89 research outputs found
Thesaurus Bibliorum : omnem utriusque vitae antidotum secùndum utriusque instrumenti veritate & historiam succintè complectens
No full textPort. con grab. xil., medallón con serpiente enroscada alrededor de Neptuno (posible marca)Sign.: 3*\p8\s, A-Z\p8\s, 2A-2Z\p8\s, 3A-3I\p8\sApostillas marginales. Index Evangeliorum, a dos col. e Index verborum, a tre
The development and evaluation of PSMA targeted therapeutic and imaging agents
No full textProstate cancer (PCa) is a significant health concern, particularly in its advanced
stages when metastasis occurs, causing immense suffering for patients. Prostate
specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells and
its expression is associated with disease progression. The use of PSMA targeting
peptides, notably the glutamate-urea-lysine (Glu-Urea-Lys) sequence, has been
investigated for the delivery of anticancer agents, radioisotopes, and monoclonal
antibodies (mAb) to PCa lesions; however, PSMA remained less utilized for targeted
immunotherapy. Gamma-delta T cells (γδ T cells) are crucial immune cells that defend
against pathogens and have potential in anti-tumour applications. Activation and
expansion of γδ T cells ex vivo can be achieved by nitrogen-containing bisphosphates
(N-BP). The use of N-BPs in targeted delivery strategies is limited and requires further
work to improve pharmacokinetic (PK) and pharmacodynamic (PD) properties.
Zoledronic acid (ZA) is a potent N-BP that has been widely used in treating metastatic
bone cancer and in the study of γδ T cell expansion; however, ZA has unfavorable PK
and PD properties, side effects, and limited structural features for modification, thus
efforts are required in its development.
In this project, PSMA-targeted BP were investigated to develop PCa specific
immunotherapies. This included the development of a conjugatable ZA derivative with
efficacy in expanding γδ T cell populations. To aid cell uptake, prodrug strategies
utilizing the cleavable pivaloyloxymethyl (POM) group were investigated. A lead
compound was selected to conjugate with a PSMA-targeted peptide which employed
the conjugation chemistry developed in this project. In addition, a novel PSMA targeted
radiopharmaceutical labelled using 19F/18F SuFEx isotopic exchange chemistry was
developed and evaluated, showing PSMA specific in vivo uptake. This included a fully
automated radiosynthesis using the GE FASTLab™ cassette-based platform,
providing radioconjugate in a 25.0 ± 2.6% radiochemical yield (decay corrected).Open Acces
The development of nuclear receptor imaging agents
No full textPositron emission tomography (PET) is a molecular imaging technique which allows visualisation and quantification of biomarkers by administering a positron-emitting molecular probe. The steroid hormone receptors for estrogen and progesterone are over-expressed in hormone-dependent cancers of the breast and ovary. Endocrine therapies targeting estrogen receptor (ER) such as Tamoxifen, a selective estrogen receptor modulator (SERM), are among the frontline treatments for these cancers. Currently patient stratification for ER therapy is carried out using immunohistochemical (IHC) assays from biopsy samples; however, this invasive technique is unsuitable for assessing metastatic lesions (multiple and difficult biopsy sampling required). IHC assays are also prone to errors arising from discordance in methodology for assessment of results and also the effect of tumour heterogeneity. Progesterone receptor (PR) expression is regulated by ER and can therefore serve as a surrogate treatment response biomarker for endocrine therapy as PR expression reports on modulation of the ER pathway even if the receptor is saturated with tamoxifen. The use of PET for quantitative interrogation of breast tumour response to endocrine therapy has been reported with steroidal PR ligand, [¹⁸F]FFNP using an in vivo breast cancer rodent model. Correlation between PR expression and tracer uptake has been evaluated in a clinical trial.A focused library of non-steroidal PR imaging agents has been synthesised, based on the benzoxazinthione core structure of tanaproget, a well-established non-steroidal PR agonist. Novel synthetic methodology for accessing thio-carbamate Tanaproget derivatives was developed to avoid the use of Lawesson’s reagent. This thesis reports the first synthesis of a 1,2,3-triazole containing PR ligand which exhibited nanomolar potency in T47D cells.This project aimed to develop surface plasmon resonance (SPR) methodology to assess ligand-receptor binding kinetics to aid lead candidate selection for radiolabelling. The development of an assay to assess ligand binding between progesterone (used as a known PR ligand) and captured PR-ligand binding domain proved to be unsuccessful even though the receptor was able to bind anti-PR monoclonal antibody (mAb). A reduction in temperature and introducing a chaotropic agent to denature the receptor were unsuccessful attempts at getting the receptor to bind to progesterone. The dependence of ligand binding on chaperone proteins like heat shock protein-90 (HSP90) was realised and a PR-HSP90 complex receptor was captured to try and facilitate ligand binding. These receptors proved to be unsuccessful at facilitating ligand binding. Compound libraries were evaluated for potency using the T47D alkaline phosphatase assay in live cells; lead candidates were selected using this data.Radiochemical methodology was developed to label lead candidates with fluorine-18. Two lead candidates were selected from the potency data of cold compounds in the breast cancer cell line T47D; these compounds were compound 26 (EC₅₀ = 4.7 nM) and 32 (EC₅₀ = 47.6 nM). Initial steps to access compound [¹⁸F]26 were developed by radiolabelling dibromopyridine precursors as a prosthetic group; however, this radiosynthesis was not completed. The radiosynthesis of [¹⁸F]32 was achieved by one-step methodology with a fluoride incorporation of 75 – 78 % in a 15 min reaction time. Work towards developing conditions to purify [¹⁸F]32 allowed some compound to be isolated and specific activity determined (0.027 GBq/μmol). Future work will involve improving the purification method to [¹⁸F]32 in anticipation of isolating compound with higher specific activity to evaluate the compound with in vitro cell uptake studies and in vivo biodistribution in an animal model
The development of nuclear receptor imaging agents
No full textPositron emission tomography (PET) is a molecular imaging technique which allows visualisation and quantification of biomarkers by administering a positron-emitting molecular probe. The steroid hormone receptors for estrogen and progesterone are over-expressed in hormone-dependent cancers of the breast and ovary. Endocrine therapies targeting estrogen receptor (ER) such as Tamoxifen, a selective estrogen receptor modulator (SERM), are among the frontline treatments for these cancers. Currently patient stratification for ER therapy is carried out using immunohistochemical (IHC) assays from biopsy samples; however, this invasive technique is unsuitable for assessing metastatic lesions (multiple and difficult biopsy sampling required). IHC assays are also prone to errors arising from discordance in methodology for assessment of results and also the effect of tumour heterogeneity. Progesterone receptor (PR) expression is regulated by ER and can therefore serve as a surrogate treatment response biomarker for endocrine therapy as PR expression reports on modulation of the ER pathway even if the receptor is saturated with tamoxifen. The use of PET for quantitative interrogation of breast tumour response to endocrine therapy has been reported with steroidal PR ligand, [¹⁸F]FFNP using an in vivo breast cancer rodent model. Correlation between PR expression and tracer uptake has been evaluated in a clinical trial.A focused library of non-steroidal PR imaging agents has been synthesised, based on the benzoxazinthione core structure of tanaproget, a well-established non-steroidal PR agonist. Novel synthetic methodology for accessing thio-carbamate Tanaproget derivatives was developed to avoid the use of Lawesson’s reagent. This thesis reports the first synthesis of a 1,2,3-triazole containing PR ligand which exhibited nanomolar potency in T47D cells.This project aimed to develop surface plasmon resonance (SPR) methodology to assess ligand-receptor binding kinetics to aid lead candidate selection for radiolabelling. The development of an assay to assess ligand binding between progesterone (used as a known PR ligand) and captured PR-ligand binding domain proved to be unsuccessful even though the receptor was able to bind anti-PR monoclonal antibody (mAb). A reduction in temperature and introducing a chaotropic agent to denature the receptor were unsuccessful attempts at getting the receptor to bind to progesterone. The dependence of ligand binding on chaperone proteins like heat shock protein-90 (HSP90) was realised and a PR-HSP90 complex receptor was captured to try and facilitate ligand binding. These receptors proved to be unsuccessful at facilitating ligand binding. Compound libraries were evaluated for potency using the T47D alkaline phosphatase assay in live cells; lead candidates were selected using this data.Radiochemical methodology was developed to label lead candidates with fluorine-18. Two lead candidates were selected from the potency data of cold compounds in the breast cancer cell line T47D; these compounds were compound 26 (EC₅₀ = 4.7 nM) and 32 (EC₅₀ = 47.6 nM). Initial steps to access compound [¹⁸F]26 were developed by radiolabelling dibromopyridine precursors as a prosthetic group; however, this radiosynthesis was not completed. The radiosynthesis of [¹⁸F]32 was achieved by one-step methodology with a fluoride incorporation of 75 – 78 % in a 15 min reaction time. Work towards developing conditions to purify [¹⁸F]32 allowed some compound to be isolated and specific activity determined (0.027 GBq/μmol). Future work will involve improving the purification method to [¹⁸F]32 in anticipation of isolating compound with higher specific activity to evaluate the compound with in vitro cell uptake studies and in vivo biodistribution in an animal model
The aluminium-[18F]fluoride revolution: simple radiochemistry with a big impact for radiolabelled biomolecules
No full textThe aluminium-[18F]fluoride ([18F]AlF) radiolabelling method combines the favourable decay characteristics of fluorine-18 with the convenience and familiarity of metal-based radiochemistry and has been used to parallel gallium-68 radiopharmaceutical developments. As such, the [18F]AlF method is popular and widely implemented in the development of radiopharmaceuticals for the clinic. In this review, we capture the current status of [18F]AlF-based technology and reflect upon its impact on nuclear medicine, as well as offering our perspective on what the future holds for this unique radiolabelling method
Chemistry considerations for the clinical translation of oncology PET radiopharmaceuticals
No full textPositron emission tomography (PET) has proven to be an invaluable tool in the staging and management of disease in oncology; however, [18F]fluorodeoxyglucose ([18F]FDG) remains the most widely used PET radiopharmaceutical despite the large financial investment in novel radiotracer development. We report our perspective and experience of translating radiopharmaceuticals into clinical studies, discussing the PET development pipeline from a chemistry perspective. We hope that, by identifying potential points of attrition along the pipeline and suggesting solutions to these problems, we may help others take their preclinical radiotracers into human studies. This review focuses primarily on the development of fluorine-18 radiopharmaceuticals, although the broader field of radiometal chemistry is considered where the translation journey is similar
How typology allows for a new analysis of the verb phrase in Burmese
No full textInternational audienceBurmese has been studied by westerner scholars since 18e century. Recent works containing good description of the language (or part of the language) are Allott (1965), Okell (1969), Bernot (1980), Wheatley (1982), Bernot et al (2001), Allott &. Okell (2001). However comparison of the description made by these authors leads to different analysis of the verbal phrase. For instance the list of optional verbal morphemes (particles and auxiliaries) varies depending of the criteria used by the author for his analysis. Moreover, as in many Asian languages, groups of verbs not separated by connectors exist in Burmese. These verbal phrases composed by several verb roots have identical form in surface. However, they cannot be analyzed in the same way. They can correspond to lexical expressions, or compounds and be listed in dictionaries. The verbal phrase may be analyzed as a prototypical serial verbs construction (SVC), here is to say, part of one clause only which refers to a unique event. Third possibility : some of the verb roots can be grammaticalized and be considered as auxiliaries. Given the identical surface forms and the different under-laying structures, we look for a model allowing us to treat together phenomenon traditionally analyzed separately. Therefore, the notion of serial verbs construction (CVS) recently developed by Déchaine (1993), Durie (1997) or, Aikhenvald & Dixon (in press) among others help us to build the adequate frame for a more global approach of the VP in Burmese
[18F]FET-βAG-TOCA: the design, evaluation and clinical translation of a fluorinated octreotide
No full textThe success of Lutathera™ ([177Lu]Lu-DOTA-TATE) in the NETTER-1 clinical trial as a peptide receptor radionuclide therapy (PRRT) for somatostatin receptor expressing (SSTR) neuroendocrine tumours (NET) is likely to increase the demand for patient stratification by positron emission tomography (PET). The current gold standard of gallium-68 radiolabelled somatostatin analogues (e.g., [68Ga]Ga-DOTA-TATE) works effectively, but access is constrained by the limited availability and scalability of gallium-68 radiopharmaceutical production. The aim of this review is three-fold: firstly, we discuss the peptide library design, biological evaluation and clinical translation of [18F]fluoroethyltriazole-βAG-TOCA ([18F]FET-βAG-TOCA), our fluorine-18 radiolabelled octreotide; secondly, to exemplify the potential of the 2-[18F]fluoroethylazide prosthetic group and copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry in accessing good manufacturing practice (GMP) compatible radiopharmaceuticals; thirdly, we aim to illustrate a framework for the translation of similarly radiolabelled peptides, in which in vivo pharmacokinetics drives candidate selection, supported by robust radiochemistry methodology and a route to GMP production. It is hoped that this review will continue to inspire the development and translation of fluorine-18 radiolabelled peptides into clinical studies for the benefit of patients
Beauty for the Present: Mill, Arnold, Ruskin and Aesthetic Education
No full textThe present thesis examines the idea of aesthetic education of three eminent Victorians: John Stuart Mill, Matthew Arnold and John Ruskin. By focusing on the essence of what they meant with ‘the cultivation of the beautiful’ and, more importantly, the way their ideas of beauty informed their criticism of society, my study aims to contribute to our understanding of the idea of aesthetic education in the Victorian context and, further, to participate in a recent debate about the nature of beauty and aesthetic education.
Chapter One focuses on John Stuart Mill’s concept of ‘feeling’ in a series of essays. I will demonstrate how Mill’s idea of ‘aesthetic education’ was an ‘education of feelings,’ and moreover, how this idea was integrated into his literary criticism, his later critique of democratisation, his description of an ideal liberal society and even his own style of writing. Chapter Two contains a comparative study of Matthew Arnold and Friedrich Schiller. Through a rereading of Arnold, I will argue that his idea of aesthetic education is essentially Schillerian and that their resemblance consists primarily in their stress on the importance of aesthetic unity for modern life, which was becoming increasingly fragmentary and multitudinous. Chapter Three examines John Ruskin’s idea of aesthetic education and concentrates particularly on the cultivation of perception. Perception, as I shall show, was pivotal in Ruskin’s idea of aesthetic education. Just as what happened in Mill and Arnold, the emphasis on the education of seeing continued from his early writings well into his art and social criticisms. It not only differentiated him from his fellow art critics; the conviction that people should perceive with a pure heart also enabled him to link observation of artistic details with moral criticism of contemporary society and, thereby, to turn the cultivation of the beautiful into a moral-aesthetic experience
Peatlands and Climate Change
No full textThis is the author manuscript version. The final version is available from Cambridge University Press via the DOI in this recordThe fundamental reason for the presence of peatlands is a positive balance between plant production and decomposition. Organic matter accumulates in these systems because prolonged waterlogged conditions result in soil anoxia (i.e., exclusion of oxygen), and under these conditions decomposition rates can be lower than those of primary production. Climate therefore plays an important role in peat accumulation, both directly by affecting productivity and decomposition processes, and indirectly through its effects on hydrology/water balance and vegetation (for a summary, refer to Yu, Beilman & Jones 2009). Climate provides broad-scale constraints or controls on peatland extent, types and vegetation, and ultimately, ecosystem functioning, carbon accumulation, greenhouse gas exchange and all of the other ecosystem services that peatlands provide. Peatlands can play a vital role in helping society mitigate and adapt to climate change, because of their carbon and water regulating functions, while at the same time, the climate sensitivity of peatlands makes them potentially vulnerable to future global warming and changes in spatial and temporal patterns of precipitation, especially if they are in a degraded state. Climate change is likely to alter the hydrology and soil temperature of peatlands, with far- reaching consequences for their biodiversity, ecology and biogeochemistry. Their involvement in the global carbon cycle will also be affected, with the possibility of drier conditions allowing peatland erosion and increases in CO2 emissions that would result in a positive feedback to climate change (Turetsky 2010). This highlights all the more the need for restoration to ensure peatlands are resilient to change so that they continue to deliver ecosystem services for human well-being. This chapter describes the interactions between climate and peatlands, in three sections. The first section explains how present climate influences peatlands, by documenting how climate limits peatland geographical extent globally, and how bioclimatic envelope models can predict peatland extent. We indicate how each type of peatland is linked to a specific climate range, and introduce the concept of ecosystem function in relation to climate. The second section looks into the past. It describes how peat preserves a record of past climates and environmental conditions that can be deciphered to reveal the history of peatland vegetation, hydrology and carbon accumulation changes in relation to past changes in climate. We highlight lessons that can be learned from the palaeorecord preserved in peat. The final section discusses the potential effects of present and future climate change on peatlands, their extent, carbon accumulation rates, fire frequency, water table and greenhouse gas exchanges. We also consider how increases in sea level and CO2 concentration, and decreases in the extent of permafrost, are likely to affect peatlands
- …
