Faculty Bibliography

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.

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.

Nickel is a naturally occurring element found in the Earth's crust and an International Agency for Research on Cancer (IARC)-classified human carcinogen. While low levels found in the natural environment pose a minor concern, the extensive use of nickel in industrial settings such as in the production of stainless steel and various alloys complicate human exposure and health effects. Notably, interactions with nickel macromolecules, primarily through inhalation, have been demonstrated to promote lung cancer. Mechanisms of nickel-carcinogenesis range from oxidative stress, DNA damage, and hypoxia-inducible pathways to epigenetic mechanisms. Recently, non-coding RNAs have drawn increased attention in cancer mechanistic studies. Specifically, nickel has been found to disrupt expression and functions of micro-RNAs and long-non-coding RNAs, resulting in subsequent changes in target gene expression levels, some of which include key cancer genes such as p53, MDM2, c-myc, and AP-1. Non-coding RNAs are also involved in well-studied mechanisms of nickel-induced lung carcinogenesis, such as the hypoxia-inducible factor (HIF) pathway, oxidative stress, DNA damage and repair, DNA hypermethylation, and alterations in tumor suppressors and oncogenes. This review provides a summary of the currently known epigenetic mechanisms involved in nickel-induced lung carcinogenesis, with a particular focus on non-coding RNAs.

Arsenic is a naturally occurring and highly potent metalloid known to elicit serious public health concerns. Today, approximately 200 million people around the globe are exposed to arsenic-contaminated drinking water at levels greater than the World Health Organization's recommended limit of 10 parts per billion. As a class I human carcinogen, arsenic exposure is known to elicit various cancers, including lung, skin, liver, and kidney. Current evidence suggests that arsenic is capable of inducing both genotoxic and cytotoxic injury, as well as activating epigenetic pathways to induce carcinogenesis. Our study identifies a novel pathway that is implicated in arsenic-induced carcinogenesis. Arsenic down-regulated miRNA-31 and the release of this inhibition caused overexpression of special AT-rich sequence-binding protein 2 (SATB2). Arsenic is known to disrupt miRNA expression, and here we report for the first time that arsenic is capable of inhibiting miR-31 expression. As a direct downstream target of miR-31, SATB2 is a prominent transcription factor and nuclear matrix binding protein implicated in many types of human diseases including lung cancer. Results from this study show that arsenic induces the overexpressing SATB2 by inhibiting miR-31 expression, which blocks the translation of SATB2 mRNA, since levels of SATB2 mRNA remain the same but protein levels decrease. Overexpression of SATB2 induces malignant transformation of human bronchial epithelial (BEAS-2B) cells indicating the importance of the expression of miR-31 in preventing carcinogenesis by suppressing SATB2 protein levels.

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 through out the environment. As an International Agency for Research on Cancer (IARC) defined Class I human carcinogen, arsenic has been found to cause multiple human cancers including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive and this review specifically focuses on the role of 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 is capable of achieving 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 in order to maximize the therapeutic and minimize the carcinogenic properties of arsenic.

Cancer cells consistently exhibit decreased stiffness, however the onset and progression of this change has 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 nano-scale 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 of the stiffness of Arsenic clones was reduced compared to 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.

This study provides the first comprehensive analysis of the seasonal variations and weekday/weekend differences in fine (PM2.5) and coarse (PM2.5-10) particulate matter mass concentrations, elemental constituents, and potential source origins in Jeddah, Saudi Arabia. Air quality samples were collected over one year, from June 2011 to May 2012 at a frequency of three times per week, and analyzed. The average mass concentrations of PM2.5 (21.9 mug/m3) and PM10 (107.8 mug/m3) during the sampling period exceeded the recommended annual average levels by the World Health Organization (WHO) for PM2.5 (10 mug/m3) and PM10 (20 mug/m3), respectively. Similar to other Middle Eastern locales, PM2.5-10 is the prevailing mass component of atmospheric particulate matter at Jeddah, accounting for approximately 80% of the PM10 mass. Considerations of enrichment factors, absolute principal component analysis (APCA), concentration roses, and backward trajectories identified the following source categories for both PM2.5 and PM2.5-10: 1) soil/road dust; 2) incineration; and 3) traffic; and for PM2.5 only, 4) residual oil burning. Soil/road dust accounted for a major portion of both the PM2.5 (27%) and PM2.5-10 (77%) mass, and the largest source contributor for PM2.5 was from residual oil burning (63%). Temporal variations of PM2.5-10 and PM2.5 were observed, with the elevated concentration levels observed for mass during the spring (due to increased dust storm frequency), and on weekdays (due to increased traffic). The predominant role of windblown soil and road dust in both the PM2.5 and PM2.5-10 masses in this city may have implications regarding the toxicity of these particles versus those in the western world where most PM health assessments have been made in the past. These results support the need for region-specific epidemiological investigations to be conducted and considered in future PM standard setting. Implications Temporal variation of fine and coarse PM mass, elemental constituents, and sources were examined in Jeddah, Saudi Arabia for the first time. The main source of PM2.5-10 is natural windblown soil and road dust, while the predominant source of PM2.5 is residual oil burning, generated from the port and oil refinery located west of the air sampler, suggesting that targeted emission controls could significantly improve the air quality in the city. The compositional differences point to a need for health effects studies to be conducted in this region, as to directly assess the applicability of the existing guidelines to the Middle East air pollution.

Tungsten or wolfram was regarded for many years as an enemy within the tin smelting and mining industry, because it conferred impurity or dirtiness in tin mining. However, later it was considered an amazing metal for its strength and flexibility, together with its diamond like hardness and its melting point which is the highest of any metal. It was first believed to be relatively inert and an only slightly toxic metal, beginning in the year 2000, the risk exerted by tungsten alloys, its dusts and particulates to induce cancer and several other adverse effects in animals as well as humans has been highlighted from in vitro and in vivo experiments. Thus, it becomes necessary to take a careful look at all the most recent data reported in the scientific literature, covering the years 2001-2016. In fact, the findings indicate that much more attention should be devoted to thoroughly investigate the toxic effects of tungsten and the involved mechanisms of tungsten metal or tungsten metal ions.