First Detection of Batrachochytrium dendrobatidis in Wild Frogs from Bangladesh

EcoHealth - Global amphibian populations are facing a novel threat, chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), which is responsible for the severe decline of a...     

Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy

Purpose

PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase-9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo.

Experimental Design

We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitonealy administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated.

Results

We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT-C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed.

Conclusion

Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression.     

Comparison of Concentrations of Selected Metals and Organics in Fish Tissue and Sediment in the Grand River,Ohio, and the Southern Lake Erie Drainage Basin

The purpose of this paper is to develop a database of fish tissue and sediment concentrations of selected chemicals in the southern Lake Erie drainage basin, to compare contaminant concentrations in fish tissue and sediment collected from the Grand River, Ohio, in the vicinity of a former soda ash and chromate plant with that for other waterbodies in the drainage basin, and to evaluate the potential human health risks posed by these chemicals, with special focus on chromium. The results of this study indicate that chemical concentrations in fish tissue and sediment from the Grand River are generally lower than that of other waterbodies in the southern Lake Erie drainage basin. Although arsenic and beryllium concentrations in Grand River sediment are above their respective human health-based concentrations, these concentrations are comparable with local and regional background and are not expected to pose a significant incremental risk to human health. In addition, sediment concentrations do not exceed ecological screening criteria. Although PCB and several pesticides were found to have concentrations in fish tissue from the Grand River in excess of human health based concentrations, these concentrations are among the lowest found in waterbodies in the southern Lake Erie drainage basin.     

Investigative Strategies for a Large Former Industrial Facility “The Diamond Shamrock Painesville Works Site”—Case Study of Preremedial Investigation Activities

Environmental managers and regulatory managers face a complex challenge when investigating large geographic sites. The goals of the two parties seem to be diametrically opposed at times. The environmental manager wants to limit his liability both in near-term expenses and in long-term remedial costs and potential litigation. The regulatory manager wants to limit potential exposure of the public and the environment to site contamination. In many ways these goals are the same. However, it appears to the environmental manager that the regulator desires ultraconservative and extensive data collection that prove no risk, whereas it appears to the regulator that the environmental manager may be reluctant to collect such extensive data due to budget limitations. This challenge is amplified when the geographic area of interest is very large. This case study presents an alternative to this dilemma, and it reveals the preliminary steps taken at the 1100-acre Diamond Shamrock Painesville Works Site in Painesville, Ohio. The goal is to strike a balance between the approaches that would be taken by either the environmental manager or the regulatory manager and for the purpose of determining whether site conditions represent human health or environmental concerns and if certain media require remediation.     

Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin

Background

The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric ¹⁴C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques.

Methodology/Principal Finding

The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for ¹⁴C content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5–15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p = 0.0014). Most plaques were echo-lucent rather than echo-rich (2.24±0.97, range 1–5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8±12.4 vs. 50.4±6.2, p = 0.00005; 57.6±26.1 vs. 39.8±25.7, p<0.0005, respectively), less collagen (45.3±6.1 vs. 51.1±9.8, p<0.05), and fewer smooth muscle cells (130±31 vs. 141±21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation.

Conclusions/Significance

Our results show, for the first time, that plaque age, as judge by relative incorporation of ¹⁴C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.     

VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations

K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a non-invasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-ras^LA1 model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations.     

Evaluation of Three Measures of Exposure Concentration: A Case Study of Surface Sediment Concentrations in the Passaic River

Arithmetic and lognormal means historically have been used as estimates of exposure concentration for both human health and ecological risk assessment. Past risk assessment guidance has emphasized the need to include all available informa tion, particularly regarding the spatial and temporal aspects of data and exposure. One estimate of exposure concentration that includes spatial information is the 95% upper confidence limit (UCL) of the area weighted mean. An area weighted mean is calculated using weightings based on the ratio of the area associated with a sample location and the total area of the study area. Currently, U.S. Environmental Protection Agency (USEPA) risk assessment guidance recommends the use of the 95% UCL of the arithmetic mean as the most appropriate measure of exposure concentration for soil and sediment in human health and ecological risk assess ments. The purpose of this study was two fold: (1) to evaluate the use of the 95% UCL of the area weighted mean vs. the 95% UCL of the arithmetic mean for the lognormal distribution and the normal distribution using a large data set from a recent riverine sediment characterization study, and (2) to evaluate the potential associated with the different approaches for reduction in surface sediment exposure concentrations for 2,3,7,8 TCDD and coplanar polychlorinated biphenyls (PCBs) for several subsets of the data. The results of this evaluation indicated that there was no significant reduction in exposure concentrations of the study area surface sediments after any of the selected higher concentration data points had been removed from the various data subsets. In addition, this evaluation indicated that, due to its dependence on the variance of the data, the 95% UCL of the arithmetic mean for a lognormal distribution produced subset exposure concentrations that were higher than the calculated concentrations of the full data set and produced the smallest percent changes in concentration compared to the other two measures. Based on this analysis, the 95% UCL of the area weighted mean was determined to be the most stable and appropriate estimator of exposure concentration for surface sediments.