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The gastrin releasing peptide receptor (GRPR) has been found to be strongly expressed in various types of cancers such as prostate and breast carcinomas. The GRPR ligands gastrin releasing peptide and bombesin can play a very significant role in cancer therapy and diagnostics. In this study we synthesized unlabeled bombesin BBN along with two conjugates in which the correct bombesin (BBN-Rhd) and a mutant bombesin (mBBN-Rhd) sequence was coupled to rhodamine, a fluorescent dye. These novel rhodamine fluorescent conjugates were used to study the targeting and uptake of bombesin on a cellular level. Nine different human cell lines including both tumor and healthy cells were examined using flow cytometry and confocal laser scanning microscopy. GRPR mRNA expression analysis was performed and it was found that the receptor is highly expressed in LNCaP and PC3 cells compared to the rest of other cell lines. Competition experiments were performed to verify the receptor dependence of the labeled conjugates using unmarked bombesin. The present study is a first attempt at direct fluorescence imaging of living cells using bombesin and its target, the GRPR. A rhodamine bombesin conjugate can be used as marker to differentiate between healthy cells and malignant cells such as prostate hyperplasia and prostate carcinoma in the early detection of cancer. [ABSTRACT FROM AUTHOR]

Background: Based on significant progress in recent years, metastatic castration-resistant prostate cancer (mCRPC) patients can be treated better and better. The medications include androgen signaling inhibitors, chemotherapy, 223 Ra, and sipuleucel-T. Most patients treated with these agents will still develop primary or secondary resistance against any given drug. The 177 Lutetium-PSMA radioligand therapy ( 177 Lu-PSMA-RLT) represents a good reserve option and can be used within compassionate use provisions demonstrating promising efficacy in the majority of patients in Germany., Objectives: Establishment of status quo of 177 Lu-PSMA-RLT in mCRPC in 2020., Materials and Methods: Presentation of the therapy landscape in mCRPC and the current evidence on 177 Lu-PSMA-RLT after PubMed based literature search., Results: Several larger retrospective studies and the first prospective trials on 177 Lu-PSMA-RLT show premature but encouraging evidence on 177 Lu-PSMA-RLT to be a promising new option in mCRPC patients. The toxicity profile seems to be favorable. The phase III trial VISION aims to provide evidence for the approval of 177 Lu-PSMA-RLT in combination with abiraterone or enzalutamide in patients having been pretreated with enzalutamide or abiraterone and docetaxel., Conclusions: Despite the promising preliminary results of 177 Lu-PSMA-RLT, the efficacy results of VISION need to be awaited prior to using the therapy outside of compassionate use provisions.

Purpose: PSMA-targeted PET in patients with prostate cancer (PCa) has a significant impact on treatment decisions. By far the most frequently used PSMA ligand is 68 Ga-labelled PSMA-11. However, due to the availability of larger amounts of activity, 18 F-labelled PSMA ligands are of major interest. The aim of the present study was to evaluate the biodistribution and performance of the novel 18 F-labelled ligand PSMA-1007 at two different time points., Methods: This retrospective analysis included 40 consecutive patients (mean age 68.7 ± 8.1 years) referred for PSMA PET/CT. 18 F-PSMA-1007 PET/CT was performed for localization of biochemical relapse, primary staging or therapy follow-up. Circular regions of interest were placed on representative slices of the liver, spleen, kidney, abdominal aortic blood pool, bone marrow (fourth lumbar vertebral body), urinary bladder and gluteus muscle at 60 and 120 min after injection. In malignant lesions the maximum standardized uptake (SUV max ) was measured within volumes of interest at both time points. All SUVs at 60 min were compared with those at 120 min after injection., Results: The activity in the blood pool, urinary bladder and gluteus muscle was very low and decreased significantly over time (P < 0.001). Uptake in the liver, spleen and kidney showed a significant increase over time and uptake in the bone marrow remained stable. Overall, 135 PCa lesions were detected at 60 min and 136 lesions at 120 min after injection. The median SUV max increased significantly (P < 0.001) from 10.98 to 15.51 between 60 and 120 min., Conclusion: PCa lesions show a significant increase in 18 F-PSMA-1007 uptake at 120 min compared with 60 min after injection. In addition, accumulation of the tracer in the urinary bladder was very low leading to improved contrast of adjacent PCa lesions. Increasing accumulation in the liver may limit the sensitivity of the tracer in detecting liver metastases.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

A role for HLA class I polymorphism in childhood acute lymphoblastic leukemia (ALL) has been suggested for many years, but unambiguous associations have not been found. Here, we show that the HLA-C-encoded supertypic epitope C2, which constitutes a high-affinity ligand for the inhibitory natural killer (NK) cell receptor KIR2DL1, is significantly increased in ALL patients (n = 320; P = .005). Stratification for ethnicity and disease subtype revealed a strong association of C2 with B-ALL in German cases (P = .0004). The effect was independent of KIR2DS1 and KIR2DL1 allelic polymorphism and copy number. Analysis of clinical outcome revealed a higher incidence of late relapse (> 2.5 years) with increasing number of C2 alleles (P = .014). Our data establish C2 as novel risk factor and homozygosity for C1 as protective for childhood B-ALL supporting a model in which NK cells are involved in immunosurveillance of pediatric B-ALL via interaction of KIR with HLA-C ligands., (© 2014 by The American Society of Hematology.)

Background: Chemokines are chemotactic mediators that are implicated in liver diseases. In viral hepatitis and primary biliary cirrhosis, a predominant chemokine receptor expressed in the liver is CXCR3, suggesting that its specific ligands are important in the progression of chronic liver diseases across different aetiologies., Methodology/principal Findings: We analysed the serum concentrations of the CXCR3 ligands, CXCL9 (monokine induced by interferon-γ), CXCL10 (interferon-γ-inducible protein 10) and CXCL11 (interferon-inducible T cell α chemo-attractant) in healthy controls (n=53), subjects with histologically determined liver fibrosis (n=109) and patients with different stages of cirrhosis (n=153) of various disease aetiologies. Chemokine concentrations were determined by cytometric bead assay or ELISA respectively. Serum concentrations of all three chemokines were significantly increased in patients with chronic liver diseases compared with healthy controls (P<0.001). In the biopsied fibrosis cohort, CXCL9 and CXCL10 were positively associated with the severity of liver fibrosis (histology and serum markers), while CXCL11 was not. In cirrhotic patients, CXCL9 was increased in early Child-Pugh stages, while CXCL11 was elevated only in Child B and C patients and CXCL10 across all stages. Notably, CXCR3 chemokines were also associated with the development of clinical complications of cirrhosis, especially portal hypertension. All chemokines significantly correlated with serum levels of the hepatoprotective cytokines interleukin (IL)-6 and IL-10, suggesting their involvement in a counter-regulatory response during the progression of liver disease, shedding new light on their involvement in the pathophysiology of chronic liver diseases., Conclusions: CXCR3 chemokines are differentially expressed during chronic liver diseases across different disease stages and aetiologies. Their association with portal hypertension and hepatoprotective cytokines implies biological functions beyond immune cell recruitment, thereby provoking new diagnostic and therapeutic concepts., (© 2011 John Wiley & Sons A/S.)

Transformations of metal species (particularly Al, Ca, Fe, Mg, Mn, Zn) in ageing humic hydrocolloids were studied, applying a competitive ligand and metal exchange approach. For this purpose, metal-containing hydrocolloids, freshly collected from humic-rich German bog lake waters (Hohlohsee (HO), Black Forest; Venner Moor (VM), Muensterland; Arnsberger Wald (AW), Northrhine-Westfalia) and conventionally pre-filtered through 0.45 microm membranes, were subjected on-site to an exchange with EDTA and Cu(II) ions, respectively, as a function of time. EDTA complexes gradually formed, metal fractions exchanged by Cu(II) (as well as free Cu(II) concentrations) were operationally discriminated by means of a small time-controlled tangential-flow ultrafiltration unit (nominal cutoff: 1 kDa). Metal and DOM (dissolved organic matter) fractions obtained this way were determined off-site using instrumental methods (AAS, ICP-OES, carbon analyzer). After weeks of storage, the collected hydrocolloids were studied again by this approach. The EDTA availability of colloid-bound metals (particularly Al and Fe) exhibited different ageing trends, dependent on the sample (VM: decrease of Fe availability (98-76%), HO: increase of Fe availability (76-82%)). In contrast, the Cu(II) exchange equilibria of colloid-bound metals revealed merely low availability of Al (16-38%) and Fe (5-11%) towards Cu(II) ions, also dependent on ageing effects. In particular, the conditional copper exchange constants Kex obtained from the exchange between Cu(II) ions and available metal species (such as Ca, Mg, Mn, Zn) exhibited a strong decrease (by a factor of 2-100) during sample storage, indicating considerable non-equilibria complexation of these metal ions in the original bogwaters studied on-site.

Natural killer (NK) cell-mediated cytolysis is stimulated and downregulated through the interaction of distinct human leukocyte antigen (HLA) class I molecules on target cells with specific killer cell immunoglobulinlike receptors (KIRs) on NK cells. Killer cell immunoglobulinlike receptors are highly polymorphic and are clonally distributed on NK cell populations within individuals. However, the regulation of KIR expression by individual HLA class I phenotypes is not well understood. To examine a potential influence of the HLA class I phenotype on KIR expression patterns we studied the KIR expression in individuals that were subgrouped according to the major HLA-C encoded KIR-epitopes (group C1 versus C2). In these individuals, NK cells were analyzed for KIR expression using flow cytometry and RNA-based expression analysis. Our results demonstrate that KIR genes are transmitted very heterogeneously with two main patterns of KIR genotypes as previously described; group A and group B (with 21 different genotypes). There are distinct populations exhibiting different densities of CD158a and/or CD158b positive NK cells that coexist in all individuals. A clear correlation between KIR expression and the currently known HLA class I ligands was not observed. In conclusion, the surface expression of KIRs in individuals with different HLA class I genotypes indicates that other non-HLA class I encoded factors contribute to the shaping of the KIR repertoire.