Arsenic: A Global Environmental Challenge.

Arsenic is a naturally occurring metalloid and one of the few metals that can be metabolized inside the human body. The pervasive presence of arsenic in nature and anthropogenic sources from agricultural and medical use have perpetuated human exposure to this toxic and carcinogenic element. Highly exposed individuals are susceptible to various illnesses, including skin disorders; cognitive impairment; and cancers of the lung, liver, and kidneys. In fact, across the globe, approximately 200 million people are exposed to potentially toxic levels of arsenic, which has prompted substantial research and mitigation efforts to combat this extensive public health issue. This review provides an up-to-date look at arsenic-related challenges facing the global community, including current sources of arsenic, global disease burden, arsenic resistance, and shortcomings of ongoing mitigation measures, and discusses potential next steps.

Introduction to the Theme "Old and New Toxicology: Interfaces with Pharmacology".

The theme of Volume 61 is "Old and New Toxicology: Interfaces with Pharmacology." Old toxicology is exemplified by the authors of the autobiographical articles: B.M. Olivera's work on toxins and venoms from cone snails and P. Taylor's studies of acetylcholinesterase and the nicotinic cholinergic receptor, which serve as sites of action for numerous pesticides and venoms. Other articles in this volume focus on new understanding and new types of toxicology, including (a) arsenic toxicity, which is an ancient poison that, through evolution, has caused most multicellular organisms to express an active arsenic methyltransferase to methylate arsenite, which accelerates the excretion of arsenic from the body; (b) small molecules that react with lipid dicarbonyls, which are now considered the most toxic oxidative stress end products; (c) immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy but have numerous immune-related adverse events, including cardiovascular complications; (d) autoimmunity caused by the environment; (e) idiosyncratic drug-induced liver disease, which together with the toxicity of ICIs represents new toxicology interfacing with pharmacology; and (f) sex differences in the development of cardiovascular disease, with men more susceptible than women to vascular inflammation that initiates and perpetuates disease. These articles and others in Volume 61 reflect the interface and close integration of pharmacology and toxicology that began long ago but continues today.

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.

Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.

Toxic element contaminations of prenatal vitamins.

The detrimental effects of gestational and lactational exposure to adverse chemical agents are gathering increasing attention. In our study, the presence of toxic heavy metals in several prenatal vitamins from six brands available in supermarkets and pharmacies was measured using ICP mass spectrometry. Several toxic heavy metals were detected, some at levels that could have potential toxicity to the fetus and the mother as well. Previous studies have also detected toxic heavy metals in prenatal and other vitamins. One of the reasons for toxic heavy metals in "natural vitamins" sold to consumers is that they are produced from naturally grown material and not synthesized. They are likely exposed to the heavy metals from the ground that they are grown in and there has not been any significant attempt to get rid of them before the vitamin pill was sold to consumers. Thus, this problem is not an isolated issue and regulatory agencies should be dealing more aggressively than they have been doing. In fact, several papers have already been published showing similar findings as we are reporting here. The vitamin pills we analyzed have elevated levels of boron, aluminum, molybdenum, barium, lead, titanium, nickel, arsenic, strontium, and cadmium. The levels of total chromium were also elevated but we did not separately determine Cr(III) and the much more hazardous Cr(VI), because of the tedious procedure required to separate these two forms of Cr.

Hexavalent chromium inhibits myogenic differentiation and induces myotube atrophy.

Hexavalent chromium [Cr(VI)] is extensively used in many industrial processes. Previous studies reported that Cr(VI) exposures during early embryonic development reduced body weight with musculoskeletal malformations in rodents while exposures in adult mice increased serum creatine kinase activity, a marker of muscle damage. However, the impacts of Cr(VI) on muscle differentiation remain largely unknown. Here, we report that acute exposures to Cr(VI) in mouse C2C12 myoblasts inhibit myogenic differentiation in a dose-dependent manner. Exposure to 2 µM of Cr(VI) resulted in delayed myotube formation, as evidenced by a significant decrease in myotube formation and expression of muscle-specific markers, such as muscle creatine kinase (Mck), Myocyte enhancer factor 2 (Mef2), Myomaker (Mymk) and Myomixer (Mymx). Interestingly, exposure to 5 µM of Cr(VI) completely abolished myotube formation in differentiating C2C12 cells. Moreover, the expression of key myogenic regulatory factors (MRFs) including myoblast determination protein 1 (MyoD), myogenin (MyoG), myogenic factor 5 (Myf5), and myogenic factor 6 (Myf6) were significantly altered in Cr(VI)-treated cells. The inhibitory effect of Cr(VI) on myogenic differentiation was further confirmed in freshly isolated mouse satellite cells, a stem cell population essential for adult skeletal muscle regeneration. Furthermore, Cr(VI) exposure to fully differentiated C2C12 myotubes resulted in a decrease in myotube diameter, which was exacerbated upon co-treatment with dexamethasone. Together, our results demonstrate that Cr(VI) inhibits myogenic differentiation and induces myotube atrophy in vitro.

A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes.

OBJECTIVE: It is well established that exposure of human skin to airborne pollution, particularly in the form of particulate matter sized 2.5 µm (PM2.5 ), is associated with oxidative stress, DNA damage and inflammation, leading to premature signs of skin aging. Because much of the damage results from oxidative stress, we examined the effects of a topical composition containing three antioxidants in an in vitro model system to assess the potential for amelioration of premature aging. The use of multiple antioxidants was of interest based on the typical composition of therapeutic skincare products. It is important to determine the efficacy of multiple antioxidants together and develop a short-term assay for larger scale efficacy testing. METHODS: Normal human epidermal keratinocytes were exposed to a rural-derived source of PM2.5 in the presence and absence of an antioxidant mixture of resveratrol, niacinamide and GHK peptide. Endpoints related to inflammation, premature aging and carcinogenicity were monitored after 5 h of exposure and included IL-6, CXCL10, MMP-1 and NRF2. Differentially expressed genes were monitored by RNA-seq. RESULTS: Pre-treatment of keratinocytes with the antioxidant preparation in the absence of PM2.5 reduced baseline levels of MMP-1, IL-6 and CYP1A1 and reduced PM2.5 -induced increases in all four endpoints, MMP-1, IL-6, CXCL10 and CYP1A1. Antioxidants significantly increased NRF2 protein in the presence of PM2.5 , indicating a protective response. RNA-seq interrogation of antioxidant-treated cells further showed increased expression of NRF2 inducible genes. The expression of CYP1A1 and genes related to aryl hydrocarbon activation were induced by PM2.5 and suppressed by antioxidants. CONCLUSIONS: Specific signalling pathways known to be correlated with skin inflammation and aging were examined based on their suitability for use in efficacy testing for the prevention of skin damage due to ambient hydrocarbon pollution. Endpoints examined after only 5 h of exposure provide a useful method amenable to high through-put screening. The results obtained reinforce the concept that a multiple antioxidant preparation, topically applied, may reduce pro-inflammatory signalling and cellular damage and thereby reduce premature skin aging due to exposure to rural-derived airborne pollution.

OBJECTIF: Il est bien établi que l'exposition de la peau humaine à la pollution atmosphérique, en particulier sous forme de particules d'une taille de 2,5 µm (PM2,5 ), est associée à un stress oxydatif, à des dommages à l'ADN et à une inflammation entraînant des signes prématurés de vieillissement cutané. Étant donné que la plupart des dommages résultent du stress oxydatif, nous avons examiné les effets d'une composition topique contenant trois antioxydants dans un système de modèle in vitro afin d'évaluer le potentiel d'amélioration du vieillissement prématuré. L'utilisation de plusieurs antioxydants a été intéressante en raison de la composition typique des produits thérapeutiques de soin de la peau. Il est important de déterminer l'efficacité de plusieurs antioxydants combinés et de développer un test à court terme pour des tests d'efficacité à plus grande échelle. MÉTHODES: Des kératinocytes épidermiques humains normaux ont été exposés à une source de PM2,5 rurale en présence et en l'absence d'un mélange antioxydant de resvératrol, de niacinamide et de peptide GHK. Les critères d'évaluation liés à l'inflammation, au vieillissement prématuré et à la carcinogénicité ont été surveillés après 5 heures d'exposition et comprenaient l'IL-6, CXCL10, MMP-1 et le NRF2. Les gènes exprimés de manière différentielle ont été surveillés par séquençage de l'ARN. RÉSULTATS: Le prétraitement des kératinocytes par la préparation antioxydante en l'absence de PM2,5 a réduit les taux initiaux de MMP-1, IL-6 et de CYP1A1 et a réduit les augmentations induites par les PM2,5 dans les quatre critères d'évaluation, MMP-1, IL-6, CXCL10 et CYP1A1. Les antioxydants ont significativement augmenté la protéine NRF2 en présence de PM2,5 , ce qui indique une réponse protectrice. L'interrogation des séquences d'ARN des cellules traitées par antioxydants a également montré une expression accrue des gènes inductibles par NRF2. L'expression du CYP1A1 et des gènes liés à l'activation des hydrocarbures aryles a été induite par les PM2,5 et supprimée par les antioxydants. CONCLUSIONS: Les voies de signalisation spécifiques connues pour être corrélées à l'inflammation cutanée et au vieillissement ont été examinées en fonction de leur adéquation à l'utilisation dans les tests d'efficacité pour la prévention des lésions cutanées dues à la pollution des hydrocarbures ambiants. Les critères d'évaluation examinés après seulement 5 heures d'exposition fournissent une méthode utile pouvant être utilisée pour un dépistage à haut débit. Les résultats obtenus renforcent le principe selon lequel une préparation antioxydante multiple, appliquée par voie topique, peut réduire la signalisation pro-inflammatoire et les dommages cellulaires et ainsi réduire le vieillissement prématuré de la peau résultant de l'exposition à la pollution atmosphérique d'origine rurale.

p62 functions as a signal hub in metal carcinogenesis.

A number of metals are toxic and carcinogenic to humans. Reactive oxygen species (ROS) play an important role in metal carcinogenesis. Oxidative stress acts as the converging point among various stressors with ROS being the main intracellular signal transducer. In metal-transformed cells, persistent expression of p62 and erythroid 2-related factor 2 (Nrf2) result in apoptosis resistance, angiogenesis, inflammatory microenvironment, and metabolic reprogramming, contributing to overall mechanism of metal carcinogenesis. Autophagy, a conserved intracellular process, maintains cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. In addition to being a substrate of autophagy, p62 is also a crucial molecule in a myriad of cellular functions and in molecular events, which include oxidative stress, inflammation, apoptosis, cell proliferation, metabolic reprogramming, that modulate cell survival and tumor growth. The multiple functions of p62 are appreciated by its ability to interact with several key components involved in various oncogenic pathways. This review summarizes the current knowledge and progress in studies of p62 and metal carcinogenesis with emphasis on oncogenic pathways related to oxidative stress, inflammation, apoptosis, and metabolic reprogramming.

Metals and Mechanisms of Carcinogenesis.

Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most prevalent carcinogenic metals, arsenic, nickel, cadmium, chromium, and beryllium, and their potential to drive carcinogenesis in humans. A comprehensive understanding of the mechanisms behind the development of metal-induced cancer can provide valuable insights for therapeutic intervention involving molecular targets in metal-induced carcinogenesis.

The role of NUPR1 in response to stress and cancer development.

Stress contributes to the development of many human diseases, including cancer. Based on the source of stress, it can be divided into external stress, such as environmental carcinogens, chemicals, and radiation, and internal stress, like endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Nuclear Protein 1 (NUPR1, p8 or Com-1) is a small, highly basic transcriptional regulator that participates in regulating a variety of cellular processes including DNA repair, ER stress, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis and chromatin remodeling. A large number of studies have reported that NUPR1 expression can be stimulated rapidly in response to various stresses. Thus, NUPR1 is also known as a stress-response gene. Since the role of NUPR1 in breast cancer was identified in 1999, an increasing number of studies sought to reveal its function in cancer. High expression of NUPR1 has been identified in oral squamous cell carcinoma, breast cancer, lung cancer, multiple myeloma, liver cancer and renal cancer. In this review, we summarize current studies of NUPR1 in response to multiple external stressors and internal stressors, and its role in mediating stressors to cause different cell signaling responses. In addition, this review discusses the function of NUPR1 in carcinogenesis, tumorigenesis, metastasis, and cancer therapy. Thus, this review gives a comprehensive insight into the role of NUPR1 in mediating signals from stress to different cell responses, and this process plays a role in the development of cancer.

Extracellular Vesicles as Mediators of Nickel-Induced Cancer Progression.

Emerging evidence suggests that extracellular vesicles (EVs), which represent a crucial mode of intercellular communication, play important roles in cancer progression by transferring oncogenic materials. Nickel (Ni) has been identified as a human group I carcinogen; however, the underlying mechanisms governing Ni-induced carcinogenesis are still being elucidated. Here, we present data demonstrating that Ni exposure generates EVs that contribute to Ni-mediated carcinogenesis and cancer progression. Human bronchial epithelial (BEAS-2B) cells and human embryonic kidney-293 (HEK293) cells were chronically exposed to Ni to generate Ni-treated cells (Ni-6W), Ni-transformed BEAS-2B cells (Ni-3) and Ni-transformed HEK293 cells (HNi-4). The signatures of EVs isolated from Ni-6W, Ni-3, HNi-4, BEAS-2B, and HEK293 were analyzed. Compared to their respective untreated cells, Ni-6W, Ni-3, and HNi-4 released more EVs. This change in EV release coincided with increased transcription of the EV biogenesis markers CD82, CD63, and flotillin-1 (FLOT). Additionally, EVs from Ni-transformed cells had enriched protein and RNA, a phenotype also observed in other studies characterizing EVs from cancer cells. Interestingly, both epithelial cells and human umbilical vein endothelial (HUVEC) cells showed a preference for taking up Ni-altered EVs compared to EVs released from the untreated cells. Moreover, these Ni-altered EVs induced inflammatory responses in both epithelial and endothelial cells and increased the expression of coagulation markers in endothelial cells. Prolonged treatment of Ni-alerted EVs for two weeks induced the epithelial-to-mesenchymal transition (EMT) in BEAS-2B cells. This study is the first to characterize the effect of Ni on EVs and suggests the potential role of EVs in Ni-induced cancer progression.

Index Coding with Multiple Interpretations.

The index coding problem consists of a system with a server and multiple receivers with different side information and demand sets, connected by a noiseless broadcast channel. The server knows the side information available to the receivers. The objective is to design an encoding scheme that enables all receivers to decode their demanded messages with a minimum number of transmissions, referred to as an index code length. The problem of finding the minimum length index code that enables all receivers to correct a specific number of errors has also been studied. This work establishes a connection between index coding and error-correcting codes with multiple interpretations from the tree construction of nested cyclic codes. The notion of multiple interpretations using nested codes is as follows: different data packets are independently encoded, and then combined by addition and transmitted as a single codeword, minimizing the number of channel uses and offering error protection. The resulting packet can be decoded and interpreted in different ways, increasing the error correction capability, depending on the amount of side information available at each receiver. Motivating applications are network downlink transmissions, information retrieval from datacenters, cache management, and sensor networks.

Downregulation of hedgehog-interacting protein (HHIP) contributes to hexavalent chromium-induced malignant transformation of human bronchial epithelial cells.

Hexavalent chromium [Cr(VI)] is a potent human lung carcinogen. Multiple mechanisms have been proposed that contribute to Cr(VI)-induced lung carcinogenesis including oxidative stress, DNA damage, genomic instability and epigenetic modulation. However, the molecular mechanisms and pathways mediating Cr(VI) carcinogenicity have not been fully elucidated. Hedgehog (Hh) signaling is a key pathway that plays important roles in the formation of multiple tissues during embryogenesis and in the maintenance of stem cell populations in adults. Dysregulation of Hh signaling pathway has been reported in many human cancers. Here, we report a drastic reduction in both mRNA and protein levels of hedgehog-interacting protein (HHIP), a downstream target and a negative regulator of Hh signaling, in Cr(VI)-transformed cells. These findings point to a potential role of Hh signaling in Cr(VI)-induced malignant transformation and lung carcinogenesis. Cr(VI)-transformed cells exhibited DNA hypermethylation and silencing histone marks in the promoter region of HHIP, indicating that an epigenetic mechanism mediates Cr(VI)-induced silencing of HHIP. In addition, the major targets of Hh signaling (GLI1-3 and PTCH1) were significantly increased in Cr(VI)-transformed cells, suggesting an aberrant activation of Hh signaling in these cells. Moreover, ectopically expressing HHIP not only suppressed Hh signaling but also inhibited cell proliferation and anchorage-independent growth in Cr(VI)-transformed cells. In conclusion, these findings establish a novel regulatory mechanism underlying Cr(VI)-induced lung carcinogenesis and provide new insights for developing a better diagnostic and prognostic strategy for Cr(VI)-related human lung cancer.

Wrong place, wrong time: Runt-related transcription factor 2/SATB2 pathway in bone development and carcinogenesis.

Upregulation or aberrant expression of genes such as special AT-rich sequence-binding protein 2 (SATB2) is necessary for normal cell differentiation and tissue development and is often associated with carcinogenesis and metastatic progression. SATB2 is a critical transcription factor for biological development of various specialized cell lineages, such as osteoblasts and neurons. The dysregulation of SATB2 expression has recently been associated with various types of cancer, while the mechanisms and pathways by which it mediates tumorigenesis are not well elucidated. Runt-related transcription factor 2 (RUNX2) is a master regulator for osteogenesis, and it shares common pathways with SATB2 to regulate bone development. Interestingly, these two transcription factors co-occur in several epithelial and mesenchymal cancers and are linked by multiple cancer-related proteins and microRNAs. This review examines the interactions between RUNX2 and SATB2 in a network necessary for normal bone development and the circumstances in which the expression of RUNX2 and SATB2 in the wrong place and time leads to carcinogenesis.

Metals and molecular carcinogenesis.

Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and environmental contaminations in drinking water, air pollution and foods, which can result in serious health problems such as cancer. Arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr) and nickel (Ni) are classified as Group 1 carcinogens by the International Agency for Research on Cancer. This review provides a comprehensive summary of current concepts of the molecular mechanisms of metal-induced carcinogenesis and focusing on a variety of pathways, including genotoxicity, mutagenesis, oxidative stress, epigenetic modifications such as DNA methylation, histone post-translational modification and alteration in microRNA regulation, competition with essential metal ions and cancer-related signaling pathways. This review takes a broader perspective and aims to assist in guiding future research with respect to the prevention and therapy of metal exposure in human diseases including cancer.

Deregulation of SATB2 in carcinogenesis with emphasis on miRNA-mediated control.

The special AT-rich DNA binding protein (SATB2) is a nuclear matrix-associated protein and an important transcription factor for biological development, gene regulation and chromatin remodeling. Aberrant regulation of SATB2 has been found to highly correlate with various types of cancers including lung, colon, prostate, breast, gastric and liver. Recent studies have revealed that a subset of small non-coding RNAs, termed microRNAs (miRNAs), are important regulators of SATB2 function. As post-transcriptional regulators, miRNAs have been found to have fundament importance maintaining normal cellular development. Evidence suggests that multiple miRNAs, including miR-31, miR-34, miR-182, miR-211, miR-599, are capable of regulating SATB2 in cancers of the lung, liver, colon and breast. This review examines the molecular functions of SATB2 and miRNAs in the text of cancer development and potential strategies for cancer therapy with a focus on systemic miRNA delivery.

Review of arsenic toxicity, speciation and polyadenylation of canonical histones.

Arsenic contamination impacts hundreds of millions of people in the world. Arsenic is a well-established human carcinogen and has been shown to cause skin, lung, bladder, liver, prostate and kidney cancers, in humans. Mechanisms that underlie arsenic-mediated carcinogenesis, including epigenetic alterations, remain largely unknown. Human exposure to Arsenic is reviewed, and the mechanisms of its acute and chronic toxicity and mechanisms of its carcinogenesis in humans are discussed. Arsenic is one of the few metals that is metabolized in vivo, and Arsenic methylation and how this results in a shorter half-life in vivo are discussed. A review of recent findings that Arsenic causes loss in the cellular levels of Stem Loop Binding Protein (SLBP) resulting in polyadenylation of canonical histones (H3.1) as a default, increasing levels of H3.1 protein outside of S-Phase. Malignant cell transformation is induced by knockdown of SLBP and by overexpression of polyadenylated H3.1. Arsenic induced polyadenylation of H3.1 causes enhanced levels of H3.1 protein displacing H3.3 protein from its cellular binding sites, since the two proteins differ by only 5 amino acids. Knockdown of H3.3 alone can induce carcinogenesis, and therefore displacement of functional H3.3 protein by increased H3.1 protein, is likely a mechanism of arsenic carcinogenesis.

Molecular and epigenetic mechanisms of Cr(VI)-induced carcinogenesis.

Chromium (Cr) is a naturally occurring metallic element found in the Earth's crust. While trivalent chromium ([Cr(III)] is considered non-carcinogenic, hexavalent chromium [Cr(VI)] has long been established as an IARC class I human carcinogen, known to induce cancers of the lung. Current literature suggests that Cr(VI) is capable of inducing carcinogenesis through both genetic and epigenetic mechanisms. Although much has been learned about the molecular etiology of Cr(VI)-induced lung carcinogenesis, more remains to be explored. In particular, the explicit epigenetic alterations induced by Cr(VI) in lung cancer including histone modifications and miRNAs, remain understudied. Through comprehensive review of available literature found between 1973 and 2019, this article provides a summary of updated understanding of the molecular mechanisms of Cr(VI)-carcinogenesis. In addition, this review identifies potential research gaps in the areas of histone modifications and miRNAs, which may prompt new niches for future research.

Bituminous coal combustion and Xuan Wei Lung cancer: a review of the epidemiology, intervention, carcinogens, and carcinogenesis.

Indoor air pollution from bituminous coal combustion has been linked to the extremely high lung cancer rates of nonsmoking women in Xuan Wei County, Yunnan Province, China. Venting the smoke outdoors by installing chimneys was found to be effective at reducing the lung cancer risk in a cohort study of 21,232 farmers in central Xuan Wei. However, the lung cancer mortality rates in all 1.2 million residents of Xuan Wei have been increasing dramatically over the last four decades. It was higher than that in Yunnan Province and China overall, with significant heterogeneities in the geographic patterns of Xuan Wei. Intervention measures targeting certain types of coal or certain carcinogenic components in coal smoke need to be explored. To inform targeted intervention policies, it is essential to pinpoint the specific substance (particulate matter, organic extract, PAHs, free radicals, crystalline silica, and inorganic matter) that might account for the carcinogenicity of bituminous coal smoke. Exploring the underlying carcinogenesis mechanisms would also contribute to the intervention and control of the lung cancer epidemic in Xuan Wei, China. Here we review the suspected carcinogens and carcinogenesis mechanisms and discuss future research directions towards a better understanding of the etiology of lung cancer in Xuan Wei, China.

PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis.

Arsenic is a naturally occurring, ubiquitous metalloid found in the Earth's crust. In its inorganic form, arsenic is highly toxic and carcinogenic and is widely found across the globe and throughout the environment. As an International Agency for Research on Cancer-defined class 1 human carcinogen, arsenic can cause multiple human cancers, including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive, and this review focuses specifically on the role of the PI3K/AKT/mTOR pathway in promoting cancer development. In addition to exerting potent carcinogenic responses, arsenic is also known for its therapeutic effects against acute promyelocytic leukemia. Current literature suggests that arsenic can achieve both therapeutic as well as carcinogenic effects, and this review serves to examine the paradoxical effects of arsenic, specifically through the PI3K/AKT/mTOR pathway. Furthermore, a comprehensive review of current literature reveals an imperative need for future studies to establish and pinpoint the exact conditions for which arsenic can, and through what mechanisms it is able to, differentially regulate the PI3K/AKT/mTOR pathway to maximize the therapeutic and minimize the carcinogenic properties of arsenic.

Cellular shear stiffness reflects progression of arsenic-induced transformation during G1.

Cancer cells consistently exhibit decreased stiffness; however, the onset and progression of this change have not been characterized. To study the development of cell stiffness changes, we evaluated the shear stiffness of populations of cells during transformation to a carcinogenic state. Bronchial epithelial cells were exposed to sodium arsenite to initiate early stages of transformation. Exposed cells were cultured in soft agar to further transformation and select for clonal populations exhibiting anchorage-independent growth. Shear stiffness of various cell populations in G1 was assessed using a novel non-invasive assay that applies shear stress with fluid flow and evaluates nanoscale deformation using quantitative phase imaging (QPI). Arsenic-treated cells exhibited reduced stiffness relative to control cells, while arsenic clonal lines, selected by growth in soft agar, were found to have reduced stiffness relative to control clonal lines, which were cultured in soft agar but did not receive arsenic treatment. The relative standard deviation (RSD) of the stiffness of Arsenic clones was reduced compared with control clones, as well as to the arsenic-exposed cell population. Cell stiffness at the population level exhibits potential to be a novel and sensitive framework for identifying the development of cancerous cells.