AN INSTRUCTIONAL SCENARIO (LESSON PLAN): THE IMPORTANCE OF ARTERIAL PULSE

This article aims to present a lesson plan entitled: "An instructional scenario: The Importance of Arterial pulse". This teaching plan lasts for one teaching hour. It was carried out with modern educational form through the Cisco WebEx Meetings platform and concerns the course Nursing Theory II for the 3rd Class of Vocational High School (EPAL), specializing in Nursing of the Health, Welfare & Wellness Sector. This lesson plan was implemented in the context of the training of B2 level ICT trainees, organized by the Institute of Educational Policy (IEP) with the co-financing support of Greece and the European Union. The article aims to present a teaching plan so that students can deepen their knowledge in the topic of Vital Signs with emphasis on the importance of arterial pulse. More specifically, students learn to define what an arterial pulse is, to list the points where the arterial pulse is taken, and to state each time the arterial pulse should be taken. The strategy on which it was based is collaborative learning. In particular, through the working groups, the participation and the interaction with the students are reinforced. Students were asked to complete interactive exercises created in the e-me content, then work on a collaborative document (google forms), and at the end of the course fill in a worksheet for feedback.  Article visualizations

AN INSTRUCTIONAL SCENARIO (LESSON PLAN): THE IMPORTANCE OF BREATHING. IS IT POSSIBLE WITHOUT BREATHING?

This article aims to present a lesson plan entitled “The importance of breathing. Is it possible to live without breathing?” This lesson lasts for one teaching hour. It was carried out through the Cisco WebEx Meetings platform of modern training and concerns the course Nursing Theory II for the 3rd Class of Vocational High School (EPAL), specializing in Nursing Assistant in the Health, Welfare & Wellness Sector. This script material was part of the training of B2 level ICT trainees, organized by the Institute of Educational Policy (IEP) with the co-financing of Greece and the European Union. The article aims to present a lesson plan so that students can deepen their knowledge in the thematic unit of Vital Signs with emphasis on the importance of breathing. More specifically, students learn to define what respiration is, to name and interpret the different types of respiration, but also to know when respirations should be counted. The strategy they relied on is collaborative learning. In particular, by organizing working groups, participation and interaction among students are enhanced. Students were asked to complete an interactive exercise created on e-me content, then worked on a collaborative document (Google forms) and completed a feedback quiz at the end of the lesson. Article visualizations

Prostaglandin D2/J2 signaling pathway in a rat model of neuroinflammation displaying progressive parkinsonian-like pathology: potential novel therapeutic targets

Background: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson’s disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2. Methods: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH). Nigral dopaminergic (DA) and microglial distribution and expression levels of these key factors of the prostaglandin D2/J2 pathway were evaluated by immunohistochemistry. PGJ2-induced motor deficits were assessed with the cylinder test. We also determined whether oral treatment with ibuprofen improved the PD-like pathology induced by PGJ2. Results: PGJ2 treatment induced progressive PD-like pathology in the rats. Concomitant with DA neuronal loss in the substantia nigra pars compacta (SNpc), PGJ2-treated rats exhibited microglia and astrocyte activation and motor deficits. In DA neurons, COX-2, L-PGDS, and 15-PGDH levelsincreased significantly in PGJ2-treated rats compared to controls, while DP2 receptor levels were unchanged. In microglia, DP2 receptors were basically non-detectable, while COX-2 and L-PGDS levels increased upon PGJ2-treatment, and 15-PGDH remained unchanged. 15-PGDH was also detected in oligodendrocytes. Notably, ibuprofen prevented most PGJ2-induced PD-like pathology. Conclusions: The PGJ2-induced rat model develops progressive PD pathology, which is a hard-to-mimic aspect of this disorder. Moreover, prevention of most PGJ2-induced PD-like pathology with ibuprofen suggests a positive feedback mechanism between PGJ2 and COX-2 that could lead to chronic neuroinflammation. Notably, this is the first study that analyzes the nigral dopaminergic and microglial distribution and levels of factors of the PGD2/J2 signaling pathway in rodents. Our findings support the notions that upregulation of COX-2 and L-PGDS may be important in the PGJ2 evoked PD-like pathology, and that neuronal DP2 receptor antagonists and L-PGDS inhibitors may be novel pharmacotherapeutics to relieve neuroinflammation-mediated neurodegeneration in PD, circumventing the adverse side effects of cyclooxygenase inhibitors

Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones

Wind Turbine Contribution to Ancillary Services under Increased Renewable Penetration levels

Wind constitutes a dominant form of sustainable energy that is expected to grow rapidly in the years to come. Increased inverter-based wind power penetration may however endanger grid stability and reliability, if not enriched with the capability to provide crucial ancillary services to the grid, such as frequency regulation. In order for the wind turbine technology to participate in the ancillary service provision, a more in depth understanding of the wind turbine dynamic behavior is acquired. Therefore, this Master Thesis Project was formulated to study how the wind turbine technology can assist in providing ancillary services under increased renewable penetration levels with a concentration on the frequency support. This project proposes the frequency controllers both at the single wind turbine level and the wind farm level to facilitate the provision of ancillary services. The power system transient simulation package PSCADTM/EMTDCTM V4.6.2 is used for the controller design and the simulation study. The single wind turbine frequency controller enables the provision of the necessary positive or negative active power reserves in proportion to the measured grid frequency, via the kinetic energy stored in the rotating masses and pitch control. Thus, the wind turbine generator power output is enabled to increase or decrease respectively. The full potential offered by the technology is exploited, while the limitations associated with the provision of active power reserves are identified and respected by the implemented controller. The wind farm controller allows for the coordination and control of the available wind turbines within a wind farm, despite several barriers identified in this project. A list of parameters is used to this end, which can be varied to achieve a more sustained frequency response, despite the barriers introduced by the available limitations of the electrical and mechanical components of the wind energy conversion system. An offshore wind farm case study was performed to test the performance of the implemented controllers and investigate the impact of the wind farm frequency response on the grid frequency, in various scenarios. The successful response of the implemented controllers is proven, while no violation of physical or safe limits is identified thanks to the frequency controller designed in this project. The allowable ranges within which the controller parameters can be varied without unwanted situations are analytically discussed and summarized as important lessons learned. Finally, the active power product that can be provided within the Ancillary Service Market is quantified and described, while recommendations are made at the Ancillary Service Market level that reflect the capabilities of the wind turbine technology, if enriched with the designed controller. Overall, a positive effect of the frequency response provided by the wind turbine technology on the grid frequency is observed. Significant improvements have been achieved on the frequency nadir and the rate of change of frequency by the wind farm controller parametrization under different severity of the frequency deviations. In general, the frequency response that can be achieved through the wind turbine technology is in any case proportional to the amount of power that is generated by a certain wind farm (i.e. proportional to the wind speed conditions). The response provided can last for several seconds, thus constituting a “Fast Frequency Response” service the most appropriate option for the wind turbine technology. A trade-off between the maximum reserves provided and the duration of the response provided is seen. However, in the cases that a certain wind turbine needs to recover following a period of reserves provision, a compromise between the aggressiveness and the duration of the recovery period is also observed

Synthesis and evaluation of radiolabeled synthetic somatostatin analogs in the in vivo licalization of neoplasms

The overexpression of somatostatin receptor subtype 2 (sst2) in many neoplasms of mainly neuroendocrine origin has resulted in an established method for the in vivo diagnostic imaging of sst2-positive tumors using OctreoScan® ([111Ιn-DTPA0]octreotide). Despite its initial success, OctreoScan®’s broader application is hampered by using 111In. Given that, 99mTc still remains the ideal diagnostic radionuclide of nuclear medicine due to important practical and financial advantages the development of a specific sst2-seeking [99mTc]-radiotracer as an alternative to OctreoScan® is highly attractive. In the present thesis, the synthesis and the biological evaluation of two novel somatostatin peptide analogs, functionalized at the N-terminus with an acyclic tetraamine chelator for effective 99mTc binding: Demotide ([Ν40,Tyr3]octreotide) and Demotate ([Ν40,Tyr3]octreotate) differing only at the C-terminus (Thr(ol)8 versus Thr8-OH, respectively), is described. Synthesis of Demotide was performed in solution whereas Demotate was synthesized on the solid support. Identification of new analogs comprised ESI-MS and RP-HPLC. Their binding affinity for sst2 was determined by competition binding experiments in sst2-positive rat brain cortex or AR4-2J and CA20948 cell membranes. Their hsst1-5 binding profile was determined by in vitro receptor autoradiography. Labeling with 99mTc led to [99mTc]Demotide and [99mTc]Demotate. The radiopeptide affinity for the sst2 was determined by saturation binding assays in AR4-2J membranes and their internalization was tested in AR4-2J cells. Biodistribution was studied in healthy (Swiss albino mice and Wistar rats) and pathological animal models (AR4-2J tumor-bearing Swiss nu/nu mice and CA20948 tumor-bearing Lewis rats). In conclusion, [99mTc]Demotide and [99mTc]Demotate satisfied important criteria and combined a variety of favorable properties for successful application in the targeted diagnostic imaging of sst2-positive tumors in man, such as favorable pharmacokinetics, metabolic stability as well as rapid and high in vivo sst2-targeting. These characteristics provide the prospect to implement a logistically convenient one-day clinical protocol (99mTc: t½= 6.02 h) without compromising image quality. Such a protocol will facilitate the patient management in clinical practice in comparison to OctreoScan® (111In: t½= 67.2 h). The latter is more suitable for a two-day examination protocol according to the manufacturer’s suggestion. Further studies are expected to confirm their potential diagnostic value in the clinic.____Η υπερέκφραση υποδοχέων σωματοστατίνης υπότυπου 2 (sst2) σε πολλά νεοπλάσματα νευροενδοκρινικής κυρίως προέλευσης έχει συντελέσει στην εφαρμογή μεθόδου in vivo διαγνωστικής απεικόνισης sst2-θετικών όγκων με το εμπορικό σκεύασμα OctreoScan® ([111Ιn-DTPA0]octreotide). Παρά την αρχική του επιτυχία, η ευρύτερη εφαρμογή του OctreoScan® περιορίζεται λόγω του 111In. Δεδομένου ότι το 99mTc παραμένει το ιδανικό διαγνωστικό ραδιονουκλίδιο της πυρηνικής ιατρικής λόγω σημαντικών πρακτικών και οικονομικών πλεονεκτημάτων, η ανάπτυξη ενός [99mTc]-ραδιοϊχνηθέτη εναλλακτικού του OctreoScan® είναι ιδιαίτερα ελκυστική. Στην παρούσα διατριβή περιγράφεται η σύνθεση και η βιολογική αξιολόγηση δύο νέων αναλόγων της σωματοστατίνης τροποποιημένων με τετρααμίνη ανοικτής αλυσίδας για σταθερή δέσμευση του 99mTc: Demotide ([Ν40,Tyr3]octreotide) και Demotate ([Ν40,Tyr3]octreotate), τα οποία διαφέρουν στο C-τελικό αμινοξύ (Thr(ol)8 και Thr8-OH, αντίστοιχα). Η σύνθεση του Demotide πραγματοποιήθηκε σε διάλυμα ενώ του Demotate σε στερεή φάση. Η ταυτοποίησή τους έγινε με ESI-MS και RP-HPLC. Η συγγένεια δέσμευσης των δύο νέων αναλόγων για τον sst2 προσδιορίστηκε με πειράματα ανταγωνιστικής δέσμευσης σε φλοιό εγκεφάλου επίμυα και σε μεμβράνες sst2-θετικών κυττάρων AR4-2J και CA20948. Η αξιολόγηση της συγγένειάς τους στους υπότυπους hsst1-5 μελετήθηκε με in vitro αυτοραδιογραφία υποδοχέων. Μετά την επισήμανση με 99mTc προέκυψαν τα [99mTc]Demotide και [99mTc]Demotate. Η ικανότητα δέσμευσής τους στον sst2 μελετήθηκε με πειράματα κορεσμού σε μεμβράνες AR4-2J ενώ η εσωτερίκευσή τους ελέγχθηκε σε κύτταρα AR4-2J. Η βιοκατανομή τους μελετήθηκε σε υγιή (ποντίκια Swiss albino και επίμυες Wistar) και παθολογικά πρότυπα πειραματοζώων (άθυμα ποντίκια Swiss nu/nu με όγκους AR4-2J και επίμυες Lewis με όγκους CA20948). Συμπερασματικά, τα [99mTc]Demotide και [99mTc]Demotate ικανοποίησαν και συνδύασαν σημαντικά κριτήρια για επιτυχή εφαρμογή στην στοχευμένη διαγνωστική απεικόνιση sst2-θετικών όγκων στον άνθρωπο, όπως ευνοϊκή βιοκινητική, μεταβολική σταθερότητα και ταχεία και υψηλή ικανότητα in vivo στόχευσης των sst2. Αυτό αναμένεται να επιτρέψει την εφαρμογή διαγνωστικού κλινικού πρωτοκόλλου μίας ημέρας (99mTc: t½= 6.02 h) χωρίς να “θυσιάζεται” η ποιότητα της απεικόνισης. Με αυτό τον τρόπο διευκολύνεται η διαχείριση των ασθενών στην κλινική πράξη σε σύγκριση με το OctreoScan® (111In: t½= 67.2 h), το οποίο είναι περισσότερο κατάλληλο για πρωτόκολλο δύο ημερών, όπως συνιστάται άλλωστε για την επιτυχέστερη κλινική του εφαρμογή. Περαιτέρω μελέτες αναμένεται να επιβεβαιώσουν την πιθανή διαγνωστική τους αξία στην κλινική πράξη

Bombesin receptor antagonists may be preferable to agonists for tumor targeting

Two bombesin analogs, Demobesin 4 and Demobesin 1, were characterized in vitro as gastrin-releasing peptide (GRP) receptor agonist and antagonist, respectively, and were compared as (99m)Tc-labeled ligands for their in vitro and in vivo tumor-targeting properties. METHODS: N(4)-[Pro(1),Tyr(4),Nle(14)]Bombesin (Demobesin 4) and N(4)-[d-Phe(6),Leu-NHEt(13),des-Met(14)]bombesin(6-14) (Demobesin 1) were characterized in vitro for their binding properties with GRP receptor autoradiography using GRP receptor-transfected HEK293 cells, PC3 cells, and human prostate cancer specimens. Their ability to modulate calcium mobilization in PC3 and transfected HEK293 cells was analyzed as well as their ability to trigger internalization of the GRP receptor in transfected HEK293 cells, as determined qualitatively by immunofluorescence microscopy and quantitatively by enzyme-linked immunosorbent assay (ELISA). Further, their internalization properties as (99m)Tc-labeled radioligands were tested in vitro in both cell lines. Finally, their biodistribution was analyzed in PC3 tumor-bearing mice. RESULTS: A comparable binding affinity with the 50% inhibitory concentration (IC(50)) in the nanomolar range was measured for Demobesin 4 and Demobesin 1 in all tested tissues. Demobesin 4 behaved as an agonist by strongly stimulating calcium mobilization and by triggering GRP receptor internalization. Demobesin 1 was ineffective in stimulating calcium mobilization and in triggering GRP receptor internalization. However, in these assays, it behaved as a competitive antagonist as it reversed completely the agonist-induced effects in both systems. (99m)Tc-Labeled Demobesin 1 was only weakly taken up by PC3 cells or GRP receptor-transfected HEK293 cells (10% and 5%, respectively, of total added radioactivity) compared with (99m)Tc-labeled Demobesin 4 (45% of total added radioactivity in both cell lines). Remarkably, the biodistribution study revealed a much more pronounced uptake at 1, 4, and 24 h after injection of (99m)Tc-labeled Demobesin 1 in vivo into PC3 tumors than (99m)Tc-labeled Demobesin 4. In vivo competition experiments demonstrated a specific uptake in PC3 tumors and in physiologic GRP receptor-expressing tissues. The tumor-to-kidney ratios were 0.7 for Demobesin 4 and 5.2 for Demobesin 1 at 4 h. CONCLUSION: This comparative in vitro/in vivo study with Demobesin 1 and Demobesin 4 indicates that GRP receptor antagonists may be superior targeting agents to GRP receptor agonists, suggesting a change of paradigm in the field of bombesin radiopharmaceuticals

66Ga: A Novelty or a Valuable Preclinical Screening Tool for the Design of Targeted Radiopharmaceuticals?

Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, 66Ga (t1/2 = 9.5 h, β+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of 66Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. 66Ga was produced by irradiation of a natZn target. 66Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 ± 2.8% recovery of 66Ga3+. Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [68Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of 66Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h