Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607

Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients. Several CCK2R-targeted radiopharmaceuticals have been described in recent years. As part of the European Union COST Action BM0607 we studied the in vitro and in vivo characteristics of 12 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R binding peptides. In the present study, we analysed binding and internalization characteristics. Stability, biodistribution and imaging studies have been performed in parallel by other centres involved in the project.

Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides

Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 (111)In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides.

Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans.

68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax

By targeting somatostatin receptors (sst) radiopeptides have been established for both diagnosis and therapy. For physiologically normal human tissues the study provides a normative database of maximum standardized uptake value (SUV(max)) and sst mRNA.

Ground-based and airborne in-situ measurements of the Eyjafjallajökull volcanic aerosol plume in Switzerland in spring 2010

The volcanic aerosol plume resulting from the Eyjafjallajökull eruption in Iceland in April and May 2010 was detected in clear layers above Switzerland during two periods (17–19 April 2010 and 16–19 May 2010). In-situ measurements of the airborne volcanic plume were performed both within ground-based monitoring networks and with a research aircraft up to an altitude of 6000 m a.s.l. The wide range of aerosol and gas phase parameters studied at the high altitude research station Jungfraujoch (3580 m a.s.l.) allowed for an in-depth characterization of the detected volcanic aerosol. Both the data from the Jungfraujoch and the aircraft vertical profiles showed a consistent volcanic ash mode in the aerosol volume size distribution with a mean optical diameter around 3 ± 0.3 μm. These particles were found to have an average chemical composition very similar to the trachyandesite-like composition of rock samples collected near the volcano. Furthermore, chemical processing of volcanic sulfur dioxide into sulfate clearly contributed to the accumulation mode of the aerosol at the Jungfraujoch. The combination of these in-situ data and plume dispersion modeling results showed that a significant portion of the first volcanic aerosol plume reaching Switzerland on 17 April 2010 did not reach the Jungfraujoch directly, but was first dispersed and diluted in the planetary boundary layer. The maximum PM10 mass concentrations at the Jungfraujoch reached 30 μgm−3 and 70 μgm−3 (for 10-min mean values) duri ng the April and May episode, respectively. Even low-altitude monitoring stations registered up to 45 μgm−3 of volcanic ash related PM10 (Basel, Northwestern Switzerland, 18/19 April 2010). The flights with the research aircraft on 17 April 2010 showed one order of magnitude higher number concentrations over the northern Swiss plateau compared to the Jungfraujoch, and a mass concentration of 320 (200–520) μgm−3 on 18 May 2010 over the northwestern Swiss plateau. The presented data significantly contributed to the time-critical assessment of the local ash layer properties during the initial eruption phase. Furthermore, dispersion models benefited from the detailed information on the volcanic aerosol size distribution and its chemical composition.

Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist (111)In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with (111)In and (177)Lu in three different tumour models.

The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis

We aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis.

Hypodense regions in unenhanced CT identify nonviable myocardium: validation versus 18F-FDG PET

The aim of the present study was to evaluate the accuracy of hypodense regions in non-contrast-enhanced cardiac computed tomography (unenhanced CT) to identify nonviable myocardial scar tissue.

Differences in Soil Fungal Communities between European Beech (Fagus sylvatica L.) Dominated Forests Are Related to Soil and Understory Vegetation

Fungi are important members of soil microbial communities with a crucial role in biogeochemical processes. Although soil fungi are known to be highly diverse, little is known about factors influencing variations in their diversity and community structure among forests dominated by the same tree species but spread over different regions and under different managements. We analyzed the soil fungal diversity and community composition of managed and unmanaged European beech dominated forests located in three German regions, the Schwäbische Alb in Southwestern, the Hainich-Dün in Central and the Schorfheide Chorin in the Northeastern Germany, using internal transcribed spacer (ITS) rDNA pyrotag sequencing. Multiple sequence quality filtering followed by sequence data normalization revealed 1655 fungal operational taxonomic units. Further analysis based on 722 abundant fungal OTUs revealed the phylum Basidiomycota to be dominant (54%) and its community to comprise 71.4% of ectomycorrhizal taxa. Fungal community structure differed significantly (p≤0.001) among the three regions and was characterized by non-random fungal OTUs co-occurrence. Soil parameters, herbaceous understory vegetation, and litter cover affected fungal community structure. However, within each study region we found no difference in fungal community structure between management types. Our results also showed region specific significant correlation patterns between the dominant ectomycorrhizal fungal genera. This suggests that soil fungal communities are region-specific but nevertheless composed of functionally diverse and complementary taxa.

Self-conscious emotions and depression: Rumination explains why shame, but not guilt, is maladaptive

Feelings of shame and guilt are factors associated with depression. However, studies simultaneously investigating shame and guilt suggest that only shame has a strong unique effect, although it is not yet clear which psychological processes cause shame and not shame-free guilt to be related to depression. The authors hypothesized that shame, in contrast to guilt, elicits rumination, which then leads to depression. Therefore, in this study we investigated event-related shame and guilt, event-related rumination, and depression among 149 mothers and fathers following family breakup due to marital separation. Data were analyzed using latent variable modeling. The results confirm that shame but not guilt has a strong unique effect on depression. Moreover, the results show that the effect of shame is substantially mediated by rumination. The results are discussed against the background of self-discrepancies and self-esteem.

Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer 177Lu-AMBA

PURPOSE: To investigate the in vitro binding properties of a novel radiolabelled bombesin analogue, (177)Lu-AMBA, in human neoplastic and non-neoplastic tissues selected for their expression of the bombesin receptor subtypes GRP-R, NMB-R and BRS-3. METHODS: In vitro receptor autoradiography was performed in cancers expressing the various bombesin receptor subtypes. The novel radioligand (177)Lu-AMBA was used and compared with established bombesin radioligands such as (125)I-Tyr(4)-bombesin and (125)I-[D: -Tyr(6),beta-Ala(11),Phe(13),Nle(14)]-bombesin(6-14). In vitro incidence of detection of each of the three bombesin receptor subtypes was evaluated in each tumour. RESULTS: (177)Lu-AMBA identified all GRP-R-expressing tumours, such as prostatic, mammary and renal cell carcinomas as well as gastrointestinal stromal tumours. (177)Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets. GRP-R-expressing peritumoural vessels were heavily labelled with (177)Lu-AMBA. In contrast to the strongly GRP-R-positive mouse pancreas, the human pancreas was not labelled with (177)Lu-AMBA unless chronic pancreatitis was diagnosed. In general, the sensitivity was slightly better with (177)Lu-AMBA than with the conventional bombesin radioligands. CONCLUSION: The present in vitro study suggests that (177)Lu-AMBA may be a very useful in vivo targeting agent for GRP-R-expressing tumours, NMB-R-expressing tumours and GRP-R-expressing neoangiogenic vessels.

[(99m)Tc]Demotate 2 in the detection of sst(2)-positive tumours: a preclinical comparison with [(111)In]DOTA-tate

PURPOSE: The aim of this study was to evaluate [(99m)Tc]Demotate 2 ([(99m)Tc-N(4) (0-1),Asp(0),Tyr(3)]octreotate) as a candidate for in vivo imaging of sst(2)-positive tumours and to compare it with [(111)In]DOTA-tate ([(111)In-DOTA(0),Tyr(3)]octreotate). METHODS: Labelling of Demotate 2 with (99m)Tc was performed at room temperature using SnCl(2) as reductant in the presence of citrate at alkaline pH. Radiochemical analysis involved ITLC and HPLC methods. Peptide conjugate affinities for sst(2) were determined by receptor autoradiography on rat brain cortex sections using [DOTA(0),(125)I-Tyr(3)]octreotate as the radioligand. The affinity profile of Demotate 2 for human sst(1)-sst(5) was studied by receptor autoradiography in cell preparations using the universal somatostatin radioligand [(125)I][Leu(8),(D: )Trp(22),Tyr(25)]somatostatin-28. The internalisation rates of [(99m)Tc]Demotate 2 and [(111)In]DOTA-tate were compared in sst(2)-positive and -negative control cell lines. Biodistribution of radiopeptides was studied in male Lewis rats bearing CA20948 tumours. RESULTS: Peptide conjugates showed selectivity and a high affinity binding for sst(2) (Demotate 2 IC(50)=3.2 nM and DOTA-tate IC(50)=5.4 nM). [(99m)Tc]Demotate 2, like [(111)In]DOTA-tate, internalised rapidly in all sst(2)-positive cells tested, but not in sst(2)-negative control cells. After injection in CA20948 tumour-bearing rats both radiopeptides showed high and specific uptake in the sst(2)-positive organs and in the implanted tumour and rapid excretion from non-target tissues via the kidneys. CONCLUSION: [(99m)Tc]Demotate 2, similarly to the known sst(2)-targeting agent [(111)In]DOTA-tate, showed promising biological qualities for application in the scintigraphy of sst(2)-positive tumours.