Corrosion of Steel in CRCP, HR-1004, 1975

The Materials and Research Departments cooperated in planning and performing Research Project HR-1004 during the summer of 1974. The Research Department agreed to accept responsibility for the final report; it has been delayed because of our efforts to obtain a maximum amount of information from the data by means of various statistical analyses. This memorandum contains all of the data, hopefully in a manner that will permit you to proceed with your consideration of an experimental project using cathodic protection for the CRCP steel. A more detailed report will be prepared at a later date.

Evaluation of Deicing Materials and Corrosion Reducing Treatments for Deicing Salts, TR-471, 2007

Effective winter maintenance makes use of freezing-point-depressant chemicals (also known as ice-control products) to prevent the formation of the bond between snow and ice and the highway pavement. In performing such winter maintenance, the selection of appropriate ice-control products for the bond prevention task involves consideration of a number of factors, as indicated in Nixon and Williams (2001). The factors are in essence performance measurements of the ice-control products, and as such can be easily incorporated into a specification document to allow for selection of the best ice-control products for a given agency to use in its winter maintenance activities. Once performance measures for de-icing or anti-icing chemicals have been specified, this allows the creation of a quality control program for the acceptance of those chemicals. This study presents a series of performance measurement tests for ice-control products, and discusses the role that they can play in such a quality control program. Some tests are simple and rapid enough that they can be performed on every load of icecontrol products received, while for others, a sampling technique must be used. An appropriate sampling technique is presented. Further, each test is categorized as to whether it should be applied to every load of ice-control products or on a sampling basis. The study includes a detailed literature review that considers the performance of ice-control products in three areas: temperature related performance, product consistency, and negative side effects. The negative side effects are further broken down into three areas, namely operational side effects (such as chemical slipperiness), environmental side effects, and infrastructural side effects (such as corrosion of vehicles and damage to concrete). The review indicated that in the area of side effects the field performance of ice-control products is currently so difficult to model in the laboratory that no particular specification tests can be recommended at this time. A study of the impact of ice-control products on concrete was performed by Professor Wang of Iowa State University as a sub-contract to this study, and has been presented to the Iowa Highway Research Board prior to this report.

Investigation of Materials for the Reduction and Prevention of Corrosion on Highway Maintenance Equipment, TR-472, 2009

The issue of corrosion of winter maintenance equipment is becoming of greater concern because of the increased use of liquid solutions of ice control chemicals, as opposed to their application in solid form. Being in liquid form, the ice control chemicals can more easily penetrate into the nooks and crannies on equipment and avoid being cleansed from the vehicle. Given this enhanced corrosive ability, methods must be found to minimize corrosion. The methods may include coatings, additives, cleansing techniques, other methods, and may also include doing nothing, and accepting a reduced equipment lifetime as a valid (perhaps) trade off with the enhanced benefits of using liquid ice control chemicals. In reality, some combination of these methods may prove to be optimal. Whatever solutions are selected, they must be relatively cheap and durable. The latter point is critical because of the environment in which maintenance trucks operate, in which scrapes, scratches and dents are facts of life. Protection methods that are not robust simply will not work. The purpose of this study is to determine how corrosion occurs on maintenance trucks, to find methods that would minimize the major corrosion mechanisms, and to

Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion.

Targeted angiostatic therapy receives major attention for the treatment of cancer and exudative age-related macular degeneration (AMD). Photodynamic therapy (PDT) has been used as an effective clinical approach for these diseases. As PDT can cause an angiogenic response in the treated tissue, combination of PDT with anti-angiogenic compounds should lead to improved therapy. This study was undertaken to test the clinically used small molecule kinase inhibitors Nexavar® (sorafenib), Tarceva® (erlotinib) and Sutent® (sunitinib) for this purpose, and to compare the results to the combination of Visudyne®-PDT with Avastin® (bevacizumab) treatment. When topically applied to the chicken chorioallantoic membrane at embryo development day (EDD) 7, a clear inhibition of blood vessel development was observed, with sorafenib being most efficient. To investigate the combination with phototherapy, Visudyne®-PDT was first applied on EDD11 to close all <100 μm vessels. Application of angiostatics after PDT resulted in a significant decrease in vessel regrowth in terms of reduced vessel density and number of branching points/mm(2) . As the 50% effective dose (ED50) for all compounds was approximately 10-fold lower, Sorafenib outperformed the other compounds. In vitro, all kinase inhibitors decreased the viability of human umbilical vein endothelial cells. Sunitinib convincingly inhibited the in vitro migration of endothelial cells. These results suggest the therapeutic potential of these compounds for application in combination with PDT in anti-cancer approaches, and possibly also in the treatment of other diseases where angiogenesis plays an important role.

Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.

Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

BACKGROUND: Histone deacetylase inhibitors (HDACi) are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB) is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. RESULTS: We show here that the HDACi Sodium Butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA) strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. CONCLUSION: HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

ALK inhibitors in the treatment of advanced NSCLC.

Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.

Heavy metal ions are potent inhibitors of protein folding.

Environmental and occupational exposure to heavy metals such as cadmium, mercury and lead results in severe health hazards including prenatal and developmental defects. The deleterious effects of heavy metal ions have hitherto been attributed to their interactions with specific, particularly susceptible native proteins. Here, we report an as yet undescribed mode of heavy metal toxicity. Cd2+, Hg2+ and Pb2+ proved to inhibit very efficiently the spontaneous refolding of chemically denatured proteins by forming high-affinity multidentate complexes with thiol and other functional groups (IC(50) in the nanomolar range). With similar efficacy, the heavy metal ions inhibited the chaperone-assisted refolding of chemically denatured and heat-denatured proteins. Thus, the toxic effects of heavy metal ions may result as well from their interaction with the more readily accessible functional groups of proteins in nascent and other non-native form. The toxic scope of heavy metals seems to be substantially larger than assumed so far.

The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders

Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue. Thus the biological importance of prolyl-specific peptidases points to a high potential for drug discovery for this family of enzymes. Panels of inhibitors have been synthesized and their effects, determined in biological models, suggest the inhibition of families of enzymes with similar activities. Prolyl-specific aminodipeptidases include dipeptidyl-aminodipeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protease-alpha (FAP-alpha)/seprase, able to release X-Pro dipeptides from the N-terminus of peptides. DPP IV inhibitors are in clinical use for type 2 diabetes. In this review, the expression and the potential functions of prolyl-aminodipeptidases are reviewed in diseases, and the inhibitors developed for these enzymes are discussed, with a specific focus on inhibitors able to discriminate between DPP IV and fibroblast activation protease-alpha (FAPalpha)/seprase as potential leads for the treatment of fibrogenic diseases.

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib.

Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein-targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations.

Evaluation of Corrosion Resistance of Different Steel Reinforcement Types, 2006

The corrosion of steel reinforcement in an aging highway infrastructure is a major problem currently facing the transportation engineering community. In the United States alone, maintenance and replacement costs for deficient bridges are measured in billions of dollars. The application of corrosion-resistant steel reinforcement as an alternative reinforcement to existing mild steel reinforced concrete bridge decks has potential to mitigate corrosion problems, due to the fundamental properties associated with the materials. To investigate corrosion prevention through the use of corrosion-resistant alloys, the performance of corrosion resistance of MMFX microcomposite steel reinforcement, a high-strength, high-chromium steel reinforcement, was evaluated. The study consisted of both field and laboratory components conducted at the Iowa State University Bridge Engineering Center to determine whether MMFX reinforcement provides superior corrosion resistance to epoxy-coated mild steel reinforcement in bridge decks. Because definitive field evidence of the corrosion resistance of MMFX reinforcement may require several years of monitoring, strict attention was given to investigating reinforcement under accelerated conditions in the laboratory, based on typical ASTM and Rapid Macrocell accelerated corrosion tests. After 40 weeks of laboratory testing, the ASTM ACT corrosion potentials indicate that corrosion had not initiated for either MMFX or the as-delivered epoxy-coated reinforcement. Conversely, uncoated mild steel specimens underwent corrosion within the fifth week, while epoxy-coated reinforcement specimens with induced holidays underwent corrosion between 15 and 30 weeks. Within the fifth week of testing, the Rapid Macrocell ACT produced corrosion risk potentials that indicate active corrosion for all reinforcement types tested. While the limited results from the 40 weeks of laboratory testing may not constitute a prediction of life expectancy and life-cycle cost, a procedure is presented herein to determine life expectancy and associated life-cycle costs.

Potential of antimicrobial volatile organic compounds to control Sclerotinia sclerotiorum in bean seeds

The objective of this work was to evaluate the potential of an artificial mixture of volatile organic compounds (VOCs), produced by Saccharomyces cerevisiae, to control Sclerotinia sclerotiorum in vitro and in bean seeds. The phytopathogenic fungus was exposed, in polystyrene plates, to an artificial atmosphere containing a mixture of six VOCs formed by alcohols (ethanol, 3-methyl-1-butanol, 2-methyl-1-butanol and phenylethyl alcohol) and esters (ethyl acetate and ethyl octanoate), in the proportions found in the atmosphere naturally produced by yeast. Bean seeds artificially contamined with the pathogen were fumigated with the mixture of VOCs in sealed glass flasks for four and seven days. In the in vitro assays, the compounds 2-methyl-1-butanol and 3-methyl-1-butanol were the most active against S. sclerotiorum, completely inhibiting its mycelial growth at 0.8 µL mL-1, followed by the ethyl acetate, at 1.2 µL mL-1. Bean seeds fumigated with the VOCs at 3.5 µL mL-1 showed a 75% reduction in S. sclerotiorum incidence after four days of fumigation. The VOCs produced by S. cerevisiae have potential to control the pathogen in stored seeds.

Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).

Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.

siRNA-Mediated Knock-Down of P-Glycoprotein Expression Reveals Distinct Cellular Disposition of Anticancer Tyrosine Kinases Inhibitors.

Studies on the cellular disposition of targeted anticancer tyrosine kinases inhibitors (TKIs) have mostly focused on imatinib while the functional importance of P-glycoprotein (Pgp) the gene product of MDR1 remains controversial for more recent TKIs. By using RNA interference-mediated knockdown of MDR1, we have investigated and compared the specific functional consequence of Pgp on the cellular disposition of the major clinically in use TKIs imatinib, dasatinib, nilotinib, sunitinib and sorafenib. siRNA-mediated knockdown in K562/Dox cell lines provides a unique opportunity to dissect the specific contribution of Pgp to TKIs intracellular disposition. In these conditions, abrogating specifically Pgp-mediated efflux in vitro revealed the remarkable and statistically significant cellular accumulation of imatinib (difference in cellular levels between Pgp-expressing and silenced cells, at high and low incubation concentration, respectively: 6.1 and 6.6), dasatinib (4.9 and 5.6), sunitinib (3.7 and 7.3) and sorafenib (1.2 and 1.4), confirming that these TKIs are all substrates of Pgp. By contrast, no statistically significant difference in cellular disposition of nilotinib was observed as a result of MDR1 expression silencing (differences: 1.1 and 1.5) indicating that differential expression and/or function of Pgp is unlikely to affect nilotinib cellular disposition. This study enables for the first time a direct estimation of the specific contribution of one transporter among the various efflux and influx carriers involved in the cellular trafficking of these major TKIs in vitro. Knowledge on the distinct functional consequence of Pgp expression for these various TKIs cellular distribution is necessary to better appreciate the efficacy, toxicity, and potential drug-drug interactions of TKIs with other classes of therapeutic agents, at the systemic, tissular and cellular levels.

Nondestructive Evaluation and Assessment of Concrete Barriers for Defects and Corrosion, 2013

Wiss, Janney, Elstner Associates, Inc. (WJE) evaluated potential nondestructive evaluation (NDE) methodologies that may be effective in 1) identifying internal defects within slip formed concrete barriers and 2) assessing the corrosion condition of barrier dowel bars. The evaluation was requested by the Bridge Maintenance and Inspection Unit of the Iowa Department of Transportation (IaDOT) and the Bureau of Bridges and Structures of the Illinois Department of Transportation (IDOT). The need arose due to instances in each Department’s existing inventory of bridge barriers where internal voids and other defects associated with slip forming construction methods were attributed to poor barrier performance after completion of construction and where, in other barrier walls, unintentional exposure of the dowel bars revealed extensive corrosion-related section loss at previously uninspectable locations, reducing the capacity of the barriers to resist traffic impact loads. WJE trial tested potential NDE techniques on laboratory mock-up samples built with known defects, trial sections of cast-in-place barriers at in-service bridges in Iowa, and slip formed and cast-in-place barrier walls at in-service bridges in Illinois. The work included review of available studies performed by others, field trial testing to assess candidate test methods, verification of the test methods in identifying internal anomalies and dowel bar corrosion, and preparation of this report and nondestructive evaluation guidelines.