

Metabolism of carcinogenic nitrosamines by rat nasal mucosa and the effect of diallyl sulfide

Fish Oil Contaminated with Persistent Organic Pollutants Induces Colonic Aberrant Crypt Foci Formation and Reduces Antioxidant Enzyme Gene Expression in Rats

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells

A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation

Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

NLRP3 deletion inhibits inflammation-driven mouse lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide

Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis

Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy

Breast cancer risk reduction: no pain, no gain?

Chemical agents and related occupations

Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase

Genome-wide DNA methylation changes in transformed foci induced by nongenotoxic carcinogens

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat

Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases

Eicosapentaenoic acid attenuates obesityrelated hepatocellular carcinogenesis

Expression of selected proteins of the extrinsic and intrinsic pathways of apoptosis in human leukocytes exposed to N-nitrosodimethylamine

The influence of very low doses of Nnitrosodimethylamine (NDMA) on the apoptosis of rat neutrophils in vivo. The role of reactive oxygen species

The effect of N-nitrosodimethylamine (NDMA) on Bax and Mcl-1 expression in human neutrophils

The Effect of Nnitrosodimethylamine on TRAIL and DR5 expression in human neutrophils--preliminary study

Increased incidence of aflatoxin B1-induced liver tumors in hepatitis virus C transgenic mice

Impact of conjugated linoleic acid administered to rats prior and after carcinogenic agent on arachidonic and linoleic acid metabolites in serum and tumors

Protective effects of diallyl sulfide on Nnitrosodimethylamine-induced immunosuppression in mice

Dark Side of Cytotoxic Therapy: Chemoradiation-Induced Cell Death and Tumor Repopulation

Antiangiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators

Tumor necrosis factoralpha promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells

Epidemiology and etiology of bladder cancer

Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold

Advances in metal-induced oxidative stress and human disease

On the Cause of the Localization of Secondary Tumors at Points of Injury

Epoxy-Oxylipins and Soluble Epoxide Hydrolase Metabolic Pathway as Targets for NSAID-Induced Gastroenteropathy and Inflammation-Associated Carcinogenesis

Therapeutic targeting of the tumor microenvironment

A gammatocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice

Application of the Adverse Outcome Pathway Framework to Risk Assessment for Predicting Carcinogenicity of Chemicals

Highmobility group box 1 suppresses resolvin D1-induced phagocytosis via induction of resolvin D1-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase

Role of CYP2E1 in diethylnitrosamine-induced hepatocarcinogenesis in vivo

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

NF-kappaB as a critical link between inflammation and cancer

NF-kappaB: linking inflammation and immunity to cancer development and progression

Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway

Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution

CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis

Inflammation-induced DNA damage, mutations and cancer

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

5H-benzo[h]thiazolo[2,3-b]quinazolines ameliorate NDEA-induced hepatocellular carcinogenesis in rats through IL-6 downregulation along with oxidative and metabolic stress reduction

Connexin 43 plays an important role in the transformation of cholangiocytes with Clonochis sinensis excretory-secretory protein and N-nitrosodimethylamine

Westernstyle diets induce macrophage infiltration and contribute to colitis-associated

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Citral inhibits N-nitrosodiethylamine-induced hepatocellular carcinoma via modulation of antioxidants and xenobiotic-metabolizing enzymes

Pretreatment of carprofen impaired initiation of inflammatory-and overlapping resolution response and promoted cardiorenal syndrome in heart failure

Resolvin D1 and E1 alleviate the progress of hepatitis toward liver cancer in long-term concanavalin A-induced mice through inhibition of NF-kappaB activity

Inflammatory Alteration of Human T Cells Exposed Continuously to Asbestos

Human lung fibroblasts produce proresolving peroxisome proliferatoractivated receptor-gamma ligands in a cyclooxygenase-2-dependent manner

Inhibition of lung cancer growth in mice by dietary mixed tocopherols

Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini-infected and N-nitrosodimethylamine-treated hamsters

Epithelial-mesenchymal transition: Initiation by cues from chronic inflammatory tumor microenvironment and termination by anti-inflammatory compounds and specialized pro-resolving lipids

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma

Resolvin D1 inhibits TGF-beta1-induced epithelial mesenchymal transition of A549 lung cancer cells via lipoxin A4 receptor/formyl peptide receptor 2 and GPR32

Surgical stress promotes tumor growth in ovarian carcinoma

The role of hepatocyte heterogeneity in the initiation of hepatocarcinogenesis

Investigating the different mechanisms of genotoxic and non-genotoxic carcinogens by a gene set analysis

Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma

Diminished lipoxin biosynthesis in severe asthma

Lipid mediator class switching during acute inflammation: signals in resolution

Glucocorticoids promote the development of azoxymethane and dextran sulfate sodium-induced colorectal carcinoma in mice

Role of Resolvins in the Inflammatory Resolution of Neurological Diseases

Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration

Posttreatment with Protectin DX ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice

COX-2/sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor

Cancer-associated fibroblasts promote the stemness of CD24(+) liver cells via paracrine signaling

NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice

Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG

Chemoprevention of elite tea variety CFT-1 rich in EGCG against chemically induced liver cancer in rats

Inflammation in atherosclerosis

A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin

Induction of urinary bladder tumors in rats by administration nitrosomethyldodecylamine

Induction of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma during nitric oxide-induced apoptotic PC12 cell death

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Neutrophil-lymphocyte Ratio Plus Prognostic Nutritional Index Predicts the Outcomes of Patients with Unresectable Hepatocellular Carcinoma After Transarterial Chemoembolization

High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine

Colorectal Cancer Is Associated with a Deficiency of Lipoxin A4, an Endogenous Anti-inflammatory Mediator

Protectin DX, a double lipoxygenase product of DHA, inhibits both ROS production in human neutrophils and cyclooxygenase activities

Mitochondrial damage mediates genotoxicity of arsenic in mammalian cells

Development of a nanobody-alkaline phosphatase fusion protein and its application in a highly sensitive direct competitive fluorescence enzyme immunoassay for detection of ochratoxin A in cereal

Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment

Genotoxic evaluation of the non-halogenated disinfection by-products nitrosodimethylamine and nitrosodiethylamine

Viral, host and environmental risk factors for hepatocellular carcinoma: a prospective study in Haimen City

IL-6 and IL-8 Serum Levels Predict Tumor Response and Overall Survival after TACE for Primary and Secondary Hepatic Malignancies

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides

Resolvin D1 inhibits the proliferation of lipopolysaccharide-treated HepG2 hepatoblastoma and PLC/PRF/5 hepatocellular carcinoma cells by targeting the MAPK pathway

Nature and nurture -lessons from chemical carcinogenesis

Natural killer cell activity, phagocytosis, and number of peripheral blood cells in breast cancer patients treated with tamoxifen

A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease

Modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide Ac(2-26)

Carcinogenicity assessment: Addressing the challenges of cancer and chemicals in the environment

IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis

Impact of Heavy Metals on Host Cells: Special Focus on Nickel-Mediated Pathologies and Novel Interventional Approaches

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

The phagocytosis of rod outer segments is inhibited by selected drugs in retinal pigment epithelial cell cultures

The Carcinogenic Agent Diethylnitrosamine Induces Early Oxidative Stress, Inflammation and Proliferation in Rat Liver, Stomach and Colon: Protective Effect of Ginger Extract

Cancer: Inflaming metastasis

Cancer-related inflammation

Neutrophils in the activation and regulation of innate and adaptive immunity

Tumour-associated macrophages as treatment targets in oncology

Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development

Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells

Deletion of cyclooxygenase 2 in mouse mammary epithelial cells delays breast

Mouse skin as a model for cancer chemoprevention by nonsteroidal anti-inflammatory drugs

The COXIB experience: a look in the rearview mirror

Relevance of animal carcinogenesis findings to human cancer predictions and prevention

Resolution of sickle cell disease-associated inflammation and tissue damage with 17R-resolvin D1

In vitro effects of very low levels of aflatoxin B(1) on free radicals production and bactericidal activity of bovine blood neutrophils

COVID-19: consider cytokine storm syndromes and immunosuppression

DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis

The Interplay Between the DNA Damage Response

Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators

Perfluorooctanoic acid enhances colorectal cancer DLD-1 cells invasiveness through activating NF-kappaB mediated matrix metalloproteinase-2/-9 expression

Preoperative C-reactive protein level adjusted for comorbidities and lifestyle factors predicts overall mortality in localized renal cell carcinoma

Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer

Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC

Lipoxins inhibit Akt/PKB activation and cell cycle progression in human mesangial cells

Carcinogeninduced inflammation and immunosuppression are enhanced in xeroderma pigmentosum group A model mice associated with hyperproduction of prostaglandin E2

Ultraviolet radiation and cutaneous carcinogenesis

Topical (+)-catechin emulsified gel prevents DMBA/TPA-induced squamous cell carcinoma of the skin by modulating antioxidants and inflammatory biomarkers in BALB/c mice

Inhibition of various functions in murine peritoneal macrophages by aflatoxin B1 exposure in vivo

Analysis of in vivo mutation data can inform cancer risk assessment

New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development

Mechanisms of disease: Inflammation and the origins of cancer

Gene expression analysis on the dicyclanil-induced hepatocellular tumors in mice

Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress

Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis

Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice

Alteration of macrophage anti-tumor activity and transferrin receptor expression by exposure to dimethylnitrosamine in vivo

Alteration of macrophage differentiation into accessory and effector cells from exposure to dimethylnitrosamine (DMN) in vivo

Mechanisms of benzo(a)pyrene-induced modulation of antigen presentation

Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity

Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic

Helminth Nippostrongylus brasiliensis

Comparison of the morphological transforming activities of dibenzo[a,l]pyrene and benzo[a]pyrene in C3H10T1/2CL8 cells and characterization of the dibenzo[a,l]pyrene-DNA adducts

Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation

PFOA and cancer in a highly exposed community: new findings from the C8 science panel

Antiinflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids

Chemoprevention of DMBA-induced mammary carcinogenesis in rats by lowdose EPA and DHA

Cutting edge: humanized nano-proresolving medicines mimic inflammation-resolution and enhance wound healing

Resolution metabolomes activated by hypoxic environment

Metabololipidomic profiling of functional immunoresolvent clusters and eicosanoids in mammalian tissues

The effect of ethanol and N-nitrosodimethylamine on the iNOS-dependent NO production in human neutrophils. Role of NF-kappaB

The interplay between inflammation and oxidative stress in carcinogenesis

Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer

Resolvin E1 receptor activation signals phosphorylation and phagocytosis

Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma

Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitisassociated colon cancer

17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live E. coli

Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

EET signaling in cancer

Treatment in vitro with PPARalpha and PPARgamma ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice

Preoperative lymphocyte-tomonocyte ratio represents a superior predictor compared with neutrophil-tolymphocyte and platelet-to-lymphocyte ratios for colorectal liver-only metastases survival

Stem-cell hierarchy in skin cancer

Endogenous lipid-and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor

Stereocontrolled total synthesis of neuroprotectin D1 / protectin D1 and its aspirintriggered stereoisomer

Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters)

National exposure measurements for decisions to protect public health from environmental exposures

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma

Caloric Restriction Prevents Carcinogen-Initiated Liver Tumorigenesis in Mice

Linking DNA adduct formation and human cancer risk in chemical carcinogenesis

Carcinogen macromolecular adducts and their measurement

Tumour-educated macrophages promote tumour progression and metastasis

Employment of adult mammalian primary cells in toxicology: in vivo and in vitro genotoxic effects of environmentally significant N-nitrosodialkylamines in cells of the liver, lung, and kidney

Systemic genotoxic effects of tobacco-related nitrosamines following oral and inhalational administration to Sprague-Dawley rats

Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study

A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel

Characterization of 5,6-and 8,9-epoxyeicosatrienoic acids (5,6-and 8,9-EET) as potent in vivo angiogenic lipids

The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects

Formyl peptide receptor 1 suppresses gastric cancer angiogenesis and growth by exploiting inflammation resolution pathways

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells

Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

Skin tumorigenic potential of aflatoxin B1 in mice

Role of ERK1/2 kinase in the expression of iNOS by NDMA in human neutrophils

PI3K-Akt/PKB signaling pathway in neutrophils and mononuclear cells exposed to N-nitrosodimethylamine

Effect of tumour cells killed by x-rays upon the growth of admixed viable cells

Ultrastructure of tumors induced in the rat urinary bladder by nitrosomethyldodecylamine

Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398

The induction of cyclooxygenase-1 by a tobacco carcinogen in U937 human macrophages is correlated to the activation of NF-kappaB

Lipoxin A4 Attenuates Constitutive and TGF-beta1-Dependent Profibrotic Activity in Human Lung Myofibroblasts

Consumption of nitrate, nitrite, and nitrosodimethylamine and the risk of upper aerodigestive tract cancer

Antiinflammatory cyclopentenone prostaglandins are direct inhibitors of IkB kinase

TAM receptor signaling in immune homeostasis

Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis

Modulatory efficacy of dieckol on xenobiotic-metabolizing enzymes, cell proliferation, apoptosis, invasion and angiogenesis during NDEA-induced rat hepatocarcinogenesis

The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice

Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis

Key role of local acetaldehyde in upper GI tract carcinogenesis

A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors

Electrochemical DNA biosensor for potential carcinogen detection in food sample

Relationships between the synthesis of N-nitrosodimethylamine and immune responses to chronic infection with the carcinogenic parasite, Opisthorchis viverrini, in men

Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

Saturatedefferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids

Genotoxicity of poorly soluble particles

Soluble epoxide hydrolase is a therapeutic target for acute inflammation

Reprogramming tumor stroma using an endogenous lipid lipoxin A4 to treat pancreatic cancer

An aspirin-triggered lipoxin A4 stable analog displays a unique topical antiinflammatory profile

The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptormediated release of arachidonic acid

Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Necroptosis microenvironment directs lineage commitment in liver cancer

Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution

The resolution of inflammation: the devil in the flask and in the details

Pro-resolving lipid mediators are leads for resolution physiology

Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms

Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome

Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids

Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes

Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

The pro-tumorigenic host response to cancer therapies

15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-kappaB Regulators in Bacterial Pneumonia

Resolvin D1 and D2 inhibit tumour growth and inflammation via modulating macrophage polarization

The future of immune checkpoint therapy

Ameliorative Effects of Operculina turpethum and its Isolated Stigma-5,22dien-3-o-beta-D-glucopyranoside on the Hematological Parameters of Male Mice Exposed to N-Nitrosodimethylamine, a Potent Carcinogen

Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice

Effects of Schistosoma haematobium infection on drug-metabolizing enzymes in human bladder cancer tissues

Suppression of Oxidative Stress and NFkappaB/MAPK Signaling by Lyophilized Black Raspberries for Esophageal Cancer Prevention in Rats

Inflammation and the chemical carcinogen benzo[a]pyrene: Partners in crime

The role of cyclooxygenase inhibition in the antineoplastic effects of nonsteroidal antiinflammatory drugs (NSAIDs)

Anti-idiotypic nanobodyalkaline phosphatase fusion proteins: Development of a one-step competitive enzyme immunoassay for fumonisin B1 detection in cereal

Anti-carcinogenic effect of hesperidin against renal cell carcinoma by targeting COX-2/PGE2 pathway in Wistar rats

Lipoxin A4 selectively programs the profile of M2 tumor-associated macrophages which favour control of tumor progression

Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma

The mouse skin carcinogenesis model

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them

Activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human lung microsomes by cytochromes P450, lipoxygenase, and hydroperoxides

Perfluorooctanoic acid alters T lymphocyte phenotypes and cytokine expression in mice

Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis

Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study

Action of epoxyeicosatrienoic acids on cellular function

Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

Research Needs for Understanding the Biology of Overdiagnosis in Cancer Screening

T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein

Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia

Workgroup report: public health strategies for reducing aflatoxin exposure in developing countries

The NTP Report on Carcinogens: A valuable resource for public health, a challenge for regulatory science

Attenuation of NDEA-induced hepatocarcinogenesis by naringenin in rats

Targeting lipid mediators in cancer biology

Resolvins suppress tumor growth and enhance cancer therapy

PTUPB ameliorates high-fat diet-induced non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in mice

Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP

Aflatoxin B1 Promotes Influenza Replication and Increases Virus Related Lung Damage via Activation of TLR4 Signaling

Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, antiinflammatory properties, and enzymatic inactivation

Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors

Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta-and JNK1-dependent inflammation

Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues

Aspirintriggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors

High frequency and heterogeneous distribution of p53 mutations in aflatoxin B1-induced mouse lung tumors

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages

The effect of dimethylnitrosamine on host resistance and immunity

Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/-mice

Role of the CYP3A4-mediated 11,12-epoxyeicosatrienoic acid pathway in the development of tamoxifen-resistant breast cancer

Resolvins E1 and D1 in choroid-retinal endothelial cells and leukocytes: biosynthesis and mechanisms of antiinflammatory actions

ALOX15 as a suppressor of inflammation and cancer: Lost in the link

Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization

Human carcinogens so far identified

Avoided and avoidable risks of cancer

MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential

Commentary: is the concept of "tumor promotion" a useful paradigm?

Bad Luck Mutations": DNA Mutations Are not the Whole Answer to Understanding Cancer Risk

Role of lipoxin A4 in the cell-to-cell interaction between all-trans retinoic acid-treated acute promyelocytic leukemic cells and alveolar macrophages

Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamsters

The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases

Mechanistic Evidence for Red Meat and Processed Meat Intake and Cancer Risk: A Follow-up on the International Agency for Research on Cancer Evaluation of

Inflammation: John Hunter's "A treatise on the blood, inflammation and gunshot wounds

Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection

Experimental Hepatic Carcinogenesis: Oxidative Stress and Natural Antioxidants

Angiostatic properties of sulindac and celecoxib in the experimentally induced inflammatory colorectal cancer

Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Neutrophil-mediated formation of carcinogenic N-nitroso in vitro model for intestinal inflammation

ATL-1, a synthetic analog of lipoxin, modulates endothelial permeability and interaction with tumor cells through a VEGF-dependent mechanism

Estrogen accelerates the resolution of inflammation in macrophagic cells

Medical therapies for hepatocellular carcinoma: a critical view of the evidence

Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner

A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Comparative genotoxicity of nitrosamine drinking water disinfection byproducts in Salmonella and mammalian cells

COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation

A magic bullet for mucosal protection

Gaseous mediators in resolution of inflammation

Smoking and lung cancer: the role of inflammation

IFN-gamma-mediated downregulation of LXA4 is necessary for the maintenance of nonresolving inflammation and papilloma persistence

Eicosanoids and cancer

The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression

Role of prostanoids in gastrointestinal cancer

COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin

Genotoxicity of a Low-Dose Nitrosamine Mixture as Drinking Water Disinfection Byproducts in NIH3T3 Cells

Superiority of a fish oil-enriched emulsion to medium-chain triacylglycerols/long-chain triacylglycerols in gastrointestinal surgery patients: a randomized clinical trial

Effects of resolvin D1 on inflammatory responses and oxidative stress of lipopolysaccharide-induced acute lung injury in mice

Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis

Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation

Occurrence and profiling of multiple nitrosamines in source water and drinking water of China

Effects of aflatoxin B1 on mitochondrial respiration, ROS generation and apoptosis in broiler cardiomyocytes

Maresin 1 Inhibits Epithelial-to-Mesenchymal Transition in Vitro and Attenuates Bleomycin Induced Lung Fibrosis in Vivo

Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory B (Breg) cells

Triclosan exposure, transformation, and human health effects

Multistage carcinogenesis involves multiple genes and multiple mechanisms

Sulindac prevents carcinogen-induced intrahepatic cholangiocarcinoma formation in vivo

Communication between human macrophages and epithelial cancer cell lines dictates lipid mediator biosynthesis

Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity

Direct suppression of in vitro antibody production by mouse spleen cells by the carcinogen benzo(a)pyrene but not by the noncarcinogenic congener benzo(e)pyrene

Carcinogen substrate specificity of human COX-1 and COX-2

Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme

Use of four new human-derived liver-cell lines for the detection of J o u r n a l P r e -p r o o f genotoxic compounds in the single-cell gel electrophoresis (SCGE) assay

Melatonin suppresses eosinophils and Th17 cells in hamsters treated with a combination of human liver fluke infection and a chemical carcinogen

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

Inhibition of Pancreatic Carcinoma Growth Through Enhancing omega-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase

Longterm treatment with L-isoleucine or L-leucine in AIN-93G diet has promoting effects on rat bladder carcinogenesis

Mycotoxin exposure is associated with increased risk of esophageal squamous cell carcinoma in Huaian area

New endogenous anti-inflammatory and proresolving lipid mediators: implications for rheumatic diseases

Bovine milk-derived alpha-lactalbumin inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sodium sulfate-treated mice

Rhizoma Paridis Saponins Suppresses Tumor Growth in a Rat Model of N-Nitrosomethylbenzylamine-Induced Esophageal Cancer by Inhibiting Cyclooxygenases-2 Pathway

Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats

Chemopreventive effects of early-stage and late-stage supplementation of vitamin E and selenium on esophageal carcinogenesis in rats maintained on a low vitamin E/selenium diet

A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice

A global view of hepatocellular carcinoma: trends, risk, prevention and management

Perfluorooctanoic acid induces peroxisomal fatty acid oxidation and cytokine expression in the liver of male Japanese medaka (Oryzias latipes)

Zyflamend reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced hamster cheek pouch model

Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice

Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluoroctanoic acid in mice

Cytochrome P450 2A13 mediates aflatoxin B1-induced cytotoxicity and apoptosis in human bronchial epithelial cells

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing beta-oxidation of fatty acid in mice

Genotoxic risk and oxidative DNA damage in HepG2 cells exposed to perfluorooctanoic acid

International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family

Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma

Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma

Probabilistic health risk assessment of nitrosamines in drinking water of Shaoxing

Opisthorchis viverrini infection activates the PI3K/ AKT/PTEN and Wnt/betacatenin signaling pathways in a Cholangiocarcinogenesis model

14,15-epoxyeicosatrienoic Acid suppresses cigarette smoke extract-induced apoptosis in lung epithelial cells by inhibiting endoplasmic reticulum stress

Triclosan: A Widespread Environmental Toxicant with Many Biological Effects

Epoxygenase pathways of arachidonic acid metabolism

Anti-hepatocarcinoma effect of cordycepin against NDEA-induced hepatocellular carcinomas via the PI3K/Akt/mTOR and Nrf2/HO-1/NF-kappaB pathway in mice

Depletion of regulatory T cells facilitates growth of established tumors: a mechanism involving the regulation of myeloid-derived suppressor cells by lipoxin A4

COX-2/sEH dual inhibitor PTUPB alleviates bleomycin-induced pulmonary fibrosis in mice via inhibiting senescence

Resolution of PMAinduced skin inflammation involves interaction of IFN-gamma and ALOX15

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Detection and Concentration of Plasma Aflatoxin is Associated with Detection of Oncogenic Human Papillomavirus in Kenyan Women

Cytochrome P450 monooxygenase/soluble epoxide hydrolase-mediated eicosanoid pathway in colorectal cancer and obesity-associated colorectal cancer

Aflatoxin B1 and aflatoxin M1 induced cytotoxicity and DNA damage in differentiated and undifferentiated Caco-2 cells

Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer

Aflatoxin B1 enhances pyroptosis of hepatocytes and activation of Kupffer cells to promote liver inflammatory injury via dephosphorylation of cyclooxygenase-2: an in vitro, ex vivo and in vivo study

Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation

Experimental and Theoretical Investigation of Effects of Ethanol and Acetic Acid on Carcinogenic NDMA Formation in Simulated Gastric Fluid

Soluble epoxide hydrolase deficiency inhibits dextran sulfate sodium-induced colitis and carcinogenesis in mice

Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency

Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency

Perfluorooctanoic acid stimulates breast cancer cells invasion and up-regulates matrix metalloproteinase-2/-9 expression mediated by activating NF-kappaB

Systemic inflammation score predicts survival in patients with intrahepatic cholangiocarcinoma undergoing curative resection

A COX-2/sEH dual inhibitor PTUPB ameliorates cecal ligation and puncture-induced sepsis in mice via anti-inflammation and anti-oxidative stress

Formation of N-nitrosamines from eleven disinfection treatments of seven different surface waters

NNK-Induced Lung Tumors: A Review of Animal Model

Preventive effects of combinative natural foods produced by elite crop varieties rich in anticancer effects on J o u r n a l P r e -p r o o f N-nitrosodiethylamine-induced hepatocellular carcinoma in rats

Dietary N-nitroso compounds and risk of pancreatic cancer: results from a large case-control study

RvD1 inhibits TNFalpha-induced c-Myc expression in normal intestinal epithelial cells and destabilizes hyper-expressed c-Myc in colon cancer cells

Formation of Nnitrosodiphenylamine and two new N-containing disinfection byproducts from chloramination of water containing diphenylamine

Lipoxin A(4) inhibited hepatocyte growth factor-induced invasion of human hepatoma cells

Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-beta1 signaling in pancreatic cancer

Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer

Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis

The authors are supported by NIH grants including R01GM038765 (to

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