Integrating Aircraft Cost Modelling into Conceptual Design

The article presents cost modeling results from the application of the Genetic-Causal cost modeling principle. Industrial results from redesign are also presented to verify the opportunity for early concept cost optimization by using Genetic-Causal cost drivers to guide the conceptual design process for structural assemblies. The acquisition cost is considered through the modeling of the recurring unit cost and non-recurring design cost. The operational cost is modeled relative to acquisition cost and fuel burn for predominately metal or composites designs. The main contribution of this study is the application of the Genetic-Causal principle to the modeling of cost, helping to understand how conceptual design parameters impact on cost, and linking that to customer requirements and life cycle cost.

Modelling of aircraft manufacturing cost at the concept stage

The work presented is concerned with the estimation of manufacturing cost at the concept design stage, when little technical information is readily available. The work focuses on the nose cowl sections of a wide range of engine nacelles built at Bombardier Aerospace Shorts of Belfast. A core methodology is presented that: defines manufacturing cost elements that are prominent; utilises technical parameters that are highly influential in generating those costs; establishes the linkage between these two; and builds the associated cost estimating relations into models. The methodology is readily adapted to deal with both the early and more mature conceptual design phases, which thereby highlights the generic, flexible and fundamental nature of the method. The early concept cost model simplifies cost as a cumulative element that can be estimated using higher level complexity ratings, while the mature concept cost model breaks manufacturing cost down into a number of constituents that are each driven by their own specific drivers. Both methodologies have an average error of less that ten percent when correlated with actual findings, thus achieving an acceptable level of accuracy. By way of validity and application, the research is firmly based on industrial case studies and practice and addresses the integration of design and manufacture through cost. The main contribution of the paper is the cost modelling methodology. The elemental modelling of the cost breakdown structure through materials, part fabrication, assembly and their associated drivers is relevant to the analytical design procedure, as it utilises design definition and complexity that is understood by engineers.

Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer

Background BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER alpha) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER alpha positive. We examined a possible mechanism for the observed ER alpha-negative phenotype of BRCA1-mutant tumors.

Methods We used a breast cancer disease-specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) ( the gene encoding ER alpha), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER alpha protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA ( siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided.

Results Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors ( 95% confidence interval [CI]=2.6-fold to 40.1-fold, P =.0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ER alpha expression. BRCA1-depleted breast cancer cells expressing exogenous ER alpha were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector ( T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC40] for empty vector versus ER alpha: > 10(-5) versus 8.0 x 10(-9) M [ 95% CI=3.1x10(-10) to 3.2 x 10(-6) M]; MCF-7 cells, mean IC40 for empty vector versus ER alpha : > 10(-5) versus 4.9 x 10(-8) M [ 95% CI=2.0 x 10(-9) to 3.9 x 10(-6) M]).

Conclusions BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER alpha expression.