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1.  The Scientific Basis for Chelation: Animal Studies and Lead Chelation 
Journal of Medical Toxicology  2013;9(4):326-338.
This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.
doi:10.1007/s13181-013-0339-2
PMCID: PMC3846979  PMID: 24113857
Succimer chelation treatment; Neurobehavioral deficits; Lead poisoning; Brain lead; Autism
2.  Lycopene metabolite, apo-10′-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice 
Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10′-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9′,10′-double bond by carotene-9′,10′-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose-dependently inhibited cell growth and up-regulated sirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation (decreased inflammatory foci, TNFα, IL-6, NF-κB p65 protein expression, and STAT3 activation) in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene and protein expression, and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, this data indicates that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.
doi:10.1158/1940-6207.CAPR-13-0178
PMCID: PMC3927787  PMID: 24085778
lycopene; apo-10′-lycopenoic acid; DEN; liver cancer; inflammation; SIRT1
3.  Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 
Objective
Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK). In the present study, we investigated whether NNK treatment alone induces both preneoplastic and neoplastic lesions in the lungs of ferrets.
Methods
We exposed ferrets to NNK by i.p. injection of NNK (50 mg/kg BW) once a month for four consecutive months and then followed up for 24, 26 and 32 weeks. The incidences of pulmonary preneoplastic and neoplastic lesions were assessed by histopathological examination. The expressions of α7 nicotinic acetylcholine receptor (α7 nAChR, which has been shown to promote lung carcinogenesis) and its related molecular biomarkers in lungs were examined by immunohistochemistry and/or Western blotting analysis.
Results
Ferrets exposed to NNK alone developed both preneoplastic lesions (squamous metaplasia, dysplasia and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma), which are commonly seen in humans. The incidence of tumor induced by NNK was time-dependent in the ferrets (16.7%, 40.0% and 66.7% for 24, 26 and 32 weeks, respectively). α7 nAChR is highly expressed in the ferret bronchial/bronchiolar epithelial cells, and alveolar macrophages in ferrets exposed to NNK, and in both squamous cell carcinoma and adenocarcinoma of the ferrets. In addition, we observed the tendency for an increase in phospho-ERK and cyclin D1 protein levels (p = 0.081 and 0.080, respectively) in the lungs of ferrets exposed to NNK.
Conclusion
The development of both preneoplastic and neoplastic lesions in ferret lungs by injecting NNK alone provides a simple and highly relevant non-rodent model for studying biomarkers/molecular targets for the prevention, detection and treatment of lung carcinogenesis in humans.
PMCID: PMC4097109  PMID: 24396883
ferret; tobacco carcinogen; NNK; lung cancer; α7 nicotinic acetylcholine receptor
4.  Determinants of Manganese in Prenatal Dentin of Shed Teeth from CHAMACOS Children Living in an Agricultural Community 
Environmental science & technology  2013;47(19):11249-11257.
Manganese (Mn) is an essential nutrient, but overexposure can be neurotoxic. Over 800 000 kg of Mn-containing fungicides are applied each year in California. Manganese levels in teeth are a promising biomarker of perinatal exposure. Participants in our analysis included 207 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort study in an agricultural area of California. Mn was measured in teeth using laser-ablation-inductively coupled plasma-mass spectrometry. Our purpose was to determine environmental and lifestyle factors related to prenatal Mn levels in shed teeth. We found that storage of farmworkers’ shoes in the home, maternal farm work, agricultural use of Mn-containing fungicides within 3 km of the residence, residence built on Antioch Loam soil and Mn dust loading (μg/m2 of floor area) during pregnancy were associated with higher Mn levels in prenatal dentin (p < 0.05). Maternal smoking during pregnancy was inversely related to Mn levels in prenatal dentin (p < 0.01). Multivariable regression models explained 22–29% of the variability of Mn in prenatal dentin. Our results suggest that Mn measured in prenatal dentin provides retrospective and time specific levels of fetal exposure resulting from environmental and occupational sources.
doi:10.1021/es4018688
PMCID: PMC4167759  PMID: 24053404
5.  Consensus proposals for classification of the family Hepeviridae 
The Journal of General Virology  2014;95(Pt 10):2223-2232.
The family Hepeviridae consists of positive-stranded RNA viruses that infect a wide range of mammalian species, as well as chickens and trout. A subset of these viruses infects humans and can cause a self-limiting acute hepatitis that may become chronic in immunosuppressed individuals. Current published descriptions of the taxonomical divisions within the family Hepeviridae are contradictory in relation to the assignment of species and genotypes. Through analysis of existing sequence information, we propose a taxonomic scheme in which the family is divided into the genera Orthohepevirus (all mammalian and avian hepatitis E virus (HEV) isolates) and Piscihepevirus (cutthroat trout virus). Species within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel), Orthohepevirus B (isolates from chicken), Orthohepevirus C (isolates from rat, greater bandicoot, Asian musk shrew, ferret and mink) and Orthohepevirus D (isolates from bat). Proposals are also made for the designation of genotypes within the human and rat HEVs. This hierarchical system is congruent with hepevirus phylogeny, and the three classification levels (genus, species and genotype) are consistent with, and reflect discontinuities in the ranges of pairwise distances between amino acid sequences. Adoption of this system would include the avoidance of host names in taxonomic identifiers and provide a logical framework for the assignment of novel variants.
doi:10.1099/vir.0.068429-0
PMCID: PMC4165930  PMID: 24989172
6.  Successful Treatment of Iatrogenic Vertebral Pseudoaneurysm Using Pipeline Embolization Device 
Traumatic pseudoaneurysms are uncommon and one of the most difficult lesions to treat. Traditional treatment methods have focused on parent vessel sacrifice with or without revascularization. We report the case of a patient who underwent successful treatment of an iatrogenic extracranial vertebral artery pseudoaneurysm using the Pipeline Embolization Device. A 47-year-old man sustained an inadvertent injury to the left vertebral artery during C1-C2 fixation. Subsequent imaging revealed an iatrogenic vertebral artery pseudoaneurysm. Immediate angiogram was normal. A repeat angiogram done after 3 days of the surgery revealed a vertebral artery pseudoaneurysm. He underwent aneurysm exclusion and vascular reconstruction using the Pipeline Embolization Device. Although flow-diverting stents are currently not being used for treating traumatic pseudoaneurysms, their use may be considered in such cases if active bleeding has ceased. In our case, the patient did well and the aneurysm was excluded from circulation while reconstructing the vessel wall.
doi:10.1155/2014/341748
PMCID: PMC4167810  PMID: 25276469
7.  Chronic Ingestion of H1-Antihistamines Increase Progression of Atherosclerosis in Apolipoprotein E-/- Mice 
PLoS ONE  2014;9(7):e102165.
Although increased serum histamine levels and H1R expression in the plaque are seen in atherosclerosis, it is not known whether H1R activation is a causative factor in the development of the disease, or is a host defense response to atherogenic signals. In order to elucidate how pharmacological inhibition of histamine receptor 1 (H1R) signaling affects atherogenesis, we administered either cetirizine (1 and 4 mg/kg. b.w) or fexofenadine (10 and 40 mg/kg. b.w) to ApoE−/− mice maintained on a high fat diet for three months. Mice ingesting a low dose of cetirizine or fexofenadine had significantly higher plaque coverage in the aorta and cross-sectional lesion area at the aortic root. Surprisingly, the higher doses of cetirizine or fexofenadine did not enhance atherosclerotic lesion coverage over the controls. The low dose of fexofenadine, but not cetirizine, increased serum LDL cholesterol. Interestingly, the expression of iNOS and eNOS mRNA was increased in aortas of mice on high doses of cetirizine or fexofenadine. This may be a compensatory nitric oxide (NO)-mediated vasodilatory mechanism that accounts for the lack of increase in the progression of atherosclerosis. Although the administration of cetirizine did not alter blood pressure between the groups, there was a positive correlation between blood pressure and lesion/media ratio at the aortic root in mice receiving the low dose of cetirizine. However, this association was not observed in mice treated with the high dose of cetirizine or either doses of fexofenadine. The macrophages or T lymphocytes densities were not altered by low doses of H1-antihistamines, whereas, high doses decreased the number of macrophages but not T lymphocytes. The number of mast cells was decreased only in mice treated with low dose of fexofenadine. These results demonstrate that chronic ingestion of low therapeutic doses of cetirizine or fexofenadine enhance progression of atherosclerosis.
doi:10.1371/journal.pone.0102165
PMCID: PMC4096593  PMID: 25020133
8.  Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non-Small Cell Lung Cancer 
Cancer discovery  2013;3(4):430-443.
EML4-ALK gene rearrangements define a unique subset of non-small cell lung cancer (NSCLC) patients and the clinical success of the ALK inhibitor crizotinib in this population has become a paradigm for molecularly-targeted therapy. Here we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, resulting in greater in vitro potency, superior antitumor efficacy and prolonged animal survival compared to crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a NSCLC patient with crizotinib-resistant disease. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinases were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.
doi:10.1158/2159-8290.CD-12-0440
PMCID: PMC4086149  PMID: 23533265
Hsp90 inhibition; non-small cell lung cancer; anaplastic lymphoma kinase; ganetespib; crizotinib resistance
9.  Early life versus lifelong oral manganese exposure differently impairs skilled forelimb performance in adult rats 
Recent studies of children suggest that exposure to elevated manganese (Mn) levels disrupt aspects of motor, cognitive and behavioral functions that are dependent on dopamine brain systems. Although basal ganglia motor functions are well-known targets of adult occupational Mn exposure, the extent of motor function deficits in adults as a result of early life Mn exposure is unknown. Here we used a rodent model early life versus lifelong oral Mn exposure and the Montoya staircase test to determine whether developmental Mn exposure produces long-lasting deficits in sensorimotor performance in adulthood. Long-Evans male neonate rats (n=11/treatment) were exposed daily to oral Mn at levels of 0, 25, or 50 mg Mn/kg/d from postnatal day (PND) 1-21 (early life only), or from PND 1 - throughout life. Staircase testing began at age PND 120 and lasted 1 month to objectively quantify measures of skilled forelimb use in reaching and pellet grasping/retrieval performance. Behavioral reactivity also was rated on each trial. Results revealed that (1) behavioral reactivity scores were significantly greater in the Mn-exposed groups, compared to controls, during the staircase acclimation/training stage, but not the latter testing stages, (2) early life Mn exposure alone caused long-lasting impairments in fine motor control of reaching skills at the higher, but not lower Mn dose, (3) lifelong Mn exposure from drinking water led to widespread impairment in reaching and grasping/retrieval performance in adult rats, with the lower Mn dose group showing the greatest impairment, and (4) lifelong Mn exposure produced similar (higher Mn group) or more severe (lower Mn group) impairments compared to their early life-only Mn exposed counterparts. Collectively, these results substantiate the emerging clinical evidence in children showing associations between environmental Mn exposure and deficits in fine sensorimotor function. They also show that the objective quantification of skilled motor performance using the staircase test can serve as a sensitive measure of early life insults from environmental agents. Supported by NIEHS R01ES018990.
doi:10.1016/j.ntt.2013.04.004
PMCID: PMC3713098  PMID: 23623961
adult rats; Manganese; water intake; Montoya staircase test; skilled motor behavior; animal model, persistent effect, developmental exposure
10.  Cfh Genotype Interacts With Dietary Glycemic Index to Modulate Age-Related Macular Degeneration-Like Features in Mice 
Purpose.
Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major risk factors for AMD. We explored the effects of GI on development of early AMD-like features and changes to central nervous system (CNS) inflammation in Cfh-null mice.
Methods.
Aged 11-week-old wild type (WT) C57Bl/6J or Cfh-null mice were group pair-fed high or low GI diets for 33 weeks. At 10 months of age, mice were evaluated for early AMD-like features in the neural retina and RPE by light and electron microscopy. Brains were analyzed for Iba1 macrophage/microglia immunostaining, an indicator of inflammation.
Results.
The 10-month-old WT mice showed no retinal abnormalities on either diet. The Cfh-null mice, however, showed distinct early AMD-like features in the RPE when fed a low GI diet, including vacuolation, disruption of basal infoldings, and increased basal laminar deposits. The Cfh-null mice also showed thinning of the RPE, hypopigmentation, and increased numbers of Iba1-expressing macrophages in the brain, irrespective of diet.
Conclusions.
The presence of early AMD-like features by 10 months of age in Cfh-null mice fed a low GI diet is surprising, given the apparent protection from the development of such features in aged WT mice or humans consuming lower GI diets. Our findings highlight the need to consider gene–diet interactions when developing animal models and therapeutic approaches to treat AMD.
Risk for and progression of AMD are enhanced in all cohorts of humans and mice that consumed higher glycemic index diets. In contrast, in Cfh-null mice, RPE showed AMD-like features only when fed a low glycemic index diet, emphasizing the importance of gene–diet interactions.
doi:10.1167/iovs.13-12413
PMCID: PMC3901416  PMID: 24370827
glycemic index; complement; gene-diet interaction; inflammation; aging
11.  Secondary Ion Mass Spectrometry Imaging of Dictyostelium discoideum Aggregation Streams 
PLoS ONE  2014;9(6):e99319.
High resolution imaging mass spectrometry could become a valuable tool for cell and developmental biology, but both, high spatial and mass spectral resolution are needed to enable this. In this report, we employed Bi3 bombardment time-of-flight (Bi3 ToF-SIMS) and C60 bombardment Fourier transform ion cyclotron resonance secondary ion mass spectrometry (C60 FTICR-SIMS) to image Dictyostelium discoideum aggregation streams. Nearly 300 lipid species were identified from the aggregation streams. High resolution mass spectrometry imaging (FTICR-SIMS) enabled the generation of multiple molecular ion maps at the nominal mass level and provided good coverage for fatty acyls, prenol lipids, and sterol lipids. The comparison of Bi3 ToF-SIMS and C60 FTICR-SIMS suggested that while the first provides fast, high spatial resolution molecular ion images, the chemical complexity of biological samples warrants the use of high resolution analyzers for accurate ion identification.
doi:10.1371/journal.pone.0099319
PMCID: PMC4049834  PMID: 24911189
12.  Golgi Phosphoprotein 4 (GPP130) is a Sensitive and Selective Cellular Target of Manganese Exposure 
Synapse (New York, N.Y.)  2013;67(5):205-215.
Chronic elevated exposure to manganese (Mn) is associated with neurocognitive and fine motor deficits in children. However, relatively little is understood about cellular responses to Mn spanning the transition between physiologic to toxic levels of exposure. Here, we investigated the specificity, sensitivity, and time course of the Golgi Phosphoprotein 4 (GPP130) response to Mn exposure in AF5 GABAergic neuronal cells, and we determined the extent to which GPP130 degradation occurs in brain cells in vivo in rats subchronically exposed to Mn. Our results show that GPP130 degradation in AF5 cells was specific to Mn, and did not occur following exposure to cobalt, copper, iron, nickel, or zinc. GPP130 degradation occurred without measurable increases in intracellular Mn levels and at Mn exposures as low as 0.54 µM. GPP130 protein was detectable by immunofluorescence in only ~15–30% of cells in striatal and cortical rat brain slices, and Mn-exposed animals exhibited a significant reduction in both the number of GPP130-positive cells, and the overall levels of GPP130 protein, demonstrating the in vivo relevance of this Mn-specific response within the primary target organ of Mn toxicity. These results provide insight into specific mechanism(s) of cellular Mn regulation and toxicity within the brain, including the selective susceptibility of cells to Mn cytotoxicity.
doi:10.1002/syn.21632
PMCID: PMC3987769  PMID: 23280773
neurotoxicity; GABAergic; manganese; rodents; AF5 cells; homeostasis
13.  β-Cryptoxanthin Restores Nicotine-Reduced Lung SIRT1 to Normal Levels and Inhibits Nicotine-Promoted Lung Tumorigenesis and Emphysema in A/J Mice 
Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability; and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.
doi:10.1158/1940-6207.CAPR-12-0368
PMCID: PMC3618609  PMID: 23275008
nicotine; β-cryptoxanthin; NNK; lung cancer; emphysema; SIRT1
14.  The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer 
Investigational New Drugs  2014;32(4):577-586.
Summary
The integration of targeted agents to standard cytotoxic regimens has improved outcomes for patients with colorectal cancer (CRC) over recent years; however this malignancy remains the second leading cause of cancer mortality in industrialized countries. Small molecule inhibitors of heat shock protein 90 (HSP90) are one of the most actively pursued classes of compounds for the development of new cancer therapies. Here we evaluated the activity of ganetespib, a second-generation HSP90 inhibitor, in models of CRC. Ganetespib reduced cell viability in a panel of CRC cell lines in vitro with low nanomolar potency. Mechanistically, drug treatment exerted concomitant effects on multiple oncogenic signaling pathways, cell cycle regulation, and DNA damage repair capacity to promote apoptosis. Combinations of ganetespib and low-dose ionizing radiation enhanced the radiosensitivity of HCT 116 cells and resulted in superior cytotoxic activity over either treatment alone. In vivo, the single-agent activity of ganetespib was relatively modest, suppressing HCT 116 xenograft tumor growth by approximately half. However, ganetespib significantly potentiated the antitumor efficacy of the 5-Fluorouracil (5-FU) prodrug capecitabine in HCT 116 xenografts, causing tumor regressions in a model that is intrinsically resistant to fluoropyrimidine therapy. This demonstration of combinatorial benefit afforded by an HSP90 inhibitor to a standard CRC adjuvant regimen provides an attractive new framework for the potential application of ganetespib as an investigational agent in this disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s10637-014-0095-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10637-014-0095-4
PMCID: PMC4101249  PMID: 24682747
HSP90 inhibition; Ganetespib; Colorectal cancer; Combination therapy
15.  Hair as a Biomarker of Environmental Manganese Exposure 
Environmental science & technology  2013;47(3):1629-1637.
The absence of well-validated biomarkers of manganese (Mn) exposure in children remains a major obstacle for studies of Mn toxicity. We developed a hair cleaning methodology to establish the utility of hair as an exposure biomarker for Mn and other metals (Pb, Cr, Cu), using ICP-MS, scanning electron microscopy, and laser ablation ICP-MS to evaluate cleaning efficacy. Exogenous metal contamination on hair that was untreated or intentionally contaminated with dust or Mn-contaminated water was effectively removed using a cleaning method of 0.5% Triton X-100 sonication plus 1N nitric acid sonication. This cleaning method was then used on hair samples from children (n=121) in an ongoing study of environmental Mn exposure and related health effects. Mean hair Mn levels were 0.121 μg/g (median = 0.073 μg/g, range = 0.011 – 0.736 μg/g), which are ~4 to 70-fold lower than levels reported in other pediatric Mn studies. Hair Mn levels were also significantly higher in children living in the vicinity of active, but not historic, ferroalloy plant emissions compared to controls (P<0.001). These data show that exogenous metal contamination on hair can be effectively cleaned of exogenous metal contamination, and they substantiate the use of hair Mn levels as a biomarker of environmental Mn exposure in children.
doi:10.1021/es3035297
PMCID: PMC3583582  PMID: 23259818
17.  Maternal Blood, Plasma, and Breast Milk Lead: Lactational Transfer and Contribution to Infant Exposure 
Background: Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood.
Objectives: We explored the dose–response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant.
Methods: We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose–response relationships between blood, plasma, and milk lead levels.
Results: Maternal lead levels (mean ± SD) were as follows: blood: 7.7 ± 4.0 μg/dL; plasma: 0.1 ± 0.1 μg/L; milk: 0.8 ± 0.7 μg/L. The average M/P lead ratio was 7.7 (range, 0.6–39.8) with 97% of the ratios being > 1. The dose–response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function = 6.5, p = 0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 μg/L of plasma lead, respectively, below and above 0.1 μg/L plasma lead. Infant blood lead level (3.4 ± 2.2 μg/dL) increased by 1.8 μg/dL per 1 μg/L milk lead (p < 0.0001, R2 = 0.3).
Conclusions: The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.
Citation: Ettinger AS, Roy A, Amarasiriwardena CJ, Smith DR, Lupoli N, Mercado-García A, Lamadrid-Figueroa H, Tellez-Rojo MM, Hu H, Hernández-Avila M. 2014. Maternal blood, plasma, and breast milk lead: lactational transfer and contribution to infant exposure. Environ Health Perspect 122:87–92; http://dx.doi.org/10.1289/ehp.1307187
doi:10.1289/ehp.1307187
PMCID: PMC3888576  PMID: 24184948
18.  Predictors of virtual radial arm maze performance in adolescent Italian children 
Neurotoxicology  2012;33(5):1203-1211.
Background
Comparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The Radial Arm Maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies.
Objective
To describe the characteristics and correlates of the Virtual Radial Arm Maze (VRAM) in 255 children age 10–15 years from Italy.
Methods
We administered the VRAM using a laptop computer and measured children’s performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills.
Results
Children’s VRAM performance tended to improve between trials 1–6 and then plateaued between trials 6–8. Males finished the task 14 seconds faster (95% Confidence Interval [CI]:-20, -9) than females. Children who played 2+ hours of video games per day finished 16 seconds faster (CI:-26, -6) and with 34% (CI:5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher Cognitive/Inattention CPRS scores were associated with more working (11%; CI:1, 22) and reference memory errors (7%; CI:1, 12).
Conclusions
Consistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants.
doi:10.1016/j.neuro.2012.06.012
PMCID: PMC3470779  PMID: 22771383
Child behavior; computerized tests; environmental chemicals; epidemiology; toxicology
19.  INVERSE ASSOCIATION OF INTELLECTUAL FUNCTION WITH VERY LOW BLOOD LEAD BUT NOT WITH MANGANESE EXPOSURE IN ITALIAN ADOLESCENTS 
Environmental research  2012;118:65-71.
Background
Pediatric lead (Pb) exposure impacts cognitive function and behavior and co-exposure to manganese (Mn) may enhance neurotoxicity.
Objectives
To assess cognitive and behavioral function in adolescents with environmental exposure to Pb and Mn.
Methods
In this cross sectional study, cognitive function and behavior were examined in healthy adolescents with environmental exposure to metals. The Wechsler Intelligence Scale for Children (WISC) and the Conners-Wells’ Adolescent Self-Report Scale Long Form (CASS:L) were used to assess cognitive and behavioral function respectively. ALAD polymorphisms rs1800435 and rs1139488 were measured as potential modifiers.
Results
We examined 299 adolescents (49.2% females) aged 11–14 years. Blood lead (BPb) averaged 1.71 μg/dL (median 1.5, range 0.44 – 10.2), mean Blood Manganese (BMn) was 11.1 μg/dL (median 10.9, range 4.00 – 24.1). Average total IQ was 106.3 (verbal IQ = 102, performance IQ = 109.3). According to a multiple regression model considering the effect of other covariates, a reduction of about 2.4 IQ points resulted from a two-fold increase of BPb. The Benchmark Level of BPb associated with a loss of 1 IQ-point (BML01) was 0.19 μg/dL, with a lower 95% confidence limit (BMLL01) of 0.11 μg/dL. A very weak correlation resulted between BPb and the ADHD-like behavior (Kendall’s tau rank correlation = 0.074, p =0.07). No influence of ALAD genotype was observed on any outcome. Manganese was not associated with cognitive and behavioral outcomes, nor was there any interaction with lead.
Conclusions
These findings demonstrate that very low level of lead exposure has a significant negative impact on cognitive function in adolescent children. Being an essential micro-nutrient, manganese may not cause cognitive effects at these low exposure levels.
doi:10.1016/j.envres.2012.08.003
PMCID: PMC3477579  PMID: 22925625
20.  TREMOR, OLFACTORY AND MOTOR CHANGES IN ITALIAN ADOLESCENTS EXPOSED TO HISTORICAL FERRO-MANGANESE EMISSION 
Neurotoxicology  2012;33(4):687-696.
Background and Objective
Increased prevalence of Parkinsonism was observed in Valcamonica, Italy, a region impacted by ferroalloy plants emissions containing manganese and other metals for a century until 2001. The aim of this study was to assess neurobehavioral functions in adolescents from the impacted region and the reference area of Garda Lake.
Methods
Adolescents age 11–14 yrs were recruited through the school system for neuro-behavioral testing. Metals including manganese, lead, iron, zinc, copper were measured in airborne particulate matter collected with 24-hour personal samplers, and in soil, tap water, blood, urine and hair. Independent variables included parental education and socio-economic status, children’s body mass index, number of siblings, parity order, smoking and drinking habits.
Results
A total of 311 subjects (49.2% females), residing in either the exposed (n=154) or the reference (n=157) area participated. Average airborne and soil manganese were respectively 49.5 ng/m3 (median 31.4, range 1.24–517) and 958 ppm (median 897, range 465–1729) in the impacted area, and 27.4 ng/m3 (median 24.7, range 5.3–85.9) ng/m3 and 427 ppm (median 409 range 160–734) in the reference area. Regression models showed significant impairment of motor coordination (Luria-Nebraska test, p=0.0005), hand dexterity (Aiming Pursuit test, p= 0.0115) and odor identification (Sniffin’ task, p=0.003 ) associated with soil manganese. Tremor intensity was positively associated with blood (p=0.005) and hair (p=0.01) manganese.
Conclusion
Historical environmental exposure to manganese from ferroalloy emission reflected by the concentration in soil and the biomarkers was associated with subclinical deficits in olfactory and motor function among adolescents.
doi:10.1016/j.neuro.2012.01.005
PMCID: PMC3360122  PMID: 22322213
neuromotor changes; children; airborne particles; soil; metals; manganese
21.  Quest for Biomarkers of Treatment-Resistant Depression: Shifting the Paradigm Toward Risk 
The search for potential biomarkers of psychiatric disorders is a central topic in biological psychiatry. This review concerns published studies on potential biomarkers of treatment-resistant depression (TRD). The search for biomarkers of TRD in the bloodstream has focused on cytokines and steroids as well as brain-derived neurotropic factor. Additional approaches to identifying biomarkers of TRD have dealt with cerebrospinal fluid analysis, magnetic resonance imaging, and positron emission tomography. Some studies have also investigated potential genetic and epigenetic factors in TRD. Most studies have, however, used a post hoc experimental design that failed to determine the association between biomarkers and the initial risk of TRD. Particular attention in future studies should be on shifting the experimental paradigm toward procedures that can determine the risk for developing treatment resistance in untreated depressed individuals.
doi:10.3389/fpsyt.2013.00057
PMCID: PMC3684787  PMID: 23785338
depressive disorders; biomarkers; treatment resistance; immune system; cytokines; brain imaging; experimental design
23.  Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes 
Investigational New Drugs  2013;32(1):14-24.
Summary
Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of multiple cellular client proteins, a number of which have been implicated in the pathogenesis of breast cancer. Here we undertook a comprehensive evaluation of the activity of ganetespib, a selective Hsp90 inhibitor, in this malignancy. With low nanomolar potency, ganetespib reduced cell viability in a panel of hormone receptor-positive, HER2-overexpressing, triple-negative and inflammatory breast cancer cell lines in vitro. Ganetespib treatment induced a rapid and sustained destabilization of multiple client proteins and oncogenic signaling pathways and even brief exposure was sufficient to induce and maintain suppression of HER2 levels in cells driven by this receptor. Indeed, HER2-overexpressing BT-474 cells were comparatively more sensitive to ganetespib than the dual HER2/EGFR tyrosine kinase inhibitor lapatinib in three-dimensional culture. Ganetespib exposure caused pleiotropic effects in the inflammatory breast cancer line SUM149, including receptor tyrosine kinases, MAPK, AKT and mTOR signaling, transcription factors and proteins involved in cell cycle, stress and apoptotic regulation, as well as providing combinatorial benefit with lapatinib in these cells. This multimodal activity translated to potent antitumor efficacy in vivo, suppressing tumor growth in MCF-7 and MDA-MB-231 xenografts and inducing tumor regression in the BT-474 model. Thus, ganetespib potently inhibits Hsp90 leading to the degradation of multiple clinically-validated oncogenic client proteins in breast cancer cells, encompassing the broad spectrum of molecularly-defined subtypes. This preclinical activity profile suggests that ganetespib may offer considerable promise as a new therapeutic candidate for patients with advanced breast cancers.
Electronic supplementary material
The online version of this article (doi:10.1007/s10637-013-9971-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10637-013-9971-6
PMCID: PMC3913847  PMID: 23686707
Hsp90 inhibition; Ganetespib; Breast cancer; Cancer therapy
24.  Determining Fetal Manganese Exposure from Mantle Dentine of Deciduous Teeth 
Environmental science & technology  2012;46(9):5118-5125.
Studies addressing health effects of manganese (Mn) excess or deficiency during prenatal development are hampered by a lack of biomarkers that can reconstruct fetal exposure. We propose a method using the neonatal line, a histological feature in deciduous teeth, to identify regions of mantle dentine formed at different prenatal periods. Micro-measurements of Mn in these regions may be used to reconstruct exposure at specific times in fetal development. To test our hypothesis, we recruited pregnant women before 20 weeks gestation from a cohort of farmworkers exposed to Mn-containing pesticides. We collected house floor dust samples and mother’s blood during the second trimester; umbilical cord blood at birth; and shed deciduous incisors when the child was ~7 years of age. Mn levels in mantle dentine formed during the second trimester (as 55Mn:43Ca area under curve) were significantly associated with floor dust Mn loading (rspearman=0.40; p=0.0005; n=72). Furthermore, 55Mn:43Ca in sampling points immediately adjacent the neonatal line were significantly associated to Mn concentrations in cord blood (rspearman=0.70; p=0.003; n=16). Our results support that Mn levels in mantle dentine are useful in discerning perinatal Mn exposure, offering a potentially important biomarker for the study of health effects due to environmental Mn exposure.
doi:10.1021/es203569f
PMCID: PMC3341525  PMID: 22455722
biomarker; dentine; enamel; manganese; prenatal exposure
25.  Has the Emergence of Community-Associated Methicillin-Resistant Staphylococcus aureus Increased Trimethoprim-Sulfamethoxazole Use and Resistance?: a 10-Year Time Series Analysis 
Antimicrobial Agents and Chemotherapy  2012;56(11):5655-5660.
There are an increasing number of indications for trimethoprim-sulfamethoxazole use, including skin and soft tissue infections due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Assessing the relationship between rates of use and antibiotic resistance is important for maintaining the expected efficacy of this drug for guideline-recommended conditions. Using interrupted time series analysis, we aimed to determine whether the 2005 emergence of CA-MRSA and recommendations of trimethoprim-sulfamethoxazole as the preferred therapy were associated with changes in trimethoprim-sulfamethoxazole use and susceptibility rates. The data from all VA Boston Health Care System facilities, including 118,863 inpatient admissions, 6,272,661 outpatient clinic visits, and 10,138 isolates were collected over a 10-year period. There was a significant (P = 0.02) increase in trimethoprim-sulfamethoxazole prescriptions in the post-CA-MRSA period (1,605/year) compared to the pre-CA-MRSA period (1,538/year). Although the overall susceptibility of Escherichia coli and Proteus spp. to trimethoprim-sulfamethoxazole decreased over the study period, the rate of change in the pre- versus the post-CA-MRSA period was not significantly different. The changes in susceptibility rates of S. aureus to trimethoprim-sulfamethoxazole and to methicillin were also not significantly different. The CA-MRSA period is associated with a significant increase in use of trimethoprim-sulfamethoxazole but not with significant changes in the rates of susceptibilities among clinical isolates. There is also no evidence for selection of organisms with increased resistance to other antimicrobials in relation to increased trimethoprim-sulfamethoxazole use.
doi:10.1128/AAC.01011-12
PMCID: PMC3486583  PMID: 22908161

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