Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?

Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the  mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (As^III) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.

Leukemia risk associated with low-level benzene exposure

Background: Men who were part of an Australian petroleum industry cohort had previously been found to have an excess of lympho-hematopoietic cancer. Occupational benzene exposure is a possible cause of this excess.

Methods: We conducted a case-control study of lympho-hematopoietic cancer nested within the existing cohort study to examine the role of benzene exposure. Cases identified between 1981 and 1999 (N = 79) were age-matched to 5 control subjects from the cohort. We estimated each subject's benzene exposure using occupational histories, local site-specific information, and an algorithm using Australian petroleum industry monitoring data.

Results: Matched analyses showed that the risk of leukemia was increased at cumulative exposures above 2 ppm-years and with intensity of exposure of highest exposed job over 0.8 ppm. Risk increased with higher exposures; for the 13 case-sets with greater than 8 ppm-years cumulative exposure, the odds ratio was 11.3 (95% confidence interval = 2.85-45.1). The risk of leukemia was not associated with start date or duration of employment. The association with type of workplace was explained by cumulative exposure. There is limited evidence that short-term high exposures carry more risk than the same amount of exposure spread over a longer period. The risks for acute nonlymphocytic leukemia and chronic lymphocytic leukemia were raised for the highest exposed workers. No association was found between non-Hodgkin lymphoma or multiple myeloma and benzene exposure, nor between tobacco or alcohol consumption and any of the cancers.

Conclusions: We found an excess risk of leukemia associated with cumulative benzene exposures and benzene exposure intensities that were considerably lower than reported in previous studies. No evidence was found of a threshold cumulative exposure below which there was no risk.

Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting

Introduction:
Low dose spiral computed tomography (CT) is a sensitive screening tool for lung cancer that is currently being evaluated in both non-randomised studies and randomised controlled trials.
Methods:
We conducted a quantitative decision analysis using a Markov model to determine whether, in the Australian setting, offering spiral CT screening for lung cancer to high risk individuals would be cost-effective compared with current practice. This exploratory analysis was undertaken predominantly from the perspective of the government as third-party funder. In the base-case analysis, the costs and health outcomes (life-years saved and quality-adjusted life years) were calculated in a hypothetical cohort of 10,000 male current smokers for two alternatives: (1) screen for lung cancer with annual CT for 5 years starting at age 60 year and treat those diagnosed with cancer or (2) no screening and treat only those who present with symptomatic cancer.
Results:
For male smokers aged 60–64 years, with an annual incidence of lung cancer of 552 per 100,000, the incremental cost-effectiveness ratio was $57,325 per life-year saved and $105,090 per QALY saved. For females aged 60–64 years with the same annual incidence of lung cancer, the cost-effectiveness ratio was $51,001 per life-year saved and $88,583 per QALY saved. The model was used to examine the relationship between efficacy in terms of the expected reduction in lung cancer mortality at 7 years and cost-effectiveness. In the base-case analysis lung cancer mortality was reduced by 27% and all cause mortality by 2.1%. Changes in the estimated proportion of stage I cancers detected by screening had the greatest impact on the efficacy of the intervention and the cost-effectiveness. The results were also sensitive to assumptions about the test performance characteristics of CT scanning, the proportion of lung cancer cases overdiagnosed by screening, intervention rates for benign disease, the discount rate, the cost of CT, the quality of life in individuals with early stage screen-detected cancer and disutility associated with false positive diagnoses. Given current knowledge and practice, even under favourable assumptions, reductions in lung cancer mortality of less than 20% are unlikely to be cost-effective, using a value of $50,000 per life-year saved as the threshold to define a “cost-effective” intervention.
Conclusion:
The most feasible scenario under which CT screening for lung cancer could be cost-effective would be if very high-risk individuals are targeted and screening is either highly effective or CT screening costs fall substantially.

Measuring entrepreneurial activity in low-teledensity countries

In 2009, a team of 38 researchers carried out the Global Entrepreneurship Monitor (GEM) survey of social and business entrepreneurial activity in the Kingdom of Tonga. The GEM survey estimates the proportion of the population involved in business and social start-ups and new firm creation. This paper describes not the results of the survey but rather the methodology employed. Because Tonga is spread out over a swath of the Pacific Ocean, the team faced challenges in terms of survey design, field work, logistics, and quality control. To meet the standards of rigour, we designed a 'ruggedised method' for measuring entrepreneurial activity. Countries with a teledensity threshold of less than 30% (fixed lines per 100 inhabitants) present serious challenges to survey designers. The study discusses questionnaire preparation, recruitment and training of interviewers as well as survey design issues such as sample size, response rate, sampling weights, and lessons learned. The report will assist other teams in measuring entrepreneurial activity in low-teledensity countries and provides guidelines when the study is repeated elsewhere. The study also proposes a way forward to incorporate new technologies such as tablet PCs, GPS, and GIS to address the dilemmas of measuring entrepreneurial activity in low-teledensity countries.

Performance modelling of speculative prefetching for compound requests in low bandwidth networks

To improve the accuracy of access prediction, a prefetcher for web browsing should recognize the fact that a web page is a compound. By this term we mean that a user request for a single web page may require the retrieval of several multimedia items. Our prediction algorithm builds an access graph that captures the dynamics of web navigation rather than merely attaching probabilities to hypertext structure. When it comes to making prefetch decisions, most previous studies in speculative prefetching resort to simple heuristics, such as prefetching an item with access probabilities larger than a manually tuned threshold. The paper takes a different approach. Specifically, it models the performance of the prefetcher and develops a prefetch policy based on a theoretical analysis of the model. In the analysis, we derive a formula for the expected improvement in access time when prefetch is performed in anticipation for a compound request. We then develop an algorithm that integrates prefetch and cache replacement decisions so as to maximize this improvement. We present experimental results to demonstrate the effectiveness of compound-based prefetching in low bandwidth networks.

An ultra low power OTA with improved unity gain bandwidth product

An operational transconductance amplifier (OTA) using dynamic threshold MOS (DTMOS) and hybrid compensation technique is presented in this paper. The proposed topology is based on a bulk and gate driven input differential pair. Two separate capacitors are employed for the OTA compensation where one of them is used in a signal path and the other one in a non-signal path. The circuit is designed in the 0.18μm CMOS TSMC technology. The proposed design technique shows remarkable enhancement in unity gain-bandwidth and also in DC gain compared to the bulk driven input differential pair OTAs. The Hspice simulation results show that the amplifier has a 92dB open-loop DC gain and a unity gain-bandwidth of 135kHz while operating at 0.4V supply voltage. The total power consumption is as low as 386nW which makes it suitable for low-power bio-medical and bio-implantable applications.

Hybrid threshold adaptable quantum secret sharing scheme with reverse Huffman-Fibonacci-tree coding

With prevalent attacks in communication, sharing a secret between communicating parties is an ongoing challenge. Moreover, it is important to integrate quantum solutions with classical secret sharing schemes with low computational cost for the real world use. This paper proposes a novel hybrid threshold adaptable quantum secret sharing scheme, using an m-bonacci orbital angular momentum (OAM) pump, Lagrange interpolation polynomials, and reverse Huffman-Fibonacci-tree coding. To be exact, we employ entangled states prepared by m-bonacci sequences to detect eavesdropping. Meanwhile, we encode m-bonacci sequences in Lagrange interpolation polynomials to generate the shares of a secret with reverse Huffman-Fibonacci-tree coding. The advantages of the proposed scheme is that it can detect eavesdropping without joint quantum operations, and permits secret sharing for an arbitrary but no less than threshold-value number of classical participants with much lower bandwidth. Also, in comparison with existing quantum secret sharing schemes, it still works when there are dynamic changes, such as the unavailability of some quantum channel, the arrival of new participants and the departure of participants. Finally, we provide security analysis of the new hybrid quantum secret sharing scheme and discuss its useful features for modern applications.