Directed Linkography and Syntactic Analysis: Comparing Synchronous and Diachronic Effects of Sudden Emergence of Creative Insights on the Structure of the Design Process

This paper reports on a study of the emergence of creative insights in the architectural design process. Using detailed ethnographic observations of designers working on an architectural design task, and coding these using linkographs, we identify two poles of design creativity: incremental improvement and the sudden creative insight. We show how these can be identified in the structure of the linkograph, giving rise to the possibility of better understanding the conditions under which creativity and innovation take place. Linkography is directed in relation to the time of emergence of design utterances. It is characterised as a pivotal structure of a multi-level hierarchical network. A quantitative model is proposed to capture the structure of events and sudden changes occurring in the design process using syntactic measures of space syntax and urban graphs. Two situations are compared: synchronous designing using ‘directed linkography’ looking at the backlink relations and the completed state of the linkograph. Local, global measurements and directed j-graphs are correlated with design contents and descriptions for the concept development. Our interest lies in capturing events of drastic changes and investigating the transformation of the associated interim products. Such events are hypothesised, reflecting significant transformation in concept reasoning and the configuration of the linkograph. Through this model, we aim to answer the question: why would sudden insights divert the network to a different structure state

Order, Structure and Disorder in Space Syntax and Linkography: Intelligibility, Entropy, and Complexity Measures

There has been great interest in the use of linkographies to describe the events that take place in design processes with the aim of understanding when creativity takes place and the conditions under which creative moments emerge in the design. Linkography is a directed graph network and because of this it gives resemblance to the types of large complex graphs that are used in the space syntax community to describe urban systems. In this paper, we investigate the applications of certain measures that come from space syntax analyses of urban graphs to look at linkography systems. One hypothesis is that complexity is created in different scales in the graph system from the local sub-graph to the whole system. The method of analysis illustrates the underlying state of any system. Integration, complexity and entropy values are measured at each individual node in the system to arrive at a better understanding on the rules that frame the relationships between the parts and the whole

Design, Synthesis and Biological Evaluation of Novel Pyrimido[4,5-d]pyrimidine CDK2 Inhibitors as Anti-Tumor Agents

A series of 2,5,7-trisubstituted pyrimido[4,5-d]pyrimidine cyclin-dependent kinase (CDK2) inhibitors is designed and synthesized. 6-Amino-2-thiouracil is reacted with an aldehyde and thiourea to prepare the pyrimido[4,5-d]-pyrimidines. Alkylation and amination of the latter ones give different amino derivatives. These compounds show potent and selective CDK inhibitory activities and inhibit in vitro cellular proliferation in cultured human tumor cells

Hyperlipidemia control using the innovative association of lupin proteins and chitosan and α-cyclodextrin dietary fibers: food supplement formulation, molecular docking study, and in vivo evaluation

A dietary supplement potentially employed for the treatment and/or prevention of hyperlipidemia was developed. The proposed product is composed of a combination of natural macromolecules as chitosan (CH), α-cyclodextrin (α-CD), and lupin proteins (LP). First, the anti-hyperlipidemic effect of the α-CD and LP binary mixture was assessed and compared to that of the extensively utilized anti-hyperlipidemic CH, using a hyperlipidemic rat model. The anti-hyperlipidemic effect of their combination was also demonstrated. Additionally, ligand–target and protein–protein docking studies were performed. The in vivo results displayed that on intergroup comparison, blending CH, α-CD, and LP promised a superior therapeutic effect over α-CD and LP mixture, CH, and the marketed atorvastatin, potentiating a considerable reduction of serum lipid profile and the calculated atherogenic risk predictor indices. Molecular docking study revealed a weak hydrophobic cholesterol–CH and cholesterol–α-CD interactions, while protein–protein docking study showed a good lipase–LP interaction, involving eight hydrogen bonds. Then, on the base of the in vivo and docking study results, a tablet formulation was produced aimed to overcome the negative technological effects of the anti-hyperlipidemic macromolecules: long disintegration time and tablets mechanical resistance. The optimized tablet formulation has a disintegration time shorter than 15 min and a weight loss from friability test lower than 1%, which are in line with the regulatory specifications for uncoated tablets. Overall, this anti-hyperlipidemic formulation is attractive for the dietary and nutraceutical market, despite further clinical studies are required to assess the efficacy, possible side effects, and product compliance

A Web-based Adaptive and Intelligent Tutor by Expert Systems

Todays, Intelligent and web-based E-learning is one of regarded topics. So researchers are trying to optimize and expand its application in the field of education. The aim of this paper is developing of E-learning software which is customizable, dynamic, intelligent and adaptive with Pedagogy view for learners in intelligent schools. This system is an integration of adaptive web-based E-learning with expert systems as well. Learning process in this system is as follows. First intelligent tutor determines learning style and characteristics of learner by a questionnaire and then makes his model. After that the expert system simulator plans a pre-test and then calculates his score. If the learner gets the required score, the concept will be trained. Finally the learner will be evaluated by a post-test. The proposed system can improves the education efficiency highly as well as de-creases the costs and problems of an expert tutor. As a result, every time and eve-rywhere (ETEW) learning would be provided via web in this system. Moreover the learners can enjoy a cheap remote learning even at home in a virtual simulated physical class. So they can learn thousands courses very simple and fast.Comment: 10 pages, 3 figures, The Second International Conference on Advances in Computing and Information Technology (ACITY 2012). arXiv admin note: substantial text overlap with arXiv:1304.404

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

Background: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours. Methods:\ud Eligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. Results: Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. Conclusions: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.Peer reviewe