Selection of the first 99m^{99m} Tc-Labelled somatostatin receptor subtype 2 antagonist for clinical translation : preclinical assessment of two optimized candidates

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist

Male, National, and Religious Collective Narcissism Predict Sexism

Results of three cross-sectional studies indicate that sexism in Poland is associated with collective narcissism—a belief that one’s own group’s (the in-group’s) exaggerated exceptionality is not sufficiently recognized by others—with reference to three social identities: male, religious, and national. In Study 1 (n = 329), male collective narcissism was associated with sexism. This relationship was sequentially mediated by precarious manhood and traditional gender beliefs. In Study 2 (n = 877), Catholic collective narcissism predicted tolerance of violence against women (among men and women) over and above religious fundamentalism and in contrast to intrinsic religiosity. In Study 3 (n = 1070), national collective narcissism was associated with hostile sexism among men and women and with benevolent sexism more strongly among women than among men. In contrast, national in-group satisfaction—a belief that the nation is of a high value—predicted rejection of benevolent and hostile sexism among women but was positively associated with hostile and benevolent sexism among men. Among men and women collective narcissism was associated with tolerance of domestic violence against women, whereas national in-group satisfaction was associated with rejection of violence against women

Visible Human Projects - a step towards the virtual patient: models and simulations

This paper reports on our experiences using datasets from the Visible Human Project in different biomedical applications. Introduced 1994 by the US National Library of Medicine the digitized multimodal anatomical datasets of the Visible Man have challenged the worldwide scientific community. A significant response to this challenge from several interdisciplinary research teams has emerged as a new area of research. This area requires close interaction and collaboration among anatomists, radiologists, computer scientists, mathematicians, engineers and physicians. The digitized volumetric images of the human body have been applied not only for the computer-aided exploration of the human gross anatomy, but also as structural input for the therapy planning and simulation systems. The importance of such virtual patient model is becoming increasingly recognized in modern medicine. To effectively use these specific datasets a sophisticated framework consisting of image processing, computer graphics and mathematical modelling methods is required. In this work various aspects of the developed framework are presented and discussed. Some preliminary results of our biomedical simulations are presented

Processing of sodium sulphate solutions using the EED method: from a batch toward a continuous process

In a batch electro-electrodialysis (EED), sodium sulphate solution with an initial concentration of 80.90 g/dm3  was converted to obtain solutions of sodium hydroxide (13.96%) and sulphuric acid (10.15%) and a dialysate (3.23 g/dm3 of sulphate ions). Changes in the EED process′ performance (temperature, cell voltage, concentrations, energy consumption) with an increasing conversion degree of salt are presented. Based on the presented results of the batch experiment, conditions necessary to run the process continuously are discussed. A single pass method is inapplicable due to excessive heating of the electro-electrodialyser. A cascade method enables interstage cooling of the solutions, providing temperatures suitable for ion-exchange membranes to work. Increasing the number of stages in the cascade reduces both the number of electro-electrodialysers and specific electric energy consumption, providing the same production capacity. However, this increases the investment cost

Patient-specific graft design method for cranofacial surgical planning

This paper presents a method for computer assisted selection of optimal donor sites for autologous osseous grafts in the craniofacial surgery. At the initial graft design stage the surgeon defines in the CT data set the shape of the bone segment to be reconstructed and in the donor region CT data set a set of constraints for the optimization task. This non-automatic step is followed by a fully automatic optimization stage, which delivers a set of sub-optimal and optimal donor sites for a given template. Such approach permits the surgeon to find the best site for harvesting the graft and enables an exact anatomical reconstruction of the osseous section

Targeted alpha therapy of glioblastoma multiforme: initial clinical experience with 213Bi-substance P

Glioblastoma, the most common primary brain tumor in adults, has a very poor prognosis with a median overall survival of 15 months despite of aggressive therapy including surgery, chemotherapy and radiation therapy. New therapy options are urgently needed. Targeted alpha therapy with the short range, high LET alpha emitter 213Bi offers the potential for selective irradiation of tumors, while minimizing damage to adjacent, functional critical areas of the brain. The peptide carrier substance P is targeting neurokinin type 1 (NK-1) receptors, which are consistently over-expressed on glioblastoma cells. Here we report the first clinical experience with 213Bi-labeled DOTA-Substance P in patients with recurrent glioblastoma.JRC.E.5-Nuclear chemistr

Glioblastoma Therapy with Substance P labelled with Bismuth-213

Gliomas are the most frequent primary brain tumors in adult patients. The most malignant of them – glioblastoma multiforme (GBM), is characterized by the worst prognosis with a median survival of 15 months. The infiltrating character of the tumor, molecular heterogeneity, as well as the protective effects of blood-brain barrier are the main causes of insufficient front line treatments (surgery, radio and chemotherapy); 90% of patients have a recurrence at the original tumor location. Therefore a new type of treatment strategies is urgently needed. Because the majority of recurrences occur within 2 cm of the resection margin, local therapies are currently under investigation. Riva P et al. in 1995 have proposed local treatment of malignant gliomas (1). This method allows for a higher concentration of drug into the tumor and omitting the blood-brain barrier. This method is also suitable for local administration of radiopharmaceuticals. Different types of biologically active ligands and radioisotopes were used.JRC.E.5-Nuclear chemistr