PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists

INTRODUCTION The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with (177)Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. METHODS The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x=2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with (177)Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. RESULTS The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: -1.95 vs -2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2=246±4 and 584±20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The (177)Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1h but it shows fast washout (0.46%±0.02% IA/g and 0.29%±0.08% IA/g already at 4h). CONCLUSION Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity.

In search of the "why" behind campaign professionalisation: explaining the degree and profile of campaign professionalisation by an empirical analysis of 23 Swiss cantonal election campaigns

Die Organisation und die strategische Kommunikation von Wahlkämpfen haben sich in den letzten Jahrzehnten in den meisten westeuropäischen Staaten gewandelt, so auch in der Schweiz. Die Kommunikationswissenschaft hat dafür den Begriff der „Professionalisierung“ geprägt und Eigenschaften zusammengetragen, die zu einem „professionalisierten“ Wahlkampf gehören – wie z.B. die Beauftragung von externen Expertinnen und Experten oder die direkte Ansprache von Wählerinnen und Wählern („narrowcasting“). Welche Hintergründe diese Professionalisierung aber hat und wie das Phänomen nicht nur praktisch zu beschreiben, sondern auch theoretisch zu begründen ist, wurde bisher kaum diskutiert. Hier setzt die vorliegende Dissertation an. Basierend auf einer Analyse von 23 Wahlkämpfen aus den Kantonen Aargau, Appenzell Ausserrhoden, Bern, Neuchâtel und Zürich mithilfe der Methode Fuzzy Set Qualitative Comparative Analysis (fsQCA) kommt sie zum Schluss, dass die Professionalisierung der Wahlkämpfe vor dem theoretischen Hintergrund des soziologischen Neo-Institutionalismus als Anpassung von Wahlkämpfen an sich verändernde Bedingungen, Erwartungen und Anforderungen in den wichtigsten Anspruchsgruppen oder „Umwelten“ für den Wahlkampf (Wählerinnen und Wähler, Mitglieder, Medien, andere Parteien) definiert werden kann. Daraus folgt, dass es nicht nur „die“ Professionalisierung gibt, sondern dass jeder Wahlkampf an jene Umwelten angepasst wird, wo diese Anpassung den Wahlkampfverantwortlichen am dringlichsten erscheint. Daher sollte Professionalisierung mit vier einzelnen Messinstrumenten bzw. Professionalisierungsindices – einem pro Umwelt – gemessen werden. Misst man Professionalisierung wie bisher üblich nur mit einem einzigen Messinstrument, gibt der resultierende Wert nur ein ungenaues Bild vom Grad der Professionalisierung des Wahlkampfs wieder und verschleiert, als Anpassung an welche Umwelt die Professionalisierung geschieht. Hat man ermittelt, wie professionalisiert ein Wahlkampf im Hinblick auf jede der vier relevantesten Umwelten ist, können dann auch zuverlässiger die Gründe analysiert werden, die zur jeweiligen Professionalisierung geführt haben. Die empirische Analyse der kantonalen Wahlkämpfe bestätigte, dass hinter der Professionalisierung in Bezug auf jede der vier Umwelten auch tatsächlich unterschiedliche Gründe stecken. Wahlkämpfe werden in Bezug auf die Ansprache der Wähler angepasst („professionalisiert“), wenn sie in urbanen Kontexten stattfinden. Den Wahlkampf im Hinblick auf die Mitglieder zu professionalisieren ist besonders wichtig, wenn die Konkurrenz zwischen den Parteien gross ist oder wenn eine Ansprache der Gesamtwählerschaft für eine Partei wenig gewinnbringend erscheint. Die Professionalisierung des Wahlkampfes in Bezug auf die Medien erfolgt dann, wenn er eine grosse, regional stark verteilte oder aber eine urbane Wählerschaft ansprechen muss. Für die Professionalisierung der Wahlkämpfe gegenüber anderen Parteien kann kein aussagekräftiger Schluss gezogen werden, da nur wenige der untersuchten Kantonalparteien ihre Wahlkämpfe überhaupt im Hinblick auf andere Parteien professionalisierten, indem sie die gegnerischen Wahlkämpfe beobachteten und den eigenen wenn nötig entsprechend anpassten.

Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis

BACKGROUND During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells. METHODS The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10. RESULTS Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups. CONCLUSIONS Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.

Behavioral Profile of the Novel Cannabinoid Agonist AM4054

Although cannabinoid drugs have been used for thousands of years both recreationally and therapeutically, little has been known about their mechanisms of action until recently. Since the discovery of the endogenous cannabinoid CB1 receptor in 1988, the behavioral profile of cannabinoid receptor ligands has been much more thoroughly defined. Cannabinoid CB1 agonists have been shown to produce a variety of behavioral effects including suppression of locomotion, catalepsy, hypothermia, and analgesia. Research has also demonstrated that these behavioral effects can be inhibited by CB1 receptor antagonists including SR 141716 and AM 251. Although behavioral indicators of anxiety including thigmotaxis have been observed in several different paradigms, there is inconclusive and often times contradictory evidence to define the role of anxiety in CB1 receptor activation. The present study addressed the behavioral profile of AM 4054, a novel full agonist at the CB1 receptor, as well as the ability of the CB1 antagonist AM 251 to reverse these effects. To further identify and expand research on the suppression of locomotion and induction of thigmotaxis with the administration of a CB1 agonist, experiment 1 was conducted in the open field. In this experiment, each rat (n=40) was randomly assigned one of the five treatments: vehicle, 0.16, 0.32, 0.64, or 1.25 mg/kg AM 4054. After a 30 minute pre-treatment, each subject was tested in the open field for 18 minutes. Results indicated that AM 4054 produced a dose-related suppression of locomotion as well as the subtle presence of thigmotaxis in two out of four doses. In experiment 2, subjects (n=40) received either vehicle or 2.0 or 4.0 mg/kg AM 251 60 minutes prior to testing. After 30 minutes, the subjects were given either a 0.3 mg/kg dose of AM 4054 or vehicle. After a total pretreatment duration of 60 minutes, the animals were tested on a battery of tasks including an 18 minute session in locomotor boxes. Experiment 2 was a continuation of a previous study conducted in the same lab, which confirmed the effects of AM 4054 on this tetrad of tasks as being consistent with other cannabinoid agonists. In this experiment the effects of AM 4054 were reversed by the administration of the CB1 antagonist AM 251. Past studies have shown that AM 4054 is a highly potent drug with behavioral actions similar to other cannabinoid CB1 agonists. Furthermore, AM 4054 can be a useful drug in future studies, and has potential therapeutic value for the treatment of various conditions.

Behavioral risk profile of marathon runners

Although long distance running clearly has benefits--as witnessed by its popularity--it also has risks of injury and death. Little is known, however, about the prevalence of potentially dangerous training habits in long distance runners, although anecdotal information suggests that many runners have erroneous beliefs about risks and benefits of marathon running. We conducted a cross-sectional survey to estimate the prevalence of 19 potentially dangerous training habits (risky behaviors) among marathon runners. A 66-item self-administered questionnaire was mailed to a stratified random sample of runners who finished of the 1992 Houston-Tenneco Marathon and were 21-71 years of age. Responses were obtained from 508 runners (83%) with approximately equal representation in four age-gender groups: men $<$40 years, men $\ge$40 years, women $<$40 years, and women $\ge$40 years.^ Prevalences of risky behaviors were high. 50% or more ran in dangerously hot and humid conditions, did not cool down or stretch after running, did not wear proper running gear, or ran when injured or ill; 25-49% did not warm up, ran on dangerous surfaces, did not drink sufficient water during training, increased weekly mileage too quickly, and ran during lightning storms; 10-24% ran daily, ran in areas with high pollution, ran in the same direction as traffic, did hard runs frequently, ran more than 60 miles per week, or ran against the advice of a physician.^ Positive associations were found between the practice of risky behaviors and self-reported prevalence of musculoskeletal injuries, heat-related injuries, noncompliance with recommendations for preventive health examinations, and noncompliance with positive health habits.^ These results indicate that many marathon runners engage in training habits that may increase risk of substantial injury or illness. Further studies are needed to explore the association of risky training behaviors on the incidence of injuries, and to determine reasons for noncompliance with recommendations from sports medicine specialists. ^