When is an exploration exploratory? A comparative analysis of geometry lessons

This paper presents a comparative analysis of two textbook lessons on the same topic from U.S. textbooks to learn how differently - designed “exploratory” lessons may structure content to enable or constrain student inquiry. One lesson, representative of a “reform - based” textbook, contains investigations of conditions of triangle congruence. The second is a “technology lab” on triangle congruence fro m a "traditional" textbook, the design of which is atypical for that textbook. Framing a lesson as a mathematical story, this analysis exposes three distinct ways that these lessons are different: (a) the proportion of the lesson in which mathematical questions remain unanswered, (b) the manner in which content unfolds to address each question, and (c) the way in which open mathematical questions overlap to increase the dynamically - changing number of questions that are pursued. This contrast of the two lessons illuminates how a lesson structure can prevent an "exploration" from being exploratory

Evaluation of novel positron emission tomography radiotracers in humans: tissue distribution kinetics and potential for cancer diagnosis and staging

Positron emission tomography (PET) imaging has emerged as an important decision-making tool in oncology with respect to diagnosis, staging, and assessment of treatment response. We proposed to investigate the ligand binding and retention kinetics of two novel PET/CT tracers in human tumours that do not normally exhibit high [18F]fluorodeoxyglucose ([18F]FDG) uptake, and a third tracer in the context of specific death mechanism. Biological validation of the imaging endpoint included histological correlation with PET/CT data and establishment of an optimum PET/CT methodologies for the probe for implementation into clinical practice. The internal dosimetry and receptor-mediated tumour localisation of the ‘click’ labelled [18F]fluoroethyl triazole octreotate analogue, [18F]FET-βAG-TOCA, in neuroendocrine tumours (NETs) were investigated for the first time in humans. The biomarker demonstrated favourable dosimetry, biodistribution and safety. The calculated effective dose over all subjects (mean ± SD) was 0.029 ± 0.004 mSv/MBq. Regarding staging, [18F]FET-βAG-TOCA PET/CT showed high tumoural uptake with high sensitivity (per lesion) compared with [68Ga]DOTATATE PET/CT (92.8% vs 87.5%). Tissue retention kinetics of the novel choline analogue, [18F]fluoromethyl-[1,2-2H4]- choline ([18F]D4-FCH) were investigated in the staging of muscle invasive bladder cancer (MIBC) and non-small cell lung cancer (NSCLC). The biomarker showed high contrast in lung cancer but poor contrast in bladder cancer. In lung tumours, [18F]D4-FCH uptake was quantitatively lower than [18F]FDG. Pharmacokinetic modelling revealed net tracer influx in tumour consistent with radiotracer phosphorylation via choline kinase, however choline kinase-alpha expression did not correlate with PET parameters. Beyond staging, we evaluated for the first time a caspase-3/7 imaging biomarker, [18F](S)- 1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)- 8 pyrrolidine-1-sulfonyl) ([18F]ICMT-11), for imaging apoptosis and/or necrosis in patients; [18F]FDG-PET is not a marker of caspase-3/7 activation. In breast cancer, lung cancer and lymphoma patients receiving first-line chemotherapy treatment, [18F]ICMT-11 and cytokeratin-18 analysis (blood) were performed. [18F]ICMT-11 showed low uptake pre- and post-chemotherapy in all tumours consistent with unremarkable changes in M30/M60 cytokeratin-18 cleavage products in the breast cohort suggesting a lack of predominantly apoptotic cell death mechanism in responding patients. In lung cancer, multi-parametric [18F]ICMT-11 PET/CT, diffusion weighted (DW-MRI) and dynamic contrast enhanced-MRI (DCE-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Thus, tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions. In conclusion, the optimal clinical context whereby the [18F]ICMT-11 PET endpoint critically determines the outcome of therapy remains to be established.Open Acces

Bloqueo de procesos tumorales mediante la inhibición de angiogénesis y de la actividad de la proteína RAS

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 18/12/2015Angiogenesis, the process of new blood vessel formation, is an essential requirement for the survival and proliferation of solid tumors. Accordingly, the search for angiogenesis inhibitors has become a leading line of investigation in anticancer research, and it has translated into several drugs in the market that have clearly improved outcomes in patients with different tumor types and metastatic disease. However, several limitations still exist, such as the lack of efficacy in some patients, the appearance of adverse effects, and drug resistance. It has been suggested that when the vascular endothelial growth factor (VEGF) signaling is pharmacologically blocked, other proangiogenic factors -especially the fibroblast growth factor (FGF)- take over its signaling, thereby supporting tumor angiogenesis. Besides, it has been described that increasing tumor hypoxia during antiangiogenic therapy enhances cell survival through the stimulation of several factors, particularly the hypoxia-inducible factor-1α (HIF- 1α).7 In this context, the main objective of the present work is the identification of new small molecules able to block angiogenesis affecting various proangiogenic factors (especially VEGF and FGF signaling pathways), and to induce a sustained inhibition of the proangiogenic signaling generated by hypoxia. This overall objective involves the following steps: 1. Hit identification and hit to lead process. 2. Biological characterization of selected compound(s) in terms of impairment of proangiogenic signaling under hypoxia. 3. Antitumor effect of selected compound(s)...La angiogénesis, el proceso de formación de nuevos vasos sanguíneos, es un requerimiento esencial para la supervivencia y proliferación de los tumores sólidos. Por consiguiente, la búsqueda de inhibidores de la angiogénesis se ha convertido en una importante línea de investigación en el área de cáncer, y se ha traducido en la presencia de múltiples fármacos en el mercado que han mejorado claramente los resultados en pacientes con distintos tipos de tumores y metástasis. Sin embargo, todavía existen limitaciones, como la falta de eficacia en algunos pacientes, y la aparición de efectos adversos o de resistencia al tratamiento. Se considera que cuando se bloquea farmacológicamente la señalización del factor de crecimiento vascular endotelial (VEGF), otros factores proangiogénicos -especialmente el factor de crecimiento de fibroblastos (FGF)- cumplen su función, favoreciendo la angiogénesis tumoral. Además, se ha descrito que el aumento de la hipoxia tumoral causado por la terapia antiangiogénica potencia la supervivencia celular al estimular varios factores, particularmente el factor inducible por hipoxia-1α (HIF-1α).7 En este contexto, el principal objetivo del presente trabajo es la identificación de nuevas estructuras químicas capaces de bloquear la angiogénesis afectando varios factores proangiogénicos (especialmente VEGF y FGF), así como de inducir una inhibición sostenida de la señalización proangiogénica generada por la hipoxia. Este objetivo general supone llevar a cabo los siguientes pasos: 1. Identificación de un hit y proceso hit to lead. 2. Caracterización biológica de los compuesto(s) seleccionado(s) en relación a su capacidad para bloquear la señalización proangiogénica ante la hipoxia. 3. Estudio del efecto antitumoral de los compuesto(s) seleccionado(s)...Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEunpu

Towards the systematic construction of domain-specific transformation languages

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-09195-2-13Proceedings of 10th European Conference, ECMFA 2014, Held as Part of STAF 2014, York, UK, July 21-25, 2014General-purpose transformation languages, like ATL or QVT, are the basis for model manipulation in Model-Driven Engineering (MDE). However, as MDE moves to more complex scenarios, there is the need for specialized transformation languages for activities like model merging, migration or aspect weaving, or for specific domains of wide use like UML. Such domain-specific transformation languages (DSTLs) encapsulate transformation knowledge within a language, enabling the reuse of recurrent solutions to transformation problems. Nowadays, many DSTLs are built in an ad-hoc manner, which requires a high development cost to achieve a full-featured implementation. Alternatively, they are realised by an embedding into general-purpose transformation or programming languages like ATL or Java. In this paper, we propose a framework for the systematic creation of DSTLs. First, we look into the characteristics of domain-specific transformation tools, deriving a categorization which is the basis of our framework. Then, we propose a domain-specific language to describe DSTLs, from which we derive a ready-to-run workbench which includes the abstract syntax, concrete syntax and translational semantics of the DSTL.This work has been funded by the Spanish Ministry of Economy and Competitivity with project “Go Lite” (TIN2011-24139

Weaving Rules into [email protected] for Embedded Smart Systems

Smart systems are characterised by their ability to analyse measured data in live and to react to changes according to expert rules. Therefore, such systems exploit appropriate data models together with actions, triggered by domain-related conditions. The challenge at hand is that smart systems usually need to process thousands of updates to detect which rules need to be triggered, often even on restricted hardware like a Raspberry Pi. Despite various approaches have been investigated to efficiently check conditions on data models, they either assume to fit into main memory or rely on high latency persistence storage systems that severely damage the reactivity of smart systems. To tackle this challenge, we propose a novel composition process, which weaves executable rules into a data model with lazy loading abilities. We quantitatively show, on a smart building case study, that our approach can handle, at low latency, big sets of rules on top of large-scale data models on restricted hardware.Comment: pre-print version, published in the proceedings of MOMO-17 Worksho

Development of novel imaging biomarkers using positron emission tomography for characterization of malignant phenotype and response evaluation

Positron emission tomography (PET) enables noninvasive tumour imaging, as changes in metabolic activity secondary to therapy can be measured before changes in tumour size are evident on standard anatomic imaging. Two imaging approaches representing proliferation dependent and independent technologies are evolving as potential methods for assessing growth signalling and, thus, treatment response: [18F]3’-deoxy-3’-fluorothymidine (FLT) and [11C]choline. The validity of the former in patients with pancreatic cancer is unproven and likewise, the role of the latter in response to androgen deprivation/radiotherapy in prostate cancer (PCa) remains unexplored. Using a variety of approaches, the aim of this thesis was to provide an understanding of the role of these tracers in lesion detection and response assessment in patients by PET/computed tomography (PET/CT). Given the high physiological hepatic localisation of FLT, a recently reported kinetic spatial filtering (KSF) algorithm was evaluated as a way to de-noise abdominal FLT-PET data from patients with advanced pancreatic cancer. Application of KSF led to improved lesion detection. FLT uptake (SUV60,max) significantly increased in mid-treatment (gemcitabine based) progressors (p=0.04). In this limited number of patients, reduction in FLT uptake did not predict overall survival. The role of [11C]choline PET/CT in lesion detection and response in prostate cancer (PCa) was also investigated using semi-quantitative and quantitative methods. As a prelude to the quantitative imaging studies, it was established that irreversible tracer uptake characterised tumour (breast cancer) [11C]choline kinetics. Similar irreversible uptake characterised PCa. An important finding was that tumour [11C]choline uptake (in 29 PCa patients) correlated with choline kinase (CHK) expression but not proliferation, as assessed by Ki67 labelling index. Immunohistochemistry of the above patients’ prostate cores with CHKα antibody demonstrated a spectrum of CHKα expression, ranging from expression in prostatic-intraepithelial-neoplasia to low to high expression in malignant cores. These findings were further corroborated in a larger cohort of 75 malignant cores derived from non-imaging studies. Having established [11C]choline as a proliferation independent marker of growth, its role in assessing treatment response was investigated. [11C]choline PET was sensitive to metabolic changes within prostate tumours following androgen deprivation and radical radiotherapy. While promising data were obtained with [11C]choline PET, the radiotracer is subject to metabolic degradation complicating data analysis. To this end, a novel metabolically stable analogue of choline ([18F]fluoromethyl-[1,2-2H4]-choline ([18F]D4FCH)) was transitioned into volunteers and patients to study its pharmacokinetics and preliminary diagnostic potential. This tracer embodies deuterium isotope substitution as a means to discourage systemic metabolism. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. Preliminary results in non-small cell lung cancer showed that the tracer is taken up in tumours. Further studies are warranted to characterise this new tracer in different tumour types. As a prelude to imaging cancer cell death in tumours, a caspase-3 specific radiotracer, [18F](S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4- difluorophenoxymethyl)-pyrrolidine-1-sulfonyl) isatin ([18F]ICMT-11) was also transitioned into volunteers. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. In summary, FLT-PET/CT combined with KSF and [11C]choline PET/CT were shown to be promising methods for imaging early treatment response in patients. Further work will be required to evaluate the clinical relevance of these data in terms of overall patient outcome. Furthermore, a new choline-based radiotracer and a caspase-3 specific radiotracer have been transitioned into humans.Open Acces

Conceptualizing Mosque Tourism: A central feature of Islamic and Religious Tourism.

The increasing size of the worldwide Muslim population and the modernization of Arab countries on the international scene reinforce the rising trend of Islamic Tourism. Indeed, Islamic Tourism has gained much interest in recent years and is considered to be a very promising niche in the near future. This fairly new concept can simply be defined as intra-Muslim and intra-Arab tourism and considering Muslim countries are an emerging tourism market, this is a product with significant economic potential. It is also viewed as tourism that respects Islamic religious principles and is consequently referred to as “Halal Tourism”. In addition, it includes tourists travelling for religious purposes such as those performing the Islamic pilgrimage of Hajj. Consequently, defining Islamic Tourism is a complex matter, that can be broad or narrow, as it can de defined by its type of tourist, its place of travel, its purpose of travel and way of travel. Furthermore, it is important not to omit the cultural aspects of Islamic tourism that this paper will primarily focus on; the paper considers Islamic cultural tourism sites and attractions as another element of this trend, referring to Islamic tourism in its choice of tourist activities. Indeed, Islamic and Arabic culture, heritage and history are displayed and interpreted in order to allow the visitor to discover and understand Muslims, their beliefs and way of life while facilitating their leisurely entertainment and satisfying their tourist curiosity. In this context, this papers offers to define the concept of Mosque Tourism, a term which is inexistent in the current academic literature as well as to propose a justification of its importance as a tourist activity and a central element of Islamic tourism that should be focused on to promote a sustainable growth of this new tourist trend. Indeed, the purpose of this paper is to describe and define Islamic Tourism by reviewing the tourism literature in order to give a meaning to the term Mosque Tourism, which is one of the most important activities undertaken by Muslim tourists as a religious practice as well as a tourist activity while travelling