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Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity. [ABSTRACT FROM AUTHOR]

Risk management is widely recognized as a best practice for public agencies to ensure the successful implementation of major transportation projects. The conventional approach to identify and evaluate project risks is dominated by getting input from subject matter experts at risk workshops. However, the uniqueness of such a risk assessment approach remains unexamined. How different are the risks among various projects? Does the risk register reflect the unique feature of a project? The goal of this study is to measure the similarity of project risks across various groups by evaluating 70 major transportation projects delivered under various methods. The similarity index is calculated at three levels, that is, the entire document of the risk register, individual risk item, and the probability and consequence of each risk using a systematic comparative analysis based on natural language processing (NLP) and a state-of-the-art deep learning algorithm named Word2vec. Our study reports a high similarity of risk registers among different projects at all three levels. The analysis does show a lower similarity of risk registers for public–private partnerships (P3) projects. The primary contributions of this study are (1) develop a new approach to analyze the risk registers at the project level as the main output of risk management practice, and (2) establish the relation of risk uniqueness and project delivery method in transportation projects. Results suggest that a data-driven approach may be possible to help project teams develop a common risk register while allowing the teams to focus on each project's unique risks. [ABSTRACT FROM AUTHOR]

Projects with poor noncompete provision design have caused heavy costs for both public and private organizations, primarily due to the embedded monopoly right of the private sector to collect toll revenue. Prior studies have investigated the financial impact of including noncompete provisions in public-private partnership (PPP) contracts to ensure project attractiveness to private entities, although the potential impact of such provisions on the public interest has not been well documented. This study contributes to the literature by incorporating social benefits into an evaluation model to balance the protection of public and private interests. Three contract design alternatives—strict noncompete, compensation for competing facilities, and compete without compensation—are evaluated and compared. This study demonstrates these alternatives with the I-77 Express Lane project in North Carolina and provides several insightful results. First, a strict noncompete provision often worsens congestion, negatively affecting the public interest, and should be avoided. Second, both public and private organizations may benefit from inclusion of a compensation provision that eliminates a prospective monopoly while offering compensation for competing facilities. Third, public benefits from competing facilities present a convex curve over time, suggesting optimal timing for the government to build the competing facility. The results illustrate the significant effect of the noncompete provision on the public interest, and provide governments with a reference to balance protection of the public interest and attractiveness to private investors when designing the noncompete provision. [ABSTRACT FROM AUTHOR]

Abstract As climate risks increase, there is a challenge of combining the goals of carbon mitigation and climate adaptation into building designs. These two goals are often misaligned because adaptation measures use additional materials and equipment, which can increase greenhouse gas (GHG) emissions. This phenomenon means that building design involves tradeoffs between enhanced structural resilience and reduced GHG emissions. This paper seeks to identify the optimal investment allocation mechanisms between carbon mitigation and climate adaptation measures for the design of buildings in hurricane-prone regions. A dynamic decision-making model is developed to maximize individual investors' expected payoffs over a building's lifetime. The model is based on the damage evaluation of non-stationary hurricane occurrence and building emission performance under different mitigation scenarios. The results reveal a transition from long-advocated low-carbon investments to risk-oriented portfolios for building retrofits. A case study on Anne Arundel County, MD, for which a "60-40" resilience/abatement portfolio is recommended, shows the value of enhancing structural resilience. Discretion on the accuracy of insurance premium discounts is needed to support risk mitigation efforts. Meanwhile, subsidies for emission abatements are recommended to accommodate existing emission trading schemes and building property values. [ABSTRACT FROM AUTHOR]

The significance of global warming is shaping building procurement, with much of the effort aimed at reducing greenhouse gas emissions through a preferential bidding mechanism. However, only a limited number of studies have quantitatively estimated the potential impact of bid preference on the emission reduction from building construction. The aim of this paper is to improve our understanding of how bid discounts change owners' procurement costs and the magnitudes of emission mitigation. A two-stage optimization model is designed to help the owner determine the discount rate that would automatically control the emission of the awarded contract within a desired level. The goal is for bidders to regard emission reduction efforts as an investment, with returns coming in the form of an increased chance of winning the bid. Our results imply that for the building retrofit project studied herein, a discount rate of 0.6 is suggested for every percentage of emission reduction. This discount level reduces greenhouse gas emissions by 28.2% while raising procurement costs by 3.7% relative to a non-preference mechanism. The increased procurement costs can be partially compensated under existing cap-and-trade scheme. The results show that the choice of discount significantly alters bidders' efforts on emission mitigation, and emission control cost can be minimized with the proposed optimization algorithm. [ABSTRACT FROM AUTHOR]

Most of the construction practices in the field of risk identification focus on the expertise, views, and judgments of subject matter experts. While the conventional expert-based approaches provide worth, several challenges exist due to time-consuming and expensive aspects. Moreover, limited experience in major projects makes public agencies susceptible to subjective judgment biases. To address these limitations, this study introduced a data-driven framework for risk identification using historical data and artificial intelligence techniques, particularly word embedding models. The model matches various risk items in past projects by considering the semantic meaning of words to find high frequency and consequence risks. Risk registers from more than 70 U.S. major transportation projects form the input dataset. The model is tested with more than 66% recall and 0.59 F 1 -score for risk detection for new projects. Acquired knowledge from previous projects assists project teams and public agencies to be well-equipped with a risk identification model instead of starting from scratch. • A novel data-driven model for risk template generation is introduced. • A comprehensive risk database for major transportation projects is developed using historical data. • The model learns semantic textual features of risk items using word embedding models. • The model customizes risk templates considering risk prevalence, risk consequences, and project characteristics. • The experimental results revealed more than 66% of testing projects' risk items are covered by risk templates. [ABSTRACT FROM AUTHOR]

Project risk is an important part of managing large projects of any sort. This study contributes to the state of knowledge in project risk management by introducing a data-driven approach to measure risk identification performance using historical data. In the early phases of a project, the identification and assessment of risk is based largely on experience and expert judgment. As a project moves through its life cycle, these identified risks and the assessment of them evolve. Some risks become issues, some are mitigated, and some are retired as no longer important. This study investigated the quality of early risk registers and risk assessments on large transportation projects and compared them to how the identified risks evolved on historical projects. The investigation involved the use of textual analysis of archival risk register documents. Finite-state automation methods akin to Markov chain models were used to track the changes in risk attributes on large infrastructure projects as the projects matured. The objective was to be better able to anticipate how project risks will change as projects move forward and to be better able to forecast changes to the risk register from ex ante to ex post conditions. Results from 11 major US transportation projects suggested that, on average, fewer than 65% of ex ante identified risks ultimately occurred in projects and were mitigated, while more than 35% did not occur and were retired. In addition, more than half of the risks emerged during project execution when new information became available. Based on the categorization of risk management styles, we find that identifying risks early in the project life cycle is necessary, but not sufficient to ensure successful project delivery. A project team with positive doer behavior (i.e., actively monitoring and identifying risks during project execution) performed better in delivering projects on time and within budget. [ABSTRACT FROM AUTHOR]

Pavement rehabilitation is carbon intensive and the choice of pavement type is a critical factor in controlling greenhouse gas (GHG) emissions. The existing body of knowledge is not able to support decision-making on pavement choice due to a lack of consensus on the system boundaries, the functional units and the estimation periods. Excessive data requirements further inhibit the generalization of the existing methodologies for design evaluation at the early planning stage. This study proposes a practical life-cycle GHG estimation approach, which is arguably effective to benchmark pavement emissions given project bid tabulation. A set of case studies conducted for this study suggest that recycled asphalt pavement (e.g., foam stabilized base (FSB), and warm mix asphalt (WMA)) would prevent up to 50% of GHGs from the initial construction phase. However, from a life-cycle perspective, pavement emissions are dictated largely by the traffic characteristics and the analysis period for the use phase. The benefits from using recycled materials (e.g., FSB) are likely to diminish if the recycled products do not perform as well as those properly proportioned with less recycled materials, or if the recycled materials are locally unavailable. When the AADT reaches 10,000, use phase releases more than 97% of the life cycle emissions and the emissions difference among alternative designs will be within 1%. [Copyright &y& Elsevier]

Green principles have been increasingly incorporated into planning, design, construction, and maintenance processes in the engineering and construction industry. Along with the growth of the green initiative, going green not only demonstrates corporate social responsibility, but may yield significant economic benefits. This study compares financial performance between green and conventional firms in the engineering and construction industry. A total of 22 sample companies used in this empirical analysis are categorized into two groups-green versus conventional firms-in accordance with Engineering News Record and Newsweek green company lists. Two groups are compared in terms of short-term financial performance, long-term economic value, and market value. The analysis shows that green firms outperform conventional firms on return on equity (17.4 versus 8.2%) and economic value added margin (0.35 versus ). However, the green strategy has not yet been factored into corporate market value. The findings yield important managerial implications for engineering and construction organizations to integrate sustainability into their business operation. [ABSTRACT FROM AUTHOR]

In 1998 the New Mexico State Highway and Transportation Department (NMSHTD) agreed to pay $60 million for a 20-year pavement warranty on their Route 44 project (NM 44, now US 550). The warranty includes a ceiling clause that caps total expenditures at $110 million. As the first long-term highway warranty in the United States, the transaction set a controversial precedent that parties interested in innovative highway contracting, including other state department of transportations (DOTs), the USDOT, sureties, and contractors, view as a test case for evaluating pricing and cost-effectiveness. An interim audit report published by the State of New Mexico [Abbey (2004). Rep. to the Legislative Finance Committee, State Highway and Transportation Department, Santa Fe, N.M.] provides invaluable fiscal projections and challenges the cost effectiveness of the $60 million expenditure. This paper presents an independent analysis of the effectiveness of the warranty clauses. Based upon NMSHTD data, the analysis contends that $60 million was a fair cost of the 20-year pavement warranty at the time of acceptance if the expenditure ceiling is not considered. Furthermore, this paper argues that the ceiling on expenditure can be valuable. Using the real options approach, the paper evaluates the warranty ceiling clause on NM 44 and some policy suggestions are discussed. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [3H]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0–40 μM) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation–π bond and π–π interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports published within the issue which include the development and discovery of natural products as novel anticancer drug agents, the anticancer effects of flavonoids, and the anticancer activity of terpenoids.

Among the key barriers to profit in Energy Performance Contracting (EPC) are uncertainties about attaining the realized energy cost savings and potential disputes over the guaranteed cost savings. In this paper, a methodology has been proposed to assist the Energy Service Company (ESCO): (1) to evaluate the risk threshold if the guarantee has already been made, and (2) to determine the guarantee design, if the guarantee has not been made yet, that not only promises the ESCO’s profitability from EPC but also maintains its competitiveness to win the bid. Uncertainties within the energy cost savings are modeled stochastically using Monte-Carlo simulation, taking both the energy price fluctuation and the facility performance variability into account. Based on that, a strategic energy savings guarantee design curve is derived, that all the points on it would return as appropriate guarantees. Finally, a campus case is presented to demonstrate the applicability for finding the appropriate guaranteed savings value. This method is also worth popularizing in similar performance-based projects. [ABSTRACT FROM AUTHOR]

This paper presents a cost estimation model for long-term pavement warranties with multiple distress indicators. One application area for such warranties involves performance-based specifications (PBSs). In contrast to traditional approaches, PBS gives contractors the flexibility to select construction methods, materials, and even design. However, the contractors then must warrant the performance of their work for a specified period of time. Therefore, an accurate estimation of the risks associated with the warranty is a significant cost issue for any contractor to cover potential risks while still being competitive in bidding. Quantitative evaluation of the cost of risk incurred by the warranty has several difficulties. The deterioration of a highway project is a complex process, which is affected by pavement structure, material, traffic load, and weather conditions. Based on a probabilistic risk analysis of failures of performance indicators, the resulting model can estimate the warranty cost at a detailed level. The application of the model has been demonstrated via a numerical case study using long-term pavement performance data. [ABSTRACT FROM AUTHOR]

Reopening amid the COVID-19 pandemic has triggered a battle on social media. The supporters perceived that the lockdown policy could damage the economy and exacerbate social inequality. By contrast, the opponents believed it was necessary to contain the spread and ensure a safe environment for recovery. Anatomy into the battle is of importance to address public concerns, beliefs, and values, thereby enabling policymakers to determine the appropriate solutions to implement reopening policy. To this end, we investigated over 1.5 million related Twitter postings from April 17 to May 30, 2020. With the aid of natural language processing (NLP) techniques and machine learning classifiers, we classified each tweet into either a "supporting" or "opposing" class and then investigated the public perception from temporal and spatial perspectives. From the temporal dimension, we found that both political and scientific news that were extensively discussed on Twitter led to the perception of opposing reopening. Further, being the first mover with full reopen adversely affected the public reaction to reopening policy, while being the follower or late mover resulted in positive responses. From the spatial dimension, the correlation and regression analyses suggest that the state-level perception was very likely to be associated with political affiliation and health value. [ABSTRACT FROM AUTHOR]

Hot Mix Asphalt (HMA) is used in the construction of highway roads, parking lots and other pavement repairs in the US and worldwide. During asphalt pavement installation, a large amount of asphalt fume containing volatile organic compounds (VOCs) is emitted, causing potential health risks to construction workers. The field data investigation in this paper reports the concentration of VOCs around the workers on site using the Photo Ionization Detection (PID) device. Additionally, this paper presents a health risk evaluation model based on the Monte Carlo simulation to assess the carcinogenic and non-carcinogenic risks of workers during pavement construction. More specifically, distribution and sensitivity analyses illustrate the factors that pose the greatest health risks caused by certain VOCs. The study calls for better health risk controls by targeting the emission sources, propagating pathways, and individual receptors of the VOCs to protect workers' health during pavement construction. This paper contributes to the knowledge of VOCs generated from HMA and the potential health risks to construction workers, as well as suggests the implementation of new requirements for pavement construction codes and safety regulations. [ABSTRACT FROM AUTHOR]

Promoting household energy-saving behaviors requires devising effective messages and selecting appropriate message delivery methods. Meanwhile, the specific psychological factors that shape the effectiveness of interventions remains elusive. Based on an energy conservation intervention program carried out in communities in the city of Hangzhou, China in 2016, this paper investigates the impact of eco-feedback and energy-saving tips delivered to households via an instant messaging platform (i.e., WeChat), stickers combined with leaflets, and face-to-face consultations in promoting energy conservation. Psychological attributes including personal values and aspects of decision-making that affect pro-environmental behavior, as well as social and housing demographics were collected and analyzed to identify relationships between household characteristics and the effectiveness of an intervention. The findings suggest that, coupled with eco-feedback, stickers and leaflets (mean rank 37.54) performed better than other alternatives (mean rank 55.34 for WeChat group, 57.08 for consultation group) in encouraging household energy-saving behaviors. The effectiveness of eco-feedback using an instant messaging platform was revealed to be short-lived. Moreover, the study found that psychological features such as the perception of sufficient non-material incentives and opportunity to perform energy conservation behavior, as well as valuing environmental quality, personal health, and leisure time, are significantly correlated with energy savings. The findings not only contribute to future policymaking in demand-side energy conservation, but also provide insights for the cultivation of long-term behavioral changes at the neighborhood level through the effective design of communications and engagement. Image 1 • Compared the effectiveness of three types of delivering methods. • Sticker with eco-feedback is more effective in saving energy than other methods. • Effectiveness of delivering feedback using an instant message is short-lived. • Household psychological and social attributes are correlated with energy saving. • Households valuing environmental quality and health are likely to save energy. [ABSTRACT FROM AUTHOR]

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice. [ABSTRACT FROM AUTHOR]