A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon

Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP's. RRP's are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic "dominant model", the RRP's and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graphrepresentation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function-related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival. © 2014 Pancoska et al

Prognostic significance of the sequential detection of circulating melanoma cells by RT–PCR in high-risk melanoma patients receiving adjuvant interferon

The purpose of this study was to address the prognostic significance of circulating melanoma cells by reverse transcriptase-polymerase chain reaction in the peripheral blood of stage IIB and III melanoma patients on high-dose adjuvant interferon at multiple sequential time points from initiation of treatment. Tyrosinase mRNA in peripheral blood from these patients was assayed by reverse transcriptase polymerase chain reaction prior to initiation of adjuvant interferon, at completion of 1 month of intravenous interferon and at 3 monthly intervals until progression. Four hundred and eighteen blood samples from 60 melanoma patients were analysed. The median follow-up time calculated from the time of inclusion in the study was 23 months (range 2–38 months). Tyrosinase mRNA in blood was detected in 42 (70%) of 60 patients: 16 (76%) of 21 stage IIB patients and 26 (66%) of 39 stage III patients. The presence of tyrosinase mRNA in blood was correlated with a shorter disease-free survival (P : 0.03) and in multivariante analysis was an indepent prognostic factor for relapse. Patients who seroconverted to a negative reverse-transcriptase-polymerase chain reaction after induction treatment had a significantly lower probability of recurrence. The presence of circulating melanoma cells is a marker of a high relapse risk and shorter disease-free survival whether detected postoperatively or during follow-up. Tyrosinase mRNA amplification by reverse-transcriptase-polymerase chain reaction may be a useful tool for monitoring the efficacy of adjuvant treatment in stage IIB and III melanoma patients

Energy Sprawl or Energy Efficiency: Climate Policy Impacts on Natural Habitat for the United States of America

Concern over climate change has led the U.S. to consider a cap-and-trade system to regulate emissions. Here we illustrate the land-use impact to U.S. habitat types of new energy development resulting from different U.S. energy policies. We estimated the total new land area needed by 2030 to produce energy, under current law and under various cap-and-trade policies, and then partitioned the area impacted among habitat types with geospatial data on the feasibility of production. The land-use intensity of different energy production techniques varies over three orders of magnitude, from 1.9–2.8 km2/TW hr/yr for nuclear power to 788–1000 km2/TW hr/yr for biodiesel from soy. In all scenarios, temperate deciduous forests and temperate grasslands will be most impacted by future energy development, although the magnitude of impact by wind, biomass, and coal to different habitat types is policy-specific. Regardless of the existence or structure of a cap-and-trade bill, at least 206,000 km2 will be impacted without substantial increases in energy efficiency, which saves at least 7.6 km2 per TW hr of electricity conserved annually and 27.5 km2 per TW hr of liquid fuels conserved annually. Climate policy that reduces carbon dioxide emissions may increase the areal impact of energy, although the magnitude of this potential side effect may be substantially mitigated by increases in energy efficiency. The possibility of widespread energy sprawl increases the need for energy conservation, appropriate siting, sustainable production practices, and compensatory mitigation offsets

An Approach to Enhance the Conservation-Compatibility of Solar Energy Development

The rapid pace of climate change poses a major threat to biodiversity. Utility-scale renewable energy development (>1 MW capacity) is a key strategy to reduce greenhouse gas emissions, but development of those facilities also can have adverse effects on biodiversity. Here, we examine the synergy between renewable energy generation goals and those for biodiversity conservation in the 13 M ha Mojave Desert of the southwestern USA. We integrated spatial data on biodiversity conservation value, solar energy potential, and land surface slope angle (a key determinant of development feasibility) and found there to be sufficient area to meet renewable energy goals without developing on lands of relatively high conservation value. Indeed, we found nearly 200,000 ha of lower conservation value land below the most restrictive slope angle (<1%); that area could meet the state of California’s current 33% renewable energy goal 1.8 times over. We found over 740,000 ha below the highest slope angle (<5%) – an area that can meet California’s renewable energy goal seven times over. Our analysis also suggests that the supply of high quality habitat on private land may be insufficient to mitigate impacts from future solar projects, so enhancing public land management may need to be considered among the options to offset such impacts. Using the approach presented here, planners could reduce development impacts on areas of higher conservation value, and so reduce trade-offs between converting to a green energy economy and conserving biodiversity

Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial

<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p

Green tradable certificates versus feed-in tariffs in the promotion of renewable energy shares

The paper analyzes the relationship between CO2 mitigation policy and promotion policies designed to deploy renewable energy sources for electricity production (RES-E). If an emission cap is the only policy target, an optimal mix consisting of high and low carbon use of fossil fuels, deployment of RES-E, and energy savings can best be achieved by either setting a uniform carbon tax or by implementing a cap-and-trade system covering all CO2 sources. An additional RES-E share target causes higher costs in achieving the cap. Conversely, a more ambitious emission target automatically increases the RES-E share. In a second step we investigate different policies for inducing an RES-E quota. Such a quota can be efficiently achieved either by a system of tradable green certificates or by a budget-balancing premium system. A budget-balancing FIT system, by contrast, is not efficient, since it generates excessive fiscal distortion. We also show that differentiated, technology-specific FITs are even more inefficient

Decision making under uncertainty using a qualitative TOPSIS method for selecting sustainable energy alternatives

The final publication is available at Springer via http://dx.doi.org/10.1007/s13762-016-0982-7Multi-criteria decision-making methods support decision makers in all stages of the decision-making process by providing useful data. However, criteria are not always certain as uncertainty is a feature of the real world. MCDM methods under uncertainty and fuzzy systems are accepted as suitable techniques in conflicting problems that cannot be represented by numerical values, in particular in energy analysis and planning. In this paper, a modified TOPSIS method for multi-criteria group decision-making with qualitative linguistic labels is proposed. This method addresses uncertainty considering different levels of precision. Each decision maker’s judgment on the performance of alternatives with respect to each criterion is expressed by qualitative linguistic labels. The new method takes into account linguistic data provided by the decision makers without any previous aggregation. Decision maker judgments are incorporated into the proposed method to generate a complete ranking of alternatives. An application in energy planning is presented as an illustrative case example in which energy policy alternatives are ranked. Seven energy alternatives under nine criteria were evaluated according to the opinion of three environmental and energy experts. The weights of the criteria are determined by fuzzy AHP, and the alternatives are ranked using qualitative TOPSIS. The proposed approach is compared with a modified fuzzy TOPSIS method, showing the advantages of the proposed approach when dealing with linguistic assessments to model uncertainty and imprecision. Although the new approach requires less cognitive effort to decision makers, it yields similar results.Peer ReviewedPostprint (author's final draft