Faculty Bibliography

The Hudson River (HR) Estuary has a long history of pollution with a variety of contaminants including PCBs, and dioxins. In fact, 200 miles of the mainstem HR is designated a U.S. federal Superfund site, the largest in the nation, because of PCB contamination. The tidal HR hosts the southernmost spawning population of Atlantic tomcod, and studies revealed a correlation between exposure of juveniles to warm water temperature during summer to abundance of spawning adults of the same cohort in the following winter. Further, a battery of mechanistically linked biomarkers, ranging from the molecular to the population levels, were significantly impacted from contaminant exposures of the HR tomcod population. In response to xenobiotic insult, the HR tomcod population developed resistance to PCB sand TCDD toxicity resulting from a deletion in the aryl hydrocarbon receptor2 (AHR2) gene. Furthermore, RNA-Seq analysis of global gene expression demonstrated that effects of the AHR2 polymorphism were far more pervasive than anticipated. The most highly PCB-contaminated sediments in the upper HR were dredged between 2009 and 2015 with the objective of lowering PCB concentrations in fishes in the lower HR. Success of the remediation project has been controversial. These observations suggest that tomcod provides an informative model to evaluate the efficacy of HR PCB remediation efforts on downriver fish populations and possible interactive effects between contaminant exposure and a warming environment.

Although there is rising global concern over the environmental, ecological, and human health risks associated with the discharge of leachates from e-waste dumpsites into the aquatic ecosystems, little is known in this research area. Thus, for this study, we first defined the chemistry of the test leachate, followed by assessment of the leachate on the development of a model aquatic organism (Fundulus heteroclitus) used extensively as a bioassay organism in pollution studies. Chemical analyses revealed that levels of phosphate (20.03 mg/L), cadmium (Cd) (0.4 mg/L), lead (Pb) (0.2 mg/L), and chromium (Cr) (0.4 mg/L) were higher than the 2009 US EPA and the 2009 National Environmental Standards and Regulations Enforcement Agency (NESREA) permissible limits. Polycyclic aromatic hydrocarbon (PAH) burdens were dominated mainly by the high molecular weight congeners, specifically the ∑4rings (73 µg/L). Total polychlorinated biphenyls (PCB) levels ranged from 0.00 to 0.40 µg/L with the ∑deca PCBs reaching the highest concentration. For the biological studies, F. heteroclitus embryos (48-h post-fertilization) were divided randomly into groups and exposed to one of six e-waste leachate concentrations (10, 1, 0.1, 0.01, 0.001, 0.0001%). Significant differences (p ≤ 0.05) between treated and control groups were observed in standard and total length, and head size. Further analysis using Duncan"™s post-hoc test of multiple comparison also revealed specific differences within and between specific treatment groups. We conclude that e-waste leachate arising from indiscriminate dumping into aquatic ecosystems in Nigeria contains mixtures of toxic constituents that can threaten ecosystem and public health.

Nickel (Ni) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) and are known to be carcinogenic to the lungs. In our previous study, special AT‑rich sequence‑binding protein 2 (SATB2) was required for Ni‑induced BEAS‑2B cell transformation. In the present study, a pathway that regulates the expression of SATB2 protein was investigated in Ni‑transformed BEAS‑2B cells using western blotting and RT‑qPCR for expression, and soft agar, migration and invasion assays for cell transformation. Runt‑related transcription factor 2 (RUNX2), a master regulator of osteogenesis and an oncogene, was identified as an upstream regulator for SATB2. Ni induced RUNX2 expression and initiated BEAS‑2B transformation and metastatic potential. Previously, miRNA‑31 was identified as a negative regulator of SATB2 during arsenic‑induced cell transformation, and in the present study it was identified as a downstream target of RUNX2 during carcinogenesis. miR‑31 expression was reduced in Ni‑transformed BEAS‑2B cells, which was required to maintain cancer hallmarks. The expression level of miR‑31 was suppressed by RUNX2 in BEAS‑2B cells, and this increased the expression level of SATB2, initiating cell transformation. Ni caused the repression of miR‑31 by placing repressive marks at its promoter, which in turn increased the expression level of SATB2, leading to cell transformation.

Nickel (Ni) is carcinogenic to humans, and causes cancers of the lung, nasal cavity, and paranasal sinuses. The primary mechanisms of Ni‑mediated carcinogenesis involve the epigenetic reprogramming of cells and the ability for Ni to mimic hypoxia. However, the exact mechanisms of carcinogenesis related to Ni are obscure. Nuclear protein 1 (NUPR1) is a stress‑response gene overexpressed in cancers, and is capable of conferring chemotherapeutic resistance. Likewise, activator protein 1 (AP‑1) is highly responsive to environmental signals, and has been associated with cancer development. In this study, NUPR1 was found to be rapidly and highly induced in human bronchial epithelial (BEAS‑2B) cells exposed to Ni, and was overexpressed in Ni‑transformed BEAS‑2B cells. Similarly, AP‑1 subunits, JUN and FOS, were induced in BEAS‑2B cells following Ni exposure. Knockdown of JUN or FOS was found to significantly suppress NUPR1 induction following Ni exposure, demonstrating their importance in NUPR1 transactivation. Reactive oxygen species (ROS) are known to induce AP‑1, and Ni has been shown to produce ROS. Treatment of BEAS‑2B cells with antioxidants was unable to prevent NUPR1 induction by Ni, suggesting that NUPR1 induction by Ni relies on mechanisms other than oxidative stress. To determine how NUPR1 is transcriptionally regulated following Ni exposure, the NUPR1 promoter was cloned and inserted into a luciferase gene reporter vector. Multiple JUN binding sites reside within the NUPR1 promoter, and upon deleting a JUN binding site in the upstream most region within the NUPR1 promoter using site‑directed mutagenesis, NUPR1 promoter activity was significantly reduced. This suggests that AP‑1 transcriptionally regulates NUPR1. Moreover, knockdown of NUPR1 significantly reduced colony formation and anchorage‑independent growth in Ni‑transformed BEAS‑2B cells. Therefore, these results collectively demonstrate a novel mechanism of NUPR1 induction following Ni exposure, and provide a molecular basis by which NUPR1 may contribute to lung carcinogenesis.

Polychlorinated biphenyls (PCBs) cause significant health and reproductive problems in many vertebrates. Exposure during embryogenesis likely leads to defects in organ development, compromising survival and growth through adulthood. The present study identifies the impact of PCBs on the embryonic development of key organs and resulting consequences on survival and growth. Zebrafish embryos were treated with individual PCB congeners (126 or 104) or one of 4 Aroclor mixtures (1016, 1242, 1254, or 1260) and analyzed for changes in gross embryonic morphology. Specific organs were assessed for defects during embryonic development, using a variety of transgenic zebrafish to improve organ visualization. Resulting larvae were grown to adulthood while survival and growth were assayed. Embryonic gross development on PCB treatment was abnormal, with defects presenting in a concentration-dependent manner in the liver, pancreas, heart, and blood vessel organization. Polychlorinated biphenyl 126 treatment resulted in the most consistently severe and fatal phenotypes, whereas treatments with PCB 104 and Aroclors resulted in a range of more subtle organ defects. Survival of fish was highly variable although the growth rates of surviving fish were relatively normal, suggesting that maturing PCB-treated fish that survive develop compensatory strategies needed to reach adulthood. Life span analyses of fish from embryogenesis through adulthood, as in the present study, are scarce but important for the field because they help identify foci for further studies. Environ Toxicol Chem 2020;00:1-15. © 2020 SETAC.

Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of AS3MT have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, p16, which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of AS3MT in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the AS3MT gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.

Despite advances in our understanding of the genetic origins of acute myeloid leukemia (AML), treatment options have remained essentially unchanged for 30 years, and clinical outcomes remain poor. AML is maintained by leukemia stem cells (LSCs), which are critical for disease maintenance as well as re-initiating disease after therapy. We previously identified novel markers and therapeutic targets in AML and MDS by comparing the transcriptomes of stem cells to normal purified HSCs, leading to the identification of CD99 as an antigen selectively expressed on LSCs. Moreover, novel monoclonal antibodies against CD99 exerted significant cytotoxic effects against AML and MDS stem cells. Recently, we identified CD97 as an antigen expressed in the vast majority of human AMLs. CD97 regulates migration of normal hematopoietic cells as well as the invasive properties of solid cancers, but little is known about its function in AML. Our studies have revealed several features of CD97 that make it particularly important with in AML including: 1) CD97 is one of the most commonly expressed human AML antigens; 2) CD97 promotes blast growth and survival, and limits differentiation; 3) CD97 regulates LSC function, as demonstrated in serial and limiting dilution transplant experiments, but is not required for HSC function; 4) Consistent with the critical role CD97 in AML, CD97 is an independent prognostic variable for overall survival (OS) in both univariate and multivariate analyses. Lastly, novel monoclonal and synthetic antibodies against CD97 appear to exhibit significant anti-leukemic effect, making CD97 a viable therapeutic target.
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Introduction: Difficult cannulation of the bile duct during ERCP can occur in 5-10% of cases. Double-guidewire technique (DGWT)is one of the rescue techniques useful for accessing the bile duct. We performed an updated meta-analysis of randomized controlled trials (RCTs)to assess the efficacy and safety of the double guide-wire technique for ERCP.
Method(s): Search of Pubmed, Embase, CINHAL and the Cochrane Library was performed for all RCTs comparing DGWT to standard techniques or other advanced techniques (precut sphincterotomy or pancreatic duct placement). Data was extracted using a standardized extraction form by two reviewers. Data on cannulation rates and ERCP related complications (pancreatitis, cholangitis, perforation)were extracted. Summary risk ratios were calculated using the Comprehensive Meta-analysis software. Heterogeneity and publication bias were assessed. Random effects model was used if heterogeneity was present. Quality of the included studies was assessed using the Jadad score.
Result(s): Ten RCTs met the inclusion criteria. Four studies compared DGWT to persistent conventional techniques, 3 used a pancreatic stent to gain access into the bile duct and 3 utilized precut sphincterotomy. The indications included common bile duct stones and pancreatic or biliary malignancy. Mean age of patients ranged from 58-70 years. The percentage of female patients ranged from 43-61%. DGWT did not increase the cannulation rate compared to other techniques (1.05; 95% CI 0.91-1.20, p=0.53, I²=78%). The risk of post-ERCP pancreatitis (PEP)was higher with DGWT (RR 2.29; 95% CI 1.50-3.47, p=0.0001, I²=8%). On subgroup analysis, the risk of PEP was similar between DWGT and persistent conventional techniques (4 studies). Compared to precut sphincterotomy (3 studies)and PD stent placement (3 studies)the risk of PEP was higher with DGWT. The risk of other ERCP related complications (bleeding, perforation, cholangitis)were similar between DWGT and other techniques.
Conclusion(s): DGWT is associated with a higher risk of PEP and is not superior to other techniques in achieving biliary cannulation. PEP prophylaxis should be used if DGWT is utilized for biliary access.
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Introduction: Deep biliary cannulation can fail in 5-10% of patients during ERCP. Precut sphincterotomy has emerged as a rescue technique. However, precut sphincterotomy has been associated with higher complications after ERCP in some studies, especially post-ERCP pancreatitis (PEP). More recent studies have reported lower risk of complications with early precut sphincterotomy. We performed an updated meta-analysis of all published randomized controlled trials (RCTs)to assess the safety and cannulation rates with early precut sphincterotomy.
Method(s): Several databases were searched systematically for relevant articles (Pubmed, Embase, the Cochrane Library). Abstracts of recent gastroenterology meetings were also searched. Data was extracted by two reviewers using standardized extraction forms. There were no language restrictions. Data was extracted regarding the adverse events including pancreatitis, cholangitis, bleeding, perforation rates, cannulation success rates and need for repeat ERCP. Summary effect sizes (risk ratios)were calculated using Comprehensive Meta-analysis software. Heterogeneity and publication bias were also assessed. Quality of the studies was assessed using the Jadad score. Random effects model was used if heterogeneity was present.
Result(s): Eleven randomized controlled trials met the inclusion criteria. Ten were full length publications and 1 was an abstract publication. All studies compared early precut sphincterotomy to the standard techniques of cannulation. Sample size of the studies ranged from 62 to 375 patients. Early precut sphinctertomy was associated with a decreased risk of PEP (RR 0.47; 95% CI 0.31-0.72, p=0.0001, I²=13%). PEP occurred in 3.6% (32/884)patients with early precut sphincterotomy and 8.7% (81/933)of patients with conventional techniques. Cannulation rates were similar in both groups (RR 1.03; 95% CI 0.72-1.46, p=0.88). There was no difference in the risk of cholangitis, bleeding or perforation between the two groups. The need for repeat ERCP was similar between the two groups. No significant heterogeneity was present. No publication bias was found.
Conclusion(s): Compared to conventional techniques, the risk of PEP is lower with early precut sphincterotomy. It is not associated with higher rates of perforation, bleeding or cholangitis Early precut sphincterotomy should be considered in patients with difficult biliary access.
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Introduction: Biliary stenting is frequently performed for palliation in malignant distal biliary obstruction. Metal and plastic stents are both used for palliation. Several recent studies have compared the outcomes between the two different stents. We performed a meta-analysis of randomized controlled trials (RCTs)to compare the efficacy and adverse effects of plastic and self-expandable metal biliary stents (SEMS).
Method(s): Pubmed, Embase and Cochrane databases were searched for all RCTs comparing plastic stents and SEMS in distal malignant biliary obstruction. Data was extracted by two reviewers using a standard form. Data on patient characteristics, occlusion rates, 30-day mortality, insertion success rates, therapeutic success, re-intervention rates and adverse effects were extracted. Summary effect sizes (risk ratio or mean difference)was calculated using the Comprehensive Meta-analysis software. Studies were scored on quality using the Jadad score. Publication bias and heterogeneity was assessed. If heterogeneity was present, random effects model was used for estimating summary estimates.
Result(s): Eleven studies were included (474 patients with SEMS and 469 with plastic stents). Ten studies placed the stents endoscopically and 1 study used the percutaneous transhepatic approach. The size of the plastic stents ranged from 10Fr-12Fr. The majority of the studies (8)used uncovered metal stents, 1 used partially covered metal stent and 1 used fully covered metal stent. The mean age of patients ranged from 70 to 77 years. The insertion success rates were similar between the groups (RR 0.99; 95% CI 0.96-1.01, p= 0.37). The long-term patency was higher with SEMS (RR 0.54: 95% CI 0.43-0.67, p=0.001, I²=32%). Re-intervention rates were lower with SEMS. Therapeutic failure, risk of cholangitis and 30-day mortality were similar between the groups.
Conclusion(s): SEMS is associated with longer patency and a decreased need for re-intervention. SEMS may be more cost effective in patients with a life expectancy of > 30 days.
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