Complex dynamic system architecture evaluation through a hierarchical synthesis of tools and methods

Thesis (S.M.)--Massachusetts Institute of Technology, System Design & Management Program, 2003.Includes bibliographical references (p. 202-203).The automobile embodies complex dynamic system architecture with thousands of components and as many interconnections. The modern day vehicle architecture attempts to balance significant tradeoffs and constraints to achieve the system goals. There are innumerable combinations, which may or may not achieve success. This work proposes a new method for evaluation of complex dynamic system architecture through a hierarchical synthesis of specific qualitative and quantitative tools and methods within a system architecture framework. The proposed methodology is applied to key subsystems of a specific high performance car to assess primarily the merits of the process. Current methods for system architecture definition at the automobile manufacturer utilized for analysis rely primarily on experience-based intuition within an architecting framework. Current system architecture frameworks and the manufacturer's process utilized appear insufficient, as significant issues (often dynamics related) arise in the verification and validation phase of their product development process, requiring change to vehicle architecture. Changes in architecture at this phase of the manufacturer's product development process have significant cost, timing and perhaps functional performance implications. Many system architecture and engineering tools exist to aid architecture definition, but a hierarchy in usage and the interrelationships of the tools are not clearly defined. The proposed solution for rigorous complex dynamic system architecture evaluation includes a four phase hierarchical synthesis of known qualitative and quantitative tools and methods within a holistic system architecture framework. For purposes of this thesis, the proposed evaluation methodology is labeled "CD-SAAM" for Complex Dynamic System Architecture Assessment Methodology. The proposed methodology is a rigorous complement, superimposed on the concept development phase, to the standard product development design process. CD-SAAM mainly combines known system architecting and system engineering framework, principles and tools. Application of CD-SAAM to a high performance car's powertrain and chassis system architecture's second level form and function decomposition, serve to demonstrate many high level conclusions. The hierarchy and synthesis of framework, principles and tools in CD-SAAM provided a valuable and rigorous method to evaluate complex dynamic system architecture. While certain aspects of the proposed methodology appear time-consuming, each step and the overall process serve to greatly improve consistent success with respect to achievement of a system's goals within its constraints. Application of CD-SAAM also underscores the importance and need for explicit design parameter identification and analysis in complex dynamic system architecture assessment. The performance car application also provides insight into the value of DOE RSE methods in architecture assessment, as opposed to its typical region of use in detailed design analysis. Finally, a positive by-product of the analysis includes CD-SAAM's ability to evaluate the consistency and attainability of goals within the given constraints.by Scott M. Ahlman.S.M

Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour

Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy via sstr using [177Lu-DOTA0-Tyr3]-octreotate given to nude mice xenografted with the human midgut carcinoid GOT1. The tumours in 22 out of 23 animals given therapeutic amounts showed dose-dependent, rapid complete remission. The diagnostic amount (0.5 MBq [177Lu-DOTA0-Tyr3]-octreotate) did not influence tumour growth and was rapidly excreted. In contrast, the therapeutic amount (30 MBq [177Lu-DOTA0-Tyr3]-octreotate) induced rapid tumour regression and entrapment of 177Lu so that the activity concentration of 177Lu remained high, 7 and 13 days after injection. The entrapment phenomenon increased the absorbed dose to tumours from 1.6 to 4.0 Gy MBq−1 and the tumours in animals treated with 30 MBq received 120 Gy. Therapeutic amounts of [177Lu-DOTA0-Tyr3]-octreotate rapidly induced apoptosis and gradual development of fibrosis in grafted tumours. In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours

Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST)

Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies

Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study.

This is the author accepted manuscript. The final version is available from the American Heart Association via http://dx.doi.org/10.1161/ATVBAHA.115.306460OBJECTIVE: To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography computed tomography. APPROACH: In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using (18)F-fluorodeoxyglucose positron emission tomography computed tomography. RESULTS: Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8-8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (β=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (β=0.53; P=0.02) and vascular inflammation (β=0.48; P=0.02). CONCLUSIONS: Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.JMT is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z) and the NIHR Cambridge Biomedical Research Centre. JHFR is part-supported by the HEFCE, the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trus