Somatostatin receptor scintigraphy in patients with cat-scratch disease

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Krause, R.; Schnedl, W.J.; Hoier, S. [Div. of Infectious Diseases, Dept. of Internal Medicine, Univ. Graz (Austria); Piswanger-Soelkner, C.; Lipp, R.W. [Div. of Nuclear Medicine, Dept. of Internal Medicine, Univ. Graz (Austria); Daxboeck, F. [Clinical Inst. for Hygiene and Medical Microbiology, Div. of Hospital Hygiene, Univ. of Vienna (Austria); Reisinger, E.C. [Div. of Infectious Diseases and Tropical Medicine, Dept. of Internal Medicine, Univ. Rostock (Germany)

2006-07-01

Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

Reduced Numbers of Somatostatin Receptors in the Cerebral Cortex in Alzheimer's Disease

Science.gov (United States)

Flint Beal, M.; Mazurek, Michael F.; Tran, Vinh T.; Chattha, Geetinder; Bird, Edward D.; Martin, Joseph B.

1985-07-01

Somatostatin receptor concentrations were measured in patients with Alzheimer's disease and controls. In the frontal cortex (Brodmann areas 6, 9, and 10) and temporal cortex (Brodmann area 21), the concentrations of somatostatin in receptors in the patients were reduced to approximately 50 percent of control values. A 40 percent reduction was seen in the hippocampus, while no significant changes were found in the cingulate cortex, postcentral gyrus, temporal pole, and superior temporal gyrus. Scatchard analysis showed a reduction in receptor number rather than a change in affinity. Somatostatin-like immunoreactivity was significantly reduced in both the frontal and temporal cortex. Somatostatin-like immunoreactivity was linearly related to somatostatin-receptor binding in the cortices of Alzheimer's patients. These findings may reflect degeneration of postsynaptic neurons or cortical afferents in the patients' cerebral cortices. Alternatively, decreased somatostatinlike immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors.

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues.

NARCIS (Netherlands)

Rolleman, E.J.; Melis, M.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides

Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

International Nuclear Information System (INIS)

Lamberts, S.W.J.; Reubi, J.C.; Krenning, E.P.

1993-01-01

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.)

Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

Energy Technology Data Exchange (ETDEWEB)

Lamberts, S.W.J. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Reubi, J.C. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Krenning, E.P. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland))

1993-01-01

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.).

Molecular imaging of neuroendocrine tumors using 68Ga-labeled peptides (Somatostatin receptor PET/CT)

International Nuclear Information System (INIS)

Baum, R.P.; Prasad, V.; Hoersch, D.

2009-01-01

Receptor PET/CT using 68 Ga-labeled somatostatin analogues (DOTA-NOC, DOTA-TOC or DOTA-TATE) enables the highly sensitive molecular imaging of neuroendocrine tumors (NETs) based on the expression of somatostatin receptors and even the detection of receptor subtypes. Our experience after more than 3000 studies shows that receptor PET/CT has a significantly higher tumor detection rate than conventional scintigraphy (even in SPECT/CT technique), and that tumor lesions can be very accurately localized. By calculating standardized uptake values (SUV) - which are reproducible and investigator-independent - patients can be selected for peptide receptor radiotherapy and also the course after therapy can be controlled. Receptor-PET/CT is the most sensitive imaging modality for the detection of unknown primary tumors (CUP syndrome), which is especially true for the detection of neuroendocrine tumors of the pancreas and small bowel; whole-body staging (''one stop shop'') as well as restaging and selection of patients for peptide receptor radiotherapy can be performed using a patient-friendly procedure (examination finished within one hour) exposing the patient to less radiation than whole-body CT scanning. The 68 Ge/ 68 Ga generator has proved very reliable over the years - even in a hospital environment. The effective costs for 68 Ga labeled somatostatin analogues might be less than for scintigraphic agents, provided a certain number of studies per year are performed. The development of new tumor-specific peptides as well as of other DOTA- or NOTA-coupled radiopharmaceuticals opens a new avenue into the future: finally, the 68 Ga generator could play a similar important role for PET/CT as did the 99m Tc-Generator for conventional gamma camera imaging over the last decades. (orig.)

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

International Nuclear Information System (INIS)

Kaemmerer, Daniel; Haugvik, Sven-Petter; Hommann, Merten; Peter, Luisa; Lupp, Amelie; Schulz, Stefan; Saenger, Joerg; Prasad, Vikas; Kulkarni, Harshad; Baum, Richard Paul

2011-01-01

Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative 68 Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV max and SUV mean ) were used for PET/CT. The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV max on the PET/CT (p mean (p max on the 68 Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of 68 Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using 68 Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy. (orig.)

Development of 99mTc labelled somatostatin analogues with high affinity for somatostatin receptors

International Nuclear Information System (INIS)

Maina, T.; Nock, B.; Nicolopoulou, A.; Tsipra, C.; Poppe, M.; Chiotellis, E.

2001-01-01

A recent development in oncology involves the use of metabolically stabilized peptide hormone analogues labelled with metallic radionuclides for the diagnosis or therapy of malignant disease. This approach was successfully applied for the first time in the visualization of somatostatin positive tumours and their metastases with 111 In DTPA-octreotide. In an effort to obtain a 99m Tc somatostatin receptor affine radioligand we describe herein the synthesis, radiochemistry and preliminary biological evaluation of two novel 99m Tc labelled somatostatin analogues, N 4 -TOC and N 4 -RC-160. In these compounds a tetraamine bifunctional unit was covalently attached to the N-terminal (D)Phe 1 of the peptide chain using Boc-protection strategies. The peptide conjugates were purified by high performance liquid chromatography (HPLC) and characterized by UV/Vis and ES-MS spectroscopies. As revealed by HPLC, 99m Tc labelling was quantitative under mild conditions, leading to a single 99m Tc species in high specific activities. Affinity of 99m Tc N 4 -TOC for the somatostatin receptor, as determined by in vitro binding assays in rat brain cortex membranes, was found unaffected by the presence of the bulky metal chelate. The binding properties of 99m Tc N 4 -RC-160 could not be determined by this assay due to an extremely high non-specific binding of this radioligand, and will be shortly investigated by other methods. Tissue distribution in healthy mice revealed that 99m Tc N 4 -TOC is clearing mainly through the kidneys and the urinary tract whereas 99m Tc N 4 -RC-160 shows a high accumulation in the liver as a result of its lipophilicity. Analysis of urine samples by HPLC showed that 99m Tc N 4 -TOC is excreted integer from the body of mice, while 99m Tc N 4 -RC-160 is totally transformed to an unidentified hydrophilic metabolite in vivo. The location of this metabolism is currently investigated. In vivo blocking experiments using animals pre-treated with 50 μg octreotide

Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues.

Science.gov (United States)

Erchegyi, Judit; Cescato, Renzo; Grace, Christy Rani R; Waser, Beatrice; Piccand, Véronique; Hoyer, Daniel; Riek, Roland; Rivier, Jean E; Reubi, Jean Claude

2009-05-14

The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst(1)) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA(1,4-6,10,12,13)-[DTyr(2),DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (25) was radio-iodinated ((125)I-25) and specifically labeled sst(1)-expressing cells and tissues. 3D NMR structures were calculated for des-AA(1,4-6,10,12,13)-[DPhe(2),DTrp(8),IAmp(9)]-SRIF-Thr-NH(2) (16), des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (23), and des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9),Tyr(11)]-SRIF-NH(2) (27) in DMSO. Though the analogues have the sst(1) pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst(1) binding of these novel, less constrained sst(1)-selective family members.

DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

International Nuclear Information System (INIS)

Wild, Damian; Schmitt, Joerg S.; Ginj, Mihaela; Maecke, Helmut R.; Bernard, Bert F.; Krenning, Eric; Jong, Marion de; Wenger, Sandra; Reubi, Jean-Claude

2003-01-01

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [ 111 In, 90 Y-DOTA]-1-Nal 3 -octreotide ( 111 In, 90 Y-DOTA-NOC), was isolated which showed an improved profile. In III -DOTA-NOC exhibited the following IC 50 values (nM) when studied in competition with [ 125 I][Leu 8 , d-Trp 22 , Tyr 25 ]somatostatin-28 (values for Y III -DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. In III -DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than In III ,Y III -DOTA-Tyr 3 -octreotide (In III ,Y III -DOTA-TOC). In addition, [ 111 In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [ 111 In]DOTA-TOC and three times higher than that of [ 111 In]DOTA-octreotide ([ 111 In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steady

Receptor binding of somatostatin-14 and somatostatin-28 in rat brain: differential modulation by nucleotides and ions.

Science.gov (United States)

Srikant, C B; Dahan, A; Craig, C

1990-02-04

The tissue-selective binding of the two principal bioactive forms of somatostatin, somatostatin-14 (SS-14) and somatostatin-28 (SS-28), their ability to modulate cAMP-dependent and -independent regulation of post-receptor events to different degrees and the documentation of specific labelling of SS receptor subtypes with SS-28 but not SS-14 in discrete regions of rat brain suggest the existence of distinct SS-14 and SS-28 binding sites. Receptor binding of SS-14 ligands has been shown to be modulated by nucleotides and ions, but the effect of these agents on SS-28 binding has not been studied. In the present study we investigated the effects of adenine and guanine nucleotides as well as monovalent and divalent cations on rat brain SS receptors quantitated with radioiodinated analogs of SS-14 ([125I-Tyr11]SS14, referred to in this paper as SS-14) and SS-28 ([Leu8, D-Trp22, 125I-Tyr25] SS-28, referred to as LTT* SS-28) in order to determine if distinct receptor sites for SS-14 and SS-28 could be distinguished on the basis of their modulation by nucleotides and ions. GTP as well as ATP exerted a dose-dependent inhibition (over a concentration range of 10(-7)-10(-3) M) of the binding of the two radioligands. The nucleotide inhibition of binding resulted in a decrease the Bmax of the SS receptors, the binding affinity remaining unaltered. GTP (10(-4) M) decreased the Bmax of LTT* SS-28 binding sites to a greater extent than ATP (145 +/- 10 and 228 +/- 16 respectively, compared to control value of 320 +/- 20 pmol mg-1). Under identical conditions GTP was less effective than ATP in reducing the number of T* SS-14 binding sites (Bmax = 227 +/- 8 and 182 +/- 15, respectively, compared to 340 +/- 15 pmol mg-1 in the absence of nucleotides). Monovalent cations inhibited the binding of both radioligands, Li+ and Na+ inhibited the binding of T* SS-14 to a greater extent than K+. The effect of divalent cations on the other hand was varied. At low concentration (2 mM) Mg2+, Ba2

Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues--Observations in two patients with acromegaly and severe headache

DEFF Research Database (Denmark)

Marina, Djordje; Burman, Pia; Klose, Marianne

2015-01-01

BACKGROUND: Somatotropinomas have unique "fingerprints" of somatostatin receptor (sst) expression, which are targets in treatment of acromegaly with somatostatin analogues (SSAs). However, a significant expression of sst is not always related to the biochemical response to SSAs. Headache is a com...

Molecular imaging with {sup 68}Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Kaemmerer, Daniel; Haugvik, Sven-Petter; Hommann, Merten [Zentralklinik Bad Berka GmbH, Department of General and Visceral Surgery, Bad Berka (Germany); Peter, Luisa; Lupp, Amelie; Schulz, Stefan [University of Jena, Department of Pharmacology and Toxicology, Jena (Germany); Saenger, Joerg [Laboratory of Pathology and Cytology, Bad Berka (Germany); Prasad, Vikas; Kulkarni, Harshad; Baum, Richard Paul [Zentralklinik Bad Berka, Department of Nuclear Medicine and Center for PET, Bad Berka (Germany)

2011-09-15

Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative {sup 68}Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV{sub max} and SUV{sub mean}) were used for PET/CT. The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV{sub max} on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV{sub mean} (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. The highly significant correlation between SSTR2A and SSTR5 and the SUV{sub max} on the {sup 68}Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of {sup 68}Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using {sup 68}Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy. (orig.)

Carboxyl-terminal multi-site phosphorylation regulates internalization and desensitization of the human sst2 somatostatin receptor.

Science.gov (United States)

Lehmann, Andreas; Kliewer, Andrea; Schütz, Dagmar; Nagel, Falko; Stumm, Ralf; Schulz, Stefan

2014-04-25

The somatostatin receptor 2 (sst2) is the pharmacological target of somatostatin analogs that are widely used in the diagnosis and treatment of human neuroendocrine tumors. We have recently shown that the stable somatostatin analogs octreotide and pasireotide (SOM230) stimulate distinct patterns of sst2 receptor phosphorylation and internalization. Like somatostatin, octreotide promotes the phosphorylation of at least six carboxyl-terminal serine and threonine residues namely S341, S343, T353, T354, T356 and T359, which in turn leads to a robust receptor endocytosis. Unlike somatostatin, pasireotide stimulates a selective phosphorylation of S341 and S343 of the human sst2 receptor followed by a partial receptor internalization. Here, we show that exchange of S341 and S343 by alanine is sufficient to block pasireotide-driven internalization, whereas mutation of T353, T354, T356 and T359 to alanine is required to strongly inhibited both octreotide- and somatostatin-induced internalization. Yet, combined mutation of T353, T354, T356 and T359 is not sufficient to prevent somatostatin-driven β-arrestin mobilization and receptor desensitization. Replacement of all fourteen carboxyl-terminal serine and threonine residues by alanine completely abrogates sst2 receptor internalization and β-arrestin mobilization in HEK293 cells. Together, our findings demonstrate for the first time that agonist-selective sst2 receptor internalization is regulated by multi-site phosphorylation of its carboxyl-terminal tail. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Coupling of guanine nucleotide inhibitory protein to somatostatin receptors on pancreatic acinar membranes

International Nuclear Information System (INIS)

Sakamoto, C.; Matozaki, T.; Nagao, M.; Baba, S.

1987-01-01

Guanine nucleotides and pertussis toxin were used to investigate whether somatostatin receptors interact with the guanine nucleotide inhibitory protein (NI) on pancreatic acinar membranes in the rat. Guanine nucleotides reduced 125 I-[Tyr 1 ]somatostatin binding to acinar membranes up to 80%, with rank order of potency being 5'-guanylyl imidodiphosphate [Gpp(NH)p]>GTP>TDP>GMP. Scatchard analysis revealed that the decrease in somatostatin binding caused by Gpp(NH)p was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. The inhibitory effect of Gpp(NH)p was partially abolished in the absence of Mg 2+ . When pancreatic acini were treated with 1 μg/ml pertussis toxin for 4 h, subsequent 125 I-[Tyr 1 ]somatostatin binding to acinar membranes was reduced. Pertussis toxin treatment also abolished the inhibitory effect of somatostatin on vasoactive intestinal peptide-stimulated increase in cellular content of adenosine 3',5'-cyclic monophosphate (cAMP) in the acini. The present results suggest that 1) somatostatin probably functions in the pancreas to regulate adenylate cyclase enzyme system via Ni, 2) the extent of modification of Ni is correlated with the ability of somatostatin to inhibit cAMP accumulation in acini, and 3) guanine nucleotides also inhibit somatostatin binding to its receptor

Somatostatin-receptor imaging in the localization of endocrine tumors

International Nuclear Information System (INIS)

Lamberts, S.W.; Bakker, W.H.; Reubi, J.C.; Krenning, E.P.

1990-01-01

A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123 I-labeled Tyr3-octreotide, a somatostatin analogue, for tumor localization in 42 patients with carcinoid tumors, pancreatic endocrine tumors, or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. Primary tumors or metastases, often previously unrecognized, were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas, 8 of whom had more than one tumor, 10 temporal (tympanic or jugular), 9 carotid, and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. The 123 I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion

Clinical value of somatostatin receptor imaging in patients with suspected head and neck paragangliomas

Energy Technology Data Exchange (ETDEWEB)

Schmidt, Matthias; Dietlein, Markus; Weber, Kerstin; Moka, Detlef; Schicha, Harald [Klinik und Poliklinik fuer Nuklearmedizin, Universitaet zu Koeln, Joseph-Stelzmann-Strasse 9, 50924 Koeln (Germany); Fischer, Eva; Michel, Olaf; Stennert, Eberhard [Klinik und Poliklinik fuer Hals-, Nasen- und Ohrenheilkunde, Universitaet zu Koeln, Koeln (Germany)

2002-12-01

Paragangliomas or glomus tumours of the head and neck region are rare somatostatin receptor-expressing neuroendocrine tumours. Precise preoperative diagnosis is of special importance in order to adequately weigh the potential benefit of the operation against the inherent risks of the procedure. In this study, the clinical value of somatostatin receptor imaging was assessed in 19 patients who underwent somatostatin receptor scintigraphy because of known or suspected paraganglioma of the head and neck region. The results were compared with the results of computed tomography and/or magnetic resonance imaging, histology and clinical follow-up. [{sup 111}In-DTPA-D-Phe{sup 1}]-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 140-220 MBq {sup 111}In-octreotide. Whole-body and planar images as well as single-photon emission tomography images were acquired and lesions were graded according to qualitative tracer uptake. Somatostatin receptor imaging was positive in nine patients, identifying paragangliomas for the first time in three patients and recurrent disease in six patients. In one patient, a second, previously unknown paraganglioma site was identified. Negative results were obtained in ten patients. These patients included one suffering from chronic hyperplastic otitis externa, one with granuloma tissue and an organised haematoma, one with an acoustic neuroma, one with an asymmetric internal carotid artery, two with ectasia of the bulbus venae jugularis and one with a jugular vein thrombosis. In two patients with a strong family history of paraganglioma, individual involvement could be excluded. In only one patient did somatostatin receptor imaging and magnetic resonance imaging yield false negative results in respect of recurrent paraganglioma tissue. It is concluded that somatostatin receptor scintigraphy provides important information in patients with suspected paragangliomas of the head and neck region and has a strong impact on further

Somatostatin Receptor Scintigraphy Findings in a Patient with Metastatic Gastrinoma and MEN 1 Syndrome

Directory of Open Access Journals (Sweden)

Gözde Mütevelizade

2011-12-01

Full Text Available Liver metastases from neuroendocrine tumours frequently occur and significantly worsen their prognosis. Somatostatin receptor scintigraphy (SRS is a valuable method for the detection of somatostatin receptor-positive lesions like gastrinoma. In this case report, the importance of SRS to localize the primary tumor and the spread of disease is emphasized in a patient with neuroendocrine liver metastases. A 45-year-old man was admitted to hospital with multiple liver metastasis of neuroendocrine carcinoma. Somatostatin receptor scintigraphy showed multiple intense radiotracer uptakes in the liver and a focal tracer uptake at the right side of the upper abdominal region corresponding to duodenum or pancreas. Elevated serum gastrin levels confirmed the gastrinoma diagnosis. (MRT 2011;20:117-120

Somatostatin Receptor Scintigraphy (SRS) with 99m-Tc HYNIC-TOC

International Nuclear Information System (INIS)

Zarlenga, A.C.; Parma, P.; Arashiro, J.; Castiglia, S.; Obenaus, E.

2002-01-01

Background: This compound is a synthetic analogue of somatostatin by conjugating the Hydrazinocotinamide (Hynic) to Tyr 3 -Octreotide (Toc) radiolabeling via quelation with 99m Tc. Purpose: We have analyzed the feasibility in detecting neuroendocrine tumors (NET) by somatostatin receptor with 99m Tc Hynic-Toc. Methods: After comparative studies between 99m Tc Hynic-Toc and 111 In (pentetreotide) with excellent correlation, we have performed 48 scintigrams with 99m Tc Hynic-Toc. 35 patients with suspicions of NET were included (19 women, 16 men. Age range 22-75 y). We have performed planar images at 1,2,24 hs and tomographic images at 150 min after intravenous injection of 740 MBq 99m Tc Hynic-Toc. We compare the results with other diagnosis modalities and /or the histopathological findings after biopsy or surgery. Results: True Positive:17; True Negative:11; False Positive: 4; False Negative:3. Specificity=73.3%; Sensitivity=85%; Accuracy=80%; Not adverse effects were observed. Conclusions: 99m Tc Hynic-Toc is not limited availability of the isotope. It is a suitable radiopharmaceutical for in vivo evaluation to define tumor receptor status, staging, and for identification of patients who may benefit from therapy with somatostatin. The tumor uptake at 24 hs allows a better visualization of abdominal tumor sites. Tc Hynic-Toc is an alternative to 111 In-pentetreotide for imaging somatostatin receptor positive tumors. The study was offered to patients whom the scintigraphy with 111 In-pentetreotide offers a diagnosis alternative with high specificity and accessible cost

The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-dPhe1,Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours

International Nuclear Information System (INIS)

Stolz, B.; Weckbecker, G.; Smith-Jones, P.M.; Albert, R.; Raulf, F.; Bruns, C.

1998-01-01

Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe 1 , Tyr 3 ]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst 2 ) (human sst 2 IC 50 =0.9 nM, rat sst 2 IC 50 =0.5 nM). In vivo, 90 Y-SMT 487 distributed rapidly to the sst 2 expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg 90 Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 μg/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of 90 Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997. (orig.)

Somatostatin receptor imaging in intracranial tumours

International Nuclear Information System (INIS)

Schmidt, M.; Scheidhauer, K.; Voth, E.; Schicha, H.; Luyken, C.; Hildebrandt, G.; Klug, N.

1998-01-01

The somatostatin analogue [ 111 In-DTPA-d-Phe 1 ]-octreotide ( 111 In-octreotide) allows scintigraphic visualization of somatostatin receptor-expressing tissue. While it is well known that a large variety of tissues express somatostatin receptors and 111 In-octreotide scintigraphy has a clearly defined role in various neuroendocrine diseases, the clinical value of 111 In-octreotide scintigraphy in brain tumours is still under clinical investigation. In 124 patients with 141 brain lesions (63 meningiomas, 24 pituitary adenomas, 10 gliomas WHO class I and II, 12 gliomas WHO class III and IV, 11 neurinomas and 2 neurofibromas, 7 metastases and 12 other varieties: three non-Hodgkin B-cell lymphomas, two epidermoids, one abscess, one angioleiomyoma, one chordoma, one haemangiopericytoma, one osteosarcoma, one plasmacytoma and one pseudocyst), 111 In-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 110-220 MBq 111 In-octreotide. Planar images of the head in four views with a 128 x 128 matrix and single-photon emission tomographic images (64 x 64 matrix) were acquired, and lesions were graded according to qualitative tracer uptake. Fifty-nine of the 63 meningiomas showed moderate to intense tracer uptake. Nine of 24 pituitary adenomas were visible; the remaining 15 did not show any tracer uptake. None of the class I and II gliomas with an intact blood-brain barrier were detected whereas 11/12 class III and IV gliomas showed 111 In-octreotide uptake. None of the neurinomas or neurofibromas were positive. Five of seven metastases were classified as positive, as were the osteosarcoma, two of three non-Hodgkin B-cell lymphomas, one abscess, one angioleiomyoma, one chordoma and one haemangiopericytoma. The other varieties (one non-Hodgkin B-cell lymphoma, two epidermoids, one plasmacytoma and one pseudocyst) did not show 111 In-octreotide uptake. The results demonstrate that a large variety of intracranial lesions express somatostatin receptors and

Somatostatin receptor imaging in intracranial tumours

Energy Technology Data Exchange (ETDEWEB)

Schmidt, M.; Scheidhauer, K.; Voth, E.; Schicha, H. [Department of Nuclear Medicine, University of Koeln (Germany); Luyken, C.; Hildebrandt, G.; Klug, N. [Department of Neurosurgery, University of Kolen (Germany)

1998-07-01

The somatostatin analogue [{sup 111}In-DTPA-d-Phe{sup 1}]-octreotide ({sup 111}In-octreotide) allows scintigraphic visualization of somatostatin receptor-expressing tissue. While it is well known that a large variety of tissues express somatostatin receptors and {sup 111}In-octreotide scintigraphy has a clearly defined role in various neuroendocrine diseases, the clinical value of {sup 111}In-octreotide scintigraphy in brain tumours is still under clinical investigation. In 124 patients with 141 brain lesions (63 meningiomas, 24 pituitary adenomas, 10 gliomas WHO class I and II, 12 gliomas WHO class III and IV, 11 neurinomas and 2 neurofibromas, 7 metastases and 12 other varieties: three non-Hodgkin B-cell lymphomas, two epidermoids, one abscess, one angioleiomyoma, one chordoma, one haemangiopericytoma, one osteosarcoma, one plasmacytoma and one pseudocyst), {sup 111}In-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 110-220 MBq {sup 111}In-octreotide. Planar images of the head in four views with a 128 x 128 matrix and single-photon emission tomographic images (64 x 64 matrix) were acquired, and lesions were graded according to qualitative tracer uptake. Fifty-nine of the 63 meningiomas showed moderate to intense tracer uptake. Nine of 24 pituitary adenomas were visible; the remaining 15 did not show any tracer uptake. None of the class I and II gliomas with an intact blood-brain barrier were detected whereas 11/12 class III and IV gliomas showed {sup 111}In-octreotide uptake. None of the neurinomas or neurofibromas were positive. Five of seven metastases were classified as positive, as were the osteosarcoma, two of three non-Hodgkin B-cell lymphomas, one abscess, one angioleiomyoma, one chordoma and one haemangiopericytoma. The other varieties (one non-Hodgkin B-cell lymphoma, two epidermoids, one plasmacytoma and one pseudocyst) did not show {sup 111}In-octreotide uptake. The results demonstrate that a large variety of intracranial

Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

NARCIS (Netherlands)

Czepczynski, Rafal; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikolajczak, Renata; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Signore, Alberto

2007-01-01

Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin

Role of somatostatin receptor-2 in gentamicin-induced auditory hair cell loss in the Mammalian inner ear.

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Yves Brand

Full Text Available Hair cells and spiral ganglion neurons of the mammalian auditory system do not regenerate, and their loss leads to irreversible hearing loss. Aminoglycosides induce auditory hair cell death in vitro, and evidence suggests that phosphatidylinositol-3-kinase/Akt signaling opposes gentamicin toxicity via its downstream target, the protein kinase Akt. We previously demonstrated that somatostatin-a peptide with hormone/neurotransmitter properties-can protect hair cells from gentamicin-induced hair cell death in vitro, and that somatostatin receptors are expressed in the mammalian inner ear. However, it remains unknown how this protective effect is mediated. In the present study, we show a highly significant protective effect of octreotide (a drug that mimics and is more potent than somatostatin on gentamicin-induced hair cell death, and increased Akt phosphorylation in octreotide-treated organ of Corti explants in vitro. Moreover, we demonstrate that somatostatin receptor-1 knockout mice overexpress somatostatin receptor-2 in the organ of Corti, and are less susceptible to gentamicin-induced hair cell loss than wild-type or somatostatin-1/somatostatin-2 double-knockout mice. Finally, we show that octreotide affects auditory hair cells, enhances spiral ganglion neurite number, and decreases spiral ganglion neurite length.

Expression of somatostatin receptors subtype 2 and 5 in extraocular muscle tissue of hypothyroidism animal induced by 131I

International Nuclear Information System (INIS)

Li Fangdu; Chu Qiaomei; Xu Peikang; Yao Xiaohong; Shen Jiangfan

2012-01-01

Objective: To observe the expression and distribution of somatostatin receptors 2 and 5 (SSTR2, 5) in extraocular muscle in hypothyroidism and thyroid associated ophthalmopathy (TAO) Wister rats induced by 131 I. Methods: 20 Wister rats were randomly divided into experimental group and normal group(group D). According to 131 I doses of intraperitoneal injection, the experimental groups were divided into low (group A), middle (group B) and high dose group (group C). After 8 weeks, all rats were sacrificed and orbital tissue sections were applied to HE staining and Immunohistochemistry for the analysis of rat orbital tissue changes and SSTR2 and 5 distribution in extraocular muscle. Results: The serum FT 4 levels in group A (16.98±2.92 pmol / L), group B (1.84±0.44 pmol / L) and group C (1.35 ±0.37 pmol /L) eight weeks after 131 I injection were decreased, and had significant difference compared with group D (P 4 levels in group B and C were significantly lower than that in group A (P 0.05). Orbital tissue in experimental group showed mucoid degeneration and edema, the extent was about 25% in group A, 50% in group B, 70% in group C. The rats in group B and group C appeared obvious proliferation of fibrous and adipose tissue, muscle fibers degeneration fracture, even extraocular muscles in group C have vacuole formation. Immunohistochemical analysis displayed highest SSTR5 distribution and strongest expression was in extraocular muscle of group C, second in A B combination group (A and B groups)and weakest in group D. There were significant differences between A B combination group,group C and group D (P 0.05). Conclusion: This study observed the distribution and expression of SSTR2 and SSTR5 in extraocular muscle on the established hypothyroidism animal model. It is some significance for understanding the mechanism of somatostatin receptors in occurrence and development of TAO, similar to provide a reference for the use of somatostatin analogue orbital imaging

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)

2010-05-15

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

International Nuclear Information System (INIS)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Boerman, Otto C.

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Somatostatin receptor scintigraphy in endocrine ophthalmopathy; Somatostatin-Rezeptor-Szintigraphie bei endokriner Orbitopathie

Energy Technology Data Exchange (ETDEWEB)

Diaz, M. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany); Kahaly, G. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Muehlbach, A. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Bockisch, A. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany); Beyer, J. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Hahn, K. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany)

1994-12-01

Somatostatin receptor scintigraphy with {sup 111}In-labeled octreotide proves to be a very sensitive diagnostic tool for evaluation of inflammative activity in endocrine ophthalmopathy (EO). The results of somatostatin receptor scintigraphy (SRS) in 40 patients with EO show a high orbital accumulation of {sup 111}In-octreotide in clinically active EO (4h-median/orbit-brain-ratio: 12.6; controls 4h-median: 5.8) Patients with clinically inactive EO (4h-median: 7.1) show a similar orbital accumulation of radioactivity compared to controls. 5 patients with active orbital myositis also revealed an even higher orbital accumulation of radioactivity (4h-median: 42.3). The diagnostic value of SRS lies in its ability to act as a measure of inflammation and an be useful as an activity parameter when planning therapeutic procedure as well as for EO follow-up. The results in patients with orbital myositis nevertheless do not permit a differential diagnosis with this method. The therapeutic value of {sup 111}In-octreotide in Graves` disease has yet to be established. (orig.) [Deutsch] Die Somatostatin-Rezeptor-Szintigraphie (SRS) mit dem {sup 111}Indium-markierten Somatostatinanalogon Octreotid stellt ein sensitives Verfahren zur Einschaetzung der entzuendlichen Aktivitaet bei endokriner Orbitopathie (EO) dar. Die Untersuchungen an 40 Patienten mit EO ergaben eine im Vergleich zur Kontrollgruppe signifikant hoehere orbitale Octreotidanreicherung bei klinisch aktiver Erkrankung (4h-Median/Orbita-Hirn-Quotient: 12,6; Kontrollgruppe 4h-Median: 5,8; p=0,0032). Patienten mit klinisch nicht aktiver Erkrankung (4h-Median: 7,1) unterschieden sich bezueglich der orbitalen Octreotidanreicherung nicht wesentlich von der Kontrollgruppe. Auch 5 Patienten mit florider orbitaler Myositis zeigten eine deutlich gesteigerte orbitale Aktivitaetsanreicherung (4h-Median: 42,3). Der diagnostische Nutzen der SRS liegt somit in ihrer Eigenschaft als Aktivitaets- und Entzuendungsparameter und kann mit

High sensitivity of the in vivo detection of somatostatin receptors by 111Indium (DTPA-Octreotide)-scintigraphy in meningioma patients

International Nuclear Information System (INIS)

Hildebrandt, G.; Luyken, C.; Klug, N.; Scheidhauer, K.; Schicha, H.; Dahms, P.; Krisch, B.

1994-01-01

The recent availability of isotope-labelled somatostatin analogues has allowed one to detect somatostatin receptors in normal tissue as well as in endocrine or non-endocrine cranial tumours. The purpose of the present study was to establish the value of somatostatin receptor scintigraphy using an 111 indium-labelled somatostatin analogue, octreotide, in the diagnostic work-up of meningioma patients. Twenty-two patients (16 women, 6 men, aged from 19-70 years) with newly diagnosed, residual or recurrent cranial meningiomas were examined. 111 indium-labelled DTPA-octreotide was injected i.v.. Planar and tomographic images were obtained with a gamma camera 4-6, and 24 hours after injection. In all of the meningiomas studies a high density of somatostatin receptor was detected by scintigraphy. No false negative test result was found. Due to this, a 100% predictive value of a negative test was calculated. However, when the tumours were taken in culture differing staining intensity could be seen in the light- and electron microscopic level even on individual cells of a single culture when silver intensified somatostatin-gold was used as ligand. We conclude, that in vivo somatostatin receptor scintigraphy may aid in the pre-operative differential diagnosis of skull base tumours

The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

Energy Technology Data Exchange (ETDEWEB)

Doerr, U.; Bihl, H. (Katharinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine); Frank-Raue, K.; Raue, F. (Heidelberg Univ. (Germany). Dept. of Internal Medicine); Sautter-Bihl, M.L.; Buhr, H.J. (Staedt. Klinikum, Karlsruhe (Germany). Dept. of Radiooncology and Nuclear Medicine); Guzman, G. (Katherinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine Inst. de Neurocirugia, Investigationes Cerebrales ' Dr Asenjo' Santiago (Chile). Dept. de Medicina Nuclear)

1993-06-01

In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with [sup 111]In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author).

The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

International Nuclear Information System (INIS)

Doerr, U.; Bihl, H.; Frank-Raue, K.; Raue, F.; Sautter-Bihl, M.L.; Buhr, H.J.; Guzman, G.; Inst. de Neurocirugia, Investigationes Cerebrales 'Dr Asenjo' Santiago

1993-01-01

In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with 111 In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author)

Pertussis toxin modifies the characteristics of both the inhibitory GTP binding proteins and the somatostatin receptor in anterior pituitary tumor cells

International Nuclear Information System (INIS)

Mahy, N.; Woolkalis, M.; Thermos, K.; Carlson, K.; Manning, D.; Reisine, T.

1988-01-01

The effects of pertussis toxin treatment on the characteristics of somatostatin receptors in the anterior pituitary tumor cell line AtT-20 were examined. Pertussis toxin selectively catalyzed the ADP ribosylation of the alpha subunits of the inhibitory GTP binding proteins in AtT-20 cells. Toxin treatment abolished somatostatin inhibition of forskolin-stimulated adenylyl cyclase activity and somatostatin stimulation of GTPase activity. To examine the effects of pertussis toxin treatment on the characteristics of the somatostatin receptor, the receptor was labeled by the somatostatin analog [125I]CGP 23996. [125I]CGP 23996 binding to AtT-20 cell membranes was saturable and within a limited concentration range was to a single high affinity site. Pertussis toxin treatment reduced the apparent density of the high affinity [125I]CGP 23996 binding sites in AtT-20 cell membranes. Inhibition of [125I]CGP 23996 binding by a wide concentration range of CGP 23996 revealed the presence of two binding sites. GTP predominantly reduced the level of high affinity sites in control membranes. Pertussis toxin treatment also diminished the amount of high affinity sites. GTP did not affect [125I]CGP 23996 binding in the pertussis toxin-treated membranes. The high affinity somatostatin receptors were covalently labeled with [125I] CGP 23996 and the photoactivated crosslinking agent n-hydroxysuccinimidyl-4-azidobenzoate. No high affinity somatostatin receptors, covalently bound to [125I]CGP 23996, were detected in the pertussis toxin-treated membranes. These results are most consistent with pertussis toxin uncoupling the inhibitory G proteins from the somatostatin receptor thereby converting the receptor from a mixed population of high and low affinity sites to only low affinity receptors

The somatostatin receptor-targeted radiotherapeutic [{sup 90}Y-DOTA-dPhe{sup 1},Tyr{sup 3}]octreotide ({sup 90}Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours

Energy Technology Data Exchange (ETDEWEB)

Stolz, B.; Weckbecker, G.; Smith-Jones, P.M.; Albert, R.; Raulf, F.; Bruns, C. [Novartis Pharma AG, Basel (Switzerland)

1998-07-01

Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe{sup 1}, Tyr{sup 3}]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst{sub 2}) (human sst{sub 2} IC{sub 50}=0.9 nM, rat sst{sub 2} IC{sub 50}=0.5 nM). In vivo, {sup 90}Y-SMT 487 distributed rapidly to the sst{sub 2} expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg {sup 90}Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 {mu}g/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of {sup 90}Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997. (orig.) With 4 figs., 2 tabs., 29 refs.

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system

DEFF Research Database (Denmark)

Ádori, Csaba; Glück, Laura; Barde, Swapnali

2015-01-01

Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is n......Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites...... morphometry and mRNA profiling in a cohort of Alzheimer’s and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer’s disease, we found significantly....../IV and onwards, i.e., a process preceding advanced Alzheimer’s pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 −/− mice and...

Diagnostic value of somatostatin receptor scintigraphy in patients with intracranial tumours

International Nuclear Information System (INIS)

Luyken, C.; Hildebrandt, G.; Scheidhauer, K.; Kirsch, B.

1993-01-01

The aim of the study was to detect the SR binding sites in intracranial tumours and to evaluate the benefit of SRS in pre- and postoperative diagnostics. 86 patients with 94 intracranial tumours (39 meningiomas, 18 pituitary adenomas, 11 gliomas grade 3 or 4, 8 gliomas grade 2, 5 neurinomas, 5 intracranial metastases, 4 tumours of the orbit, 2 neurofibromas, 1 brain abscess and 1 cystic lesion) were examined. 111 In-octreotide was injected i.v. as 10 μg or 20 μg bolus, corresponding to 110 or 220 MBq (3 or 6 mCi). Gamma-camera images and SPECT were obtained 3-6 h and 24 h post injection. The scintigraphic evaluation was performed without knowledge of CT and MRI results. The histological classification corresponded to the WHO grading system. Somatostatin binding sites were detected in vito using somatostatin-gold conjugates. All patients with meningiomas showed a high focal tracer uptake corresponding to SR binding sites in vitro, whereas only in 50% of the pituitary adenomas SRS was positive. Neurinomas did not show any tracer uptake. In patients with gliomas with disturbed blood-brain-barrier positive tracer uptake was detected, while none of the gliomas with intact blood-brain-barrier could be visualized by SRS but showed somatostatin binding sites in vitro. In intracranial metastases a local tracer uptake was detected in vivo. In vitro 3 of 4 cases showed somatostatin binding sites. In 2 cases extracranial tracer uptake showed the primary tumour and metastases of the lymphnodes. Somatostatin receptor scintigraphy can help to detect or to exclude meningiomas especially in the cerebellopontine angle or in the orbit. In intracranial metastases SRS may point to the primary tumour or other metastases. In all other intracranial tumours receptor scintigraphy provides no clinical relevant information. (orig./MG) [de

Somatostatin receptor scintigraphy on thyroid carcinoma

International Nuclear Information System (INIS)

Pan Weimin; Tan Tianzhi

2004-01-01

Purpose: To study the diagnostic value and clinical method of somatostatin receptor scintigraphy on thyroid carcinoma using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent; Methods: Somatostatin receptor scintigraphy (SRS) were performed on 25 patients with thyroid carcinoma, using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent, controlling with 131 I- whole- body- imaging(1312 -WBI). Results: Of 4 patients with MTC (medullary thyroid carcinoma), positive metastasis and primary tumour were detected on 3 patients by SRS, negative results were obtained by 131 I-WBI, the positive detective rate by SRS is 3/4; of 12 patients with PTC (papillary thyroid carcinoma), positive metastasis and primary tumour were detected on 2 patients by SRS or 131 I-WBI,1 of which only by SRS, while negative results were obtained by 131 I- WBI, the positive detective rate by SRS is 3/12; of 8 patients with FTC(follicular thyroid carcinoma), positive metastasis and primary tumour were detected on 1 patients by SRS or 131 I-WBI, and 2 positive results were obtained only by SRS, while negative by 131 I-WBI, the positive detective rate by SRS is 3/8; of 1 patients with HCC (hurthle cell carcinoma ), positive metastasis and primary tumour were detected by SRS, while negative by 131 I-WBI; Conclusions: SRS using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent has high diagnostic value on thyroid carcinoma, especially on MTC and HCC. (authors)

Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

International Nuclear Information System (INIS)

Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

2010-01-01

Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

Ga-68 Somatostatin Receptor PET/CT in von Hippel-Lindau Disease

Energy Technology Data Exchange (ETDEWEB)

Oh, Jong-Ryool; Min, Jung-Joon [Chonnam National Univ. Hwasun Hospital, Hwasun (Korea, Republic of); Kulkarui, Harshad; Carreras, Cecilia; Schalch, Georg; Baum, Richard P. [Nuclear Medicine and Center for PET/CT, Zentralk Bad Berka, Bad Verka (Germany)

2012-06-15

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renalcysts and tumors, pancreatic cysts and tumors, pheochromo-cytomas, and epididymal cystadenomas. Cross-sectional mo-dalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease.

Ga-68 Somatostatin Receptor PET/CT in von Hippel-Lindau Disease

International Nuclear Information System (INIS)

Oh, Jong-Ryool; Min, Jung-Joon; Kulkarui, Harshad; Carreras, Cecilia; Schalch, Georg; Baum, Richard P.

2012-01-01

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renalcysts and tumors, pancreatic cysts and tumors, pheochromo-cytomas, and epididymal cystadenomas. Cross-sectional mo-dalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease

Physiologic basics and clinical experience with somatostatin-receptor-scintigraphy

International Nuclear Information System (INIS)

Henze, E.; Eberhardt, J.U.; Bohuslavizki, K.H.

1994-01-01

The introduction of radiolabelled octreotide, an analogon to the receptor binding hormone Somatostatin, has markedly increased the ability to detect structures and tumours carrying somatostatin receptors by nuclear medicine imaging with high sensitivity and specificity. It has been shown that in vitro receptor density and in vivo scintigraphic results correlate well in particular in tumours of neuroendocrine origin of the GI tract such as insulinomas, gastrinomas, glucagonomas, carcionoids, but also in paragangliomas, small cell lung cancer and meningiomas. As receptors were also shown to be present on so called activated leucocytes granulomas, lymphomas and autoimmune disease have been imaged with octreotide successfully. The specific tracer (In-111-DTPA-D-PHE-Octreotide, Octreoscan R ) is rapidly cleared from the blood pool by the kidneys and, partially, via the liver providing a high target to background ratio. Physiologic uptake is usually observed in the pituitary and thyroid glands, in spleen and liver. Optimum tracer accumulation for tumour scintigraphy is seen on the 24-h-images with the best target to background ratios. Additional SPECT-imaging is recommended in particular in the abdominal regions. The sensitivity in imaging the above named tumours ranges from 70 up to 100%. In-111 octreotide imaging is of diagnostic impact both for the primary diagnostic evaluation as well as for detecting or excluding secondary manifestations in known tumour sites. Of specific value is the information on relative receptor density in the tumour to be treated as may be obtained by quantitative In-111 octreotide imaging for decision making whether or not to use cold octreotide (Sandostatin R ) as a receptor blocking drug for therapy as well as for treatment follow-up studies. (author)

99Tcm labelling and in vitro binding of dextran-somatostatin conjugate

International Nuclear Information System (INIS)

Cui Haiping; China Inst. of Atomic Energy, Beijing; Zhai Shizhen; Du Jin; Beijing Univ., Beijing

2006-01-01

Natural somatostatin and dextran-20 are used to synthesis somatostatin-dextran (SMS-Dx 20 ). The in vitro somatostatin receptor competition binding study of somatostatin-dextran is carried out by using rate brain cortex membranes (express somatostatin receptor type 2) and 125 I-Tyr 3 -Octreotide as a radioligand. The somatostatin-dextran conjugate is then labelled with 99 Tc m using SnCl 2 as reduce agent and tested for its in vitro binding properties. The somatostatin-dextran conjugate shows high somatostatin receptor binding affinity, i.e. in the same IC 50 value as the reference ligand Octreotide (IC 50 ∼5.95 nmol/L). The labelling efficiency is more than 85%. The specific binding of 99 Tc m labeled somatostatin-dextran conjugate is 25%-40%. The somatostatin-dextran conjugate is worthy of further investigation for 99 Tc m radiolabeling with diagnostic possibilities for somatostatin receptor positive tumors. (authors)

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

OpenAIRE

Zhang, Libo; Vines, Douglass C.; Scollard, Deborah A.; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imagin...

Development and preclinical evaluation of radiolabelled somatostatin receptor agonists and αvβ3-integrin antagonists

International Nuclear Information System (INIS)

Stoecklin, G.; Wester, H.J.; Haubner, R.; Schottelius, M.

2002-01-01

Tumours express specific receptors for peptide ligands. This can be exploited for tumour targeting. New bioactive peptides are available, in particular new somatostatin analogs and RGD-Peptides for targeting the α V β 3 -integrin. The design and optimization of radiolabelled peptides with respect to their receptor affinity, tumour uptake, biodistribution, pharmacokinetics and stability may provide better tracers for tumour imaging and therapy. Based on two basic structures, new radioiodinated and carbohydrated somatostatin analogs and cyclic RGD-peptides were developed and evaluated. (author)

Experimental peptide receptor radionuclide therapy in radioiodine negative somatostatin receptor positive thyroid cancer

International Nuclear Information System (INIS)

Nilica, B.; Kroiss, A.; Putzer, D.; Uprimmy, C.; Warwitz, B.; Kendler, D.; Waitz, D.; Virgolini, I.

2015-01-01

Full text of publication follows. Purpose: This retrospective analysis evaluated the time to progression (TTP), progression free survival (PFS) and overall survival (OS) in patients with radioiodine negative thyroid cancer who had undergone peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTA-TATE, 177 Lu-DOTA-LAN, 90 Y-DOTA-TOC or 90 Y-DOTA-LAN after tumor progression. Methods: Data derived from twenty patients with either differentiated (n=15), anaplastic (n=1) or medullary (n=4) somatostatin receptor positive thyroid cancer who had received treatment with PRRT after tumor progression. TTP, PFS and OS were defined according to the clinical trial endpoints suggested by the FDA (Food and Drug Administration). Progressive disease was defined by sonography, FDG-PET, Ga-DOTA-TOC-PET, or CT (RECIST Criteria). Results: In 17 patients the median overall survival time after the first PRRT was 17.3 (range: 0.1 - 109.7) months. Three patients still alive are actually showing stable disease. The median of PFS in 20 Patients (6 with more than one PRRT-cycle or PRRT-substance) has been 10.9 (range: 0.1 - 44.0) months. The median TTP was 15.6 (range 4.4 to 29.2) months. Conclusion: PRRT appears to be useful in patients with somatostatin receptor positive but radioiodine negative thyroid cancer as a complementary palliative cytotoxic therapy. (authors)

Somatostatin: a metabolic regulator

International Nuclear Information System (INIS)

Dileepan, K.N.; Wagle, S.R.

1985-01-01

Somatostatin, the hypothalamic release-inhibiting factor, has been found to stimulate gluconeogenesis in rat kidney cortical slices. Stimulation by somatostatin was linear and dose-dependent. Other bioactive peptides such as cholecystokinin, gastro-intestinal peptide, secretin, neurotensin, vasoactive intestinal peptide, pancreatic polypeptide, beta endorphin and substance P did not affect the renal gluconeogenic activity. Somatostatin-induced gluconeogenesis was blocked by phentolamine (alpha adrenergic antagonist) and prazosin (alpha 1 adrenergic antagonist) but not by propranolol (beta adrenergic antagonist) and yohimbine (alpha 2 adrenergic antagonist) suggesting that the effect is via alpha 1 adrenergic stimuli. Studies on the involvement of Ca 2+ revealed that tissue depletion and omission of Ca 2+ from the reaction mixture would abolish the stimulatory effect of somatostatin. Furthermore, somatostatin enhanced the uptake of 45 calcium in renal cortical slices which could be blocked by lanthanum, an inhibitor of Ca 2+ influx. It is proposed that the stimulatory effect of somatostatin on renal gluconeogenesis is mediated by alpha 1 adrenergic receptors, or those which functionally resemble the alpha 1 receptors and that the increased influx of Ca 2+ may be the causative factor for carrying out the stimulus. 88 references

Molecular imaging of neuroendocrine tumors using {sup 68}Ga-labeled peptides (Somatostatin receptor PET/CT); Molekulare Bildgebung neuroendokriner Tumoren mit {sup 68}Ga-markierten Peptiden (Somatostatinrezeptor-PET/CT)

Energy Technology Data Exchange (ETDEWEB)

Baum, R.P.; Prasad, V. [Zentralklinik Bad Berka GmbH (Germany). Klinik fuer Nuklearmedizin/PET-Zentrum; Hoersch, D. [Zentralklinik Bad Berka GmbH (Germany). Klinik fuer Innere Medizin, Gastroenterologie, Onkologie, Endokrionologie

2009-06-15

Receptor PET/CT using {sup 68}Ga-labeled somatostatin analogues (DOTA-NOC, DOTA-TOC or DOTA-TATE) enables the highly sensitive molecular imaging of neuroendocrine tumors (NETs) based on the expression of somatostatin receptors and even the detection of receptor subtypes. Our experience after more than 3000 studies shows that receptor PET/CT has a significantly higher tumor detection rate than conventional scintigraphy (even in SPECT/CT technique), and that tumor lesions can be very accurately localized. By calculating standardized uptake values (SUV) - which are reproducible and investigator-independent - patients can be selected for peptide receptor radiotherapy and also the course after therapy can be controlled. Receptor-PET/CT is the most sensitive imaging modality for the detection of unknown primary tumors (CUP syndrome), which is especially true for the detection of neuroendocrine tumors of the pancreas and small bowel; whole-body staging (''one stop shop'') as well as restaging and selection of patients for peptide receptor radiotherapy can be performed using a patient-friendly procedure (examination finished within one hour) exposing the patient to less radiation than whole-body CT scanning. The {sup 68}Ge/{sup 68}Ga generator has proved very reliable over the years - even in a hospital environment. The effective costs for {sup 68}Ga labeled somatostatin analogues might be less than for scintigraphic agents, provided a certain number of studies per year are performed. The development of new tumor-specific peptides as well as of other DOTA- or NOTA-coupled radiopharmaceuticals opens a new avenue into the future: finally, the {sup 68}Ga generator could play a similar important role for PET/CT as did the {sup 99m}Tc-Generator for conventional gamma camera imaging over the last decades. (orig.)

Diagnostic value of somatostatin receptor scintigraphy in patients with intracranial tumours. Diagnostische Wertigkeit der Somatostatin-Rezeptor-Szintigraphie bei Patienten mit intrakraniellen Raumforderungen

Energy Technology Data Exchange (ETDEWEB)

Luyken, C. (Klinik fuer Neurochirurgie, Koeln Univ. (Germany)); Hildebrandt, G. (Klinik fuer Neurochirurgie, Koeln Univ. (Germany)); Scheidhauer, K. (Klinik fuer Nuklearmedizin, Koeln Univ. (Germany)); Kirsch, B. (Anatomisches Inst., Kiel Univ. (Germany))

1993-12-01

The aim of the study was to detect the SR binding sites in intracranial tumours and to evaluate the benefit of SRS in pre- and postoperative diagnostics. 86 patients with 94 intracranial tumours (39 meningiomas, 18 pituitary adenomas, 11 gliomas grade 3 or 4, 8 gliomas grade 2, 5 neurinomas, 5 intracranial metastases, 4 tumours of the orbit, 2 neurofibromas, 1 brain abscess and 1 cystic lesion) were examined. [sup 111]In-octreotide was injected i.v. as 10 [mu]g or 20 [mu]g bolus, corresponding to 110 or 220 MBq (3 or 6 mCi). Gamma-camera images and SPECT were obtained 3-6 h and 24 h post injection. The scintigraphic evaluation was performed without knowledge of CT and MRI results. The histological classification corresponded to the WHO grading system. Somatostatin binding sites were detected in vito using somatostatin-gold conjugates. All patients with meningiomas showed a high focal tracer uptake corresponding to SR binding sites in vitro, whereas only in 50% of the pituitary adenomas SRS was positive. Neurinomas did not show any tracer uptake. In patients with gliomas with disturbed blood-brain-barrier positive tracer uptake was detected, while none of the gliomas with intact blood-brain-barrier could be visualized by SRS but showed somatostatin binding sites in vitro. In intracranial metastases a local tracer uptake was detected in vivo. In vitro 3 of 4 cases showed somatostatin binding sites. In 2 cases extracranial tracer uptake showed the primary tumour and metastases of the lymphnodes. Somatostatin receptor scintigraphy can help to detect or to exclude meningiomas especially in the cerebellopontine angle or in the orbit. In intracranial metastases SRS may point to the primary tumour or other metastases. In all other intracranial tumours receptor scintigraphy provides no clinical relevant information. (orig./MG)

Radioautographic localization of somatostatin-14 and somatostatin-28 binding sites in the rat brain

International Nuclear Information System (INIS)

Leroux, P.; Pelletier, G.

1984-01-01

Somatostatin-14 (S14) and its precursor, somatostatin-28 (S28), are widely distributed throughout the rat brain, suggesting that they could act as neurotransmitter or neuromodulator in the central nervous system. The present study was undertaken to study the localization of S14 and S28 receptors in the rat brain determined by ''in vitro'' radioautography. The study performed on slide mounted frozen brain section with iodinated S14 and S28 analogs revealed an identical distribution of binding sites for the two forms of somatostatin. A good correlation could be observed between receptor distribution and immunohistologically localized neuropeptides except for striatum and hypothalamus. However, receptors were not detectable in the hypothalamus and were found in low concentration in the caudate-putamen nucleus, two regions containing high amounts of S28 and S14, suggesting a high occupancy of receptors in these areas by endogenous peptides or an inverse correlation between receptor and peptide concentrations

Somatostatin: a metabolic regulator

Energy Technology Data Exchange (ETDEWEB)

Dileepan, K.N.; Wagle, S.R.

1985-12-23

Somatostatin, the hypothalamic release-inhibiting factor, has been found to stimulate gluconeogenesis in rat kidney cortical slices. Stimulation by somatostatin was linear and dose-dependent. Other bioactive peptides such as cholecystokinin, gastro-intestinal peptide, secretin, neurotensin, vasoactive intestinal peptide, pancreatic polypeptide, beta endorphin and substance P did not affect the renal gluconeogenic activity. Somatostatin-induced gluconeogenesis was blocked by phentolamine (alpha adrenergic antagonist) and prazosin (alpha/sub 1/ adrenergic antagonist) but not by propranolol (beta adrenergic antagonist) and yohimbine (alpha/sub 2/ adrenergic antagonist) suggesting that the effect is via alpha/sub 1/ adrenergic stimuli. Studies on the involvement of Ca/sup 2 +/ revealed that tissue depletion and omission of Ca/sup 2 +/ from the reaction mixture would abolish the stimulatory effect of somatostatin. Furthermore, somatostatin enhanced the uptake of /sup 45/calcium in renal cortical slices which could be blocked by lanthanum, an inhibitor of Ca/sup 2 +/ influx. It is proposed that the stimulatory effect of somatostatin on renal gluconeogenesis is mediated by alpha/sub 1/ adrenergic receptors, or those which functionally resemble the alpha/sub 1/ receptors and that the increased influx of Ca/sup 2 +/ may be the causative factor for carrying out the stimulus. 88 references.

Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

Science.gov (United States)

Oh, Sowon; Prasad, Vikas; Lee, Dong Soo; Baum, R. P.

2011-01-01

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression. PMID:22121482

Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411.

Directory of Open Access Journals (Sweden)

Sif Holmboe

Full Text Available Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.

Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function?

Directory of Open Access Journals (Sweden)

Elodie Urlacher

Full Text Available Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA and its receptor (Apime-ASTA-R; and C-type allatostatins (Apime-ASTC and Apime-ASTCC and their common receptor (Apime-ASTC-R. Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling.

A 12-month phase 3 study of pasireotide in Cushing's disease

DEFF Research Database (Denmark)

Colao, Annamaria; Petersenn, Stephan; Newell-Price, John

2012-01-01

Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5.......Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5....

Somatostatin receptors in rat hippocampus: localization to intrinsic neurons

International Nuclear Information System (INIS)

Palacios, J.M.; Reubi, J.C.; Maurer, R.

1986-01-01

The effect of neurotoxic chemical and electrolytical lesions on somatostatin (SS) receptor binding in the septo-hippocampal afferents, pyramidal and granule cells of the rat hippocampus was examined by autoradiography using the stable SS analogue 125 I-204-090 as radioligand. Electrolytical lesions of the septum did not result in modification of SS binding in the hippocampus. In contrast, both granule cell lesion with colchicine and pyramidal or pyramidal and granule cell lesions with increasing kainic acid doses did result in a specific decrease of binding in the dentate gyrus and hippocampus (CA 1 and CA 3 ). These results suggest that SS receptors in the hippocampus are probably associated with elements from intrinsic neurons. (Author)

Somatostatin receptor scintigraphy - a case report and review of the literature

International Nuclear Information System (INIS)

Yamaga, Lilian Yuri Itaya; Belfer, Aron J.; Segal, Amisa

1997-01-01

The authors report a case of carcinoid tumor, diagnosed in a 75-year-old male patient, confirmed by laparotomy and anatomo-pathological study. The patient was examined by somatostatin receptor scintigraphy with In-pentetreotide, and correlation was performed with I-MIBG and CT scan. A review of current literature about this new tracer for detection of carcinoid tumor is presented. (author)

Heterogeneity of muscarinic receptor subtypes in cerebral blood vessels

International Nuclear Information System (INIS)

Garcia-Villalon, A.L.; Krause, D.N.; Ehlert, F.J.; Duckles, S.P.

1991-01-01

The identity and distribution of muscarinic cholinergic receptor subtypes and associated signal transduction mechanisms was characterized for the cerebral circulation using correlated functional and biochemical investigations. Subtypes were distinguished by the relative affinities of a panel of muscarinic antagonists, pirenzepine, AF-DX 116 [11-2-[[2-[diethylaminomethyl]- 1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one], hexahydrosiladifenidol, methoctramine, 4-diphenylacetoxy-N-methylpiperidine methobromide, dicyclomine, para-fluoro-hexahydrosiladifenidol and atropine. Muscarinic receptors characterized by inhibition of [3H]quinuclidinylbenzilate binding in membranes of bovine pial arteries were of the M2 subtype. In contrast pharmacological analysis of [3H]-quinuclidinylbenzilate binding in bovine intracerebral microvessels suggests the presence of an M4 subtype. Receptors mediating endothelium-dependent vasodilation in rabbit pial arteries were of the M3 subtype, whereas muscarinic receptors stimulating endothelium-independent phosphoinositide hydrolysis in bovine pial arteries were of the M1 subtype. These findings suggest that characteristics of muscarinic receptors in cerebral blood vessels vary depending on the type of vessel, cellular location and function mediated

Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases.

NARCIS (Netherlands)

A. Mearadji (Amir); W.A.P. Breeman (Wouter); L.J. Hofland (Leo); R.L. Marquet (Richard); J. Jeekel (Hans); E.P. Krenning (Eric); C.H.J. van Eijck (Casper); P.M. van Koetsveld (Peter)

2002-01-01

textabstractOBJECTIVE: To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.SUMMARY BACKGROUND DATA: Previously the authors have shown highly effective therapy with

δ-opioid receptor and somatostatin receptor-4 heterodimerization: possible implications in modulation of pain associated signaling.

Directory of Open Access Journals (Sweden)

Rishi K Somvanshi

Full Text Available Pain relief is the principal action of opioids. Somatostatin (SST, a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4. In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

Evolutionary history of the somatostatin and somatostatin receptors

Indian Academy of Sciences (India)

Table 1. The identified somatostations. Somatostatin (SST1). Name. Scientific name. Length. High ID (to). Low ID (to) Chromosome. GS. Drs. Danio rerio. 324. 48.1 mms ...... ancestral source. References. Baranowska B., Chmielowska M., Wolinska-Witort E., Bik W.,. Baranowska-Bik A. and Martynska L. 2006 Direct effect of.

99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy in daily clinical practice.

Science.gov (United States)

Chrapko, Beata Ewa; Nocuń, Anna; Gołebiewska, Renata; Stefaniak, Bogusław; Korobowicz, Elzbieta; Czekajska-Chehab, Elzbieta; Sawicki, Marek; Polkowski, Wojciech Piotr

2010-04-01

This study aimed to assess the impact of 99mTc-EDDA/HYNIC-TOC (99mTc-TOC) somatostatin receptor scintigraphy (SRS) in clinical practice. One hundred seventeen patients were divided into 6 groups: 1, initial detection and localization of suspected neuroendocrine tumor (NET); 2, tumor staging before therapy; 3, staging of NET of unknown origin, 4, restaging after surgery of primary tumor; 5, diagnosis of solitary pulmonary nodules (SPNs), and 6, follow-up after "cold" somatostatin analogues treatment. In group 1, clinical suspicions were not confirmed in any of the patients; in group 2, most of the primary lesions showed overexpression of somatostatin receptors (SSRT); in group 3, the primary tumor was not identified in any of the patients; in group 4, recurrences were depicted in 7 out of 47 patients; in group 5, only 1 malignant SPN was detected, and in group 6, regression of primary mass and metastases were seen on follow-up SRS in 1 patient. 99mTc-TOC SRS is useful in staging of SSRT-overexpressing tumors of known and unknown primary origin, as well as in restaging after primary tumor surgery. This method is less effective in detecting suspected NET and assessing SPNs. Further investigation is necessary to evaluate the usefulness of SRS in monitoring patients after biological treatment.

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors

DEFF Research Database (Denmark)

Malmberg, Catarina; Ripa, Rasmus Sejersten; Johnbeck, Camilla Bardram

2015-01-01

UNLABELLED: The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We...

Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells

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Allouche Stéphane

2009-06-01

Full Text Available Abstract Background opioid and somatostatin receptors (SSTRs that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. Materials and methods: SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI staining and apoptosis by annexin V-PI labelling. Results almost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also μ-opioid receptors (MOP-R. XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments. Conclusion these data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.

Somatostatin receptor scintigraphy in sarcoidosis: relation to selected clinical and laboratory markers.

Science.gov (United States)

Piotrowski, Wojciech J; Bieńkiewicz, Małgorzata; Frieske, Izabella; Marczak, Jerzy; Antczak, Adam; Górski, Paweł; Kuśmierek, Jacek; Płachcińska, Anna

2012-01-01

Discriminating between active and inactive sarcoidosis may be problematic in everyday clinical practice. There are numerous biochemical markers used in the diagnosis and monitoring of sarcoidosis. Somatostatin receptor (SR) scintigraphy with the use of 99mTc-octreotide may be used to estimate disease activity. The aim of the paper was to assess the value of traditional biomarkers (serum angiotensin-converting enzyme [SACE], C-reactive protein, markers of calcium metabolism, bronchoalveolar lavage fluid [BALF] lymphocytes) and a novel biomarker, 8-isoprostane (8-IP) in exhaled breath condensate (EBC), in the assessment of sarcoidosis activity in relation to somatostatin receptor scintigraphy. The study included 32 patients with sarcoidosis. Scintigraphy was performed using somatostatin analogue, 99mTc-HYNIC-TOC; planar and SPECT/CT images were recorded. The study group was divided into a subgroup with positive radiotracer uptake (n = 20) and without a visible uptake (n = 12). 8-IP levels were measured in EBC by an immunoenzymatic assay. RESULTS We observed a significantly higher EBC 8-IP levels in the subgroup with positive uptake compared with those with negative uptake (19.1 ± 19.8 vs. 5.4 ± 3.5 pg/ml, P = 0.02). The levels of SACE and the percentage of BALF lymphocytes were also nonsignificantly elevated. In the group of patients with positive scintigraphy results, a positive correlation was observed between the uptake ratio and SACE (r = 0.44, P = 0.041). The results indicate low value of biochemical markers in the assessment of disease activity. SR scintigraphy may have practical usefulness in the monitoring of sarcoidosis.

Multiple Receptor Subtypes for the CGRP Super-Family

Directory of Open Access Journals (Sweden)

R. Quirion

2001-01-01

Full Text Available Molecular evidence for the existence of multiple receptors for CGRP has been rather difficult to obtain. Over 10 years after suggesting the existence of at least two classes (CGRP1 and CGRP2 of CGRP receptors on the basis of pharmacological data[1], molecular data on the CGRP2 receptor subtype are still lacking as well as potent and selective antagonists. The situation is somewhat different for the functional CGRP1 subtype which is likely composed of diverse subunits CRLR, RAMP1 and possibly RCP[2]. Moreover, BIBN 4096BS was recently reported as the first nonpeptide highly potent CGRP1 receptor antagonist[3]. However, in situ hybridization and receptor autoradiographic data have clearly shown the existence of major mismatches (e.g., cerebellum between the discrete localization of CRLR, RAMP1, and specific CGRP binding sites supporting the existence of CGRP receptor subtypes. Functional studies have also provided evidence in that regard (for a recent review: [4]. Accordingly, additional studies aiming at cloning additional CGRP receptors are certainly warranted. Similarly, recent evidence from various laboratories including ours suggests the existence of more than one class (CRLR and RAMP2 of adrenomedullin receptors at least in the rat brain. In contrast, most evidence suggests the existence of a single class of amylin receptors. In brief, it appears that multiple receptors or receptor complexes do exist for CGRP and related peptides but their composition is apparently unique among the GPCR super-family and additional data are needed to fully establish the molecular organization of each subtype. Supported by CIHR of Canada.

Therapy with radiolabelled somatostatin analogs in neuroendocrine tumors

International Nuclear Information System (INIS)

Kunikowska, J.; Krolicki, L.

2007-01-01

In the 80's the discovery of somatostatin receptors expression on NET cells enabled the application of somatostatin analogues in diagnosis and therapy. Initially, 'cold' somatostatin analogs were used for therapeutical purpose, with overall good clinical response, but with minimal anti-proliferation effect. Furthermore, radiolabelled receptor-binding peptides have been shown to be an important class of radiopharmaceuticals for tumor diagnosis and therapy with minimal side-effects. Specific binding between receptor on tumor cell and peptide with beta emitting radionuclide act not only on tumor related symptoms but also on tumor cell via radiotoxic effect of beta radiation. Discoveries of next receptor combinations, allow the work over synthesis and applications of next receptors' analogs both in diagnosis and in therapy. Due to complex characteristics of NET's, the use therapeutic 'cocktail' containing the variety analogs may be of great importance. (author)

Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

Science.gov (United States)

Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

2017-03-01

Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

International Nuclear Information System (INIS)

Ugur, Oemer; Kothari, Paresh J.; Finn, Ronald D.; Zanzonico, Pat; Ruan, Shutian; Guenther, Ilonka; Maecke, Helmut R.; Larson, Steven M.

2002-01-01

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe 1 -Tyr 3 -octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T 1/2 =9.5 hr; β + =56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66 Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67 Ga- and 68 Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was >95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET TM images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0±0.7, 13.2±2.1 and 9.8±1.5 for 66 Ga-, 67 Ga-, and 68 Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66 Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively. We conclude that 66 Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66 Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio 1.64), and high kidney uptake must

The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

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Li Li

2014-01-01

Full Text Available The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG evoked by bee venom (BV. The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC

International Nuclear Information System (INIS)

Freudenberg, L.S.; Goerges, R.; Stergar, H.; Bockisch, A.; Gauler, T.; Bauer, S.; Antoch, G.; Schuette, J.

2008-01-01

Aims: objective of this prospective study was to evaluate the role of somatostatin receptor scintigraphy (SRS) in advanced renal cell carcinoma (RCC) with respect to potential therapy with somatostatin analogue (SST-A) and to assess the response rate under therapy with SST-A. Patients, methods: 16 patients with documented progression of histologically confirmed advanced RCC were included. Planar whole-body SRS was performed 4, 24 and 48h post i.v. injection of 175-200 MBq 111 In-pentetreoide. 5 and 25 h p.i. SPECT of thorax and abdomen were performed. Documentation of somatostatin receptor expression via SRS in > 50% of known tumour lesions was the criteria for treatment start with SST-A (Sandostatin LAR registered -Depot 30mg i.m. every four weeks). Results: in 9/16 of the patients SRS showed at least one metastasis with moderate (n = 5) or intense (n = 4) tracer uptake. Lesion-based SRS evaluation showed only 12.1% (20/165) of all metastases. Most false-negative lesions were located in the lungs. In too patients, the majority of the known metastases was SRS positive and these patients received SST-A therapy. The first radiographic evaluation after a two-month interval showed progressive disease in both patients. Conclusions: we conclude that SRS is of limited value in staging of advanced RCC. In our patients SST-A did not result in a growth control of RCC. Consequently, the use of SST-A in advanced RCC seems to be no relevant therapeutic option. (orig.)

Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum.

Science.gov (United States)

Allen, Jeremy P; Hathway, Gareth J; Clarke, Neil J; Jowett, Mike I; Topps, Stephanie; Kendrick, Keith M; Humphrey, Patrick P A; Wilkinson, Lawrence S; Emson, Piers C

2003-05-01

The peptide somatostatin can modulate the functional output of the basal ganglia. The exact sites and mechanisms of this action, however, are poorly understood, and the physiological context in which somatostatin acts is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional in the striatum. We have investigated the role of SSTR2 in basal ganglia function using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry demonstrated a widespread pattern of expression. By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2. In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons. Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks. However, in beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired. Together these data implicate an important neuromodulatory role for SSTR2 in the striatum.

Design, Synthesis, and Biological Evaluation of 68Ga-DOTA-PA1 for Lung Cancer: A Novel PET Tracer for Multiple Somatostatin Receptor Imaging.

Science.gov (United States)

Liu, Fei; Liu, Teli; Xu, Xiaoxia; Guo, Xiaoyi; Li, Nan; Xiong, Chiyi; Li, Chun; Zhu, Hua; Yang, Zhi

2018-02-05

Most of the radiolabeled somatostatin analogues (SSAs) are specific for subtype somatostatin receptor 2 (SSTR 2 ). Lack of ligands targeting other subtypes of SSTRs, especially SSTR 1, SSTR 3 , and SSTR 5 , limited their applications in tumors of low SSTR 2 expression, including lung tumor. In this study, we aimed to design and synthesize a positron emission tomography (PET) radiotracer targeting multi-subtypes of SSTRs for PET imaging. PA1 peptide and its conjugate with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator or fluorescein isothiocyanate (FITC) at the N-terminal of the lysine position were synthesized. 68 Ga was chelated to DOTA-PA1 to obtain 68 Ga-DOTA-PA1 radiotracer. The stability, lipophilicity, binding affinity, and binding specificity of 68 Ga-DOTA-PA1 and FITC-PA1 were evaluated by various in vitro experiments. Micro-PET imaging of 68 Ga-DOTA-PA1 was performed in nude mice bearing A549 lung adenocarcinoma, as compared with 68 Ga-DOTA-(Tyr3)-octreotate ( 68 Ga-DOTA-TATE). Histological analysis of SSTR expression in A549 tumor tissues and human tumor tissues was conducted using immunofluorescence staining and immunohistochemical assay. 68 Ga-DOTA-PA1 had high radiochemical yield and radiochemical purity of over 95% and 99%, respectively. The radiotracer was stable in vitro in different buffers over a 2 h incubation period. Cell uptake of 68 Ga-DOTA-PA1 was 1.31-, 1.33-, and 1.90-fold that of 68 Ga-DOTA-TATE, which has high binding affinity only for SSTR 2 , after 2 h incubation in H520, PG, and A549 lung cancer cell lines, respectively. Micro-PET images of 68 Ga-DOTA-PA1 showed that the PET imaging signal correlated with the total expression of SSTRs, instead of SSTR 2 only, which was measured by Western blotting and immunofluorescence analysis in mice bearing A549 tumors. In summary, a novel PET radiotracer, 68 Ga-DOTA-PA1, targeting multi-subtypes of SSTRs, was successfully synthesized and was confirmed to be useful for PET

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

Directory of Open Access Journals (Sweden)

Igor P. Dmitriev

2014-10-01

Full Text Available A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

Energy Technology Data Exchange (ETDEWEB)

Antunes, P.; Ginj, M.; Zhang, H.; Maecke, H. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Waser, B.; Reubi, J.C. [University of Bern, Institute of Pathology, Bern (Switzerland); Baum, R.P. [Zentralklinik Bad Berka, Department of Nuclear Medicine/PETCT-Center, Bad Berka (Germany)

2007-07-15

Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [{sup 68}Ga-DOTA,Tyr{sup 3}]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its {sup 111}In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. All peptides showed high affinities on hsst2, with the highest affinity for the Ga{sup III}-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga{sup III} peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all {sup 67}Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the {sup 111}In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [{sup 67}Ga-DOTA,1-Nal{sup 3}]octreotide in comparison to [{sup 111}In-DOTA,1-Nal{sup 3}]octreotide and [{sup 67}Ga-DOTA,Tyr{sup 3}]octreotide showed a significantly higher and receptor-mediated uptake of the two{sup 67}Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. This study demonstrates that {sup 67/68}Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the {sup 111}In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

International Nuclear Information System (INIS)

Antunes, P.; Ginj, M.; Zhang, H.; Maecke, H.; Waser, B.; Reubi, J.C.; Baum, R.P.

2007-01-01

Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [ 68 Ga-DOTA,Tyr 3 ]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111 In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. All peptides showed high affinities on hsst2, with the highest affinity for the Ga III -complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga III peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67 Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111 In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [ 67 Ga-DOTA,1-Nal 3 ]octreotide in comparison to [ 111 In-DOTA,1-Nal 3 ]octreotide and [ 67 Ga-DOTA,Tyr 3 ]octreotide showed a significantly higher and receptor-mediated uptake of the two 67 Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. This study demonstrates that 67/68 Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111 In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies. (orig.)

Muscarinic acetylcholine receptor subtypes: localization and structure/function

DEFF Research Database (Denmark)

Brann, M R; Ellis, J; Jørgensen, H

1993-01-01

Based on the sequence of the five cloned muscarinic receptor subtypes (m1-m5), subtype selective antibody and cDNA probes have been prepared. Use of these probes has demonstrated that each of the five subtypes has a markedly distinct distribution within the brain and among peripheral tissues...... are described, as well as the implied structures of these functional domains....

Somatostatin Receptor SPECT/CT using 99mTc Labeled HYNIC-TOC Aids in Diagnosis of Primary Optic Nerve Sheath Meningioma.

Science.gov (United States)

Chandra, Piyush; Purandare, Nilendu; Shah, Sneha; Agrawal, Archi; Rangarajan, Venkatesh

2017-01-01

Primary optic nerve sheath meningiomas (ONSM) are rare, benign and slow growing tumor involving the intra-orbital/intra-canalicular segment of the optic nerve. Untreated, they can potentially lead to visual deterioration. Magnetic resonance (MR) is the gold standard imaging modality for diagnosing the entity. Often, a clinical dilemma exists to narrow the differential diagnosis of an enhancing intra-orbital mass on MR. Molecular imaging provides a high degree of precision in diagnosing meningioma in view of relatively high levels of somatostatin receptor expression by these tumors. The following case demonstrates the potential clinical utility of somatostatin receptor SPECT using 99m Tc- labeled HYNIC-TOC in clinical diagnosis of ONSM.

[111In-DOTA]LTT-SS28, a first pansomatostatin radioligand for in vivo targeting of somatostatin receptor-positive tumors.

Science.gov (United States)

Maina, Theodosia; Cescato, Renzo; Waser, Beatrice; Tatsi, Aikaterini; Kaloudi, Aikaterini; Krenning, Eric P; de Jong, Marion; Nock, Berthold A; Reubi, Jean Claude

2014-08-14

Radiolabeled pansomatostatin-like analogues are expected to enhance the diagnostic sensitivity and to expand the clinical indications of currently applied sst2-specific radioligands. In this study, we present the somatostatin mimic [DOTA]LTT-SS28 {[(DOTA)Ser1,Leu8,D-Trp22,Tyr25]SS28} and its 111In radioligand. [DOTA]LTT-SS28 exhibited a pansomatostatin-like profile binding with high affinity to all five hsst1-hsst5 subtypes (IC50 values in the lower nanomolar range). Furthermore, [DOTA]LTT-SS28 behaved as an agonist at hsst2, hsst3, and hsst5, efficiently stimulating internalization of the three receptor subtypes. Radioligand [111In-DOTA]LTT-SS28 showed good stability in the mouse bloodstream. It displayed strong and specific uptake in AR42J tumors 4 h postinjection (9.3±1.6% ID/g vs 0.3±0.0% ID/g during sst2 blockade) in mice. Significant and specific uptake was also observed in HEK293-hsst2-, HEK293-hsst3-, and HEK293-hsst5-expressing tumors (4.43±1.5, 4.88±1.1, and DOTA]LTT-SS28 specifically localizes in sst2-, sst3-, and sst5-expressing xenografts in mice showing promise for multi-sst1-sst5 targeted tumor imaging.

Subtype selective kainic acid receptor agonists

DEFF Research Database (Denmark)

Bunch, Lennart; Krogsgaard-Larsen, Povl

2009-01-01

(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

Agonist discrimination between AMPA receptor subtypes

DEFF Research Database (Denmark)

Coquelle, T; Christensen, J K; Banke, T G

2000-01-01

The lack of subtype-selective compounds for AMPA receptors (AMPA-R) led us to search for compounds with such selectivity. Homoibotenic acid analogues were investigated at recombinant GluR1o, GluR2o(R), GluR3o and GluR1o + 3o receptors expressed in Sf9 insect cells and affinities determined in [3H...

Scintigraphy with labelled analogues of the somatostatin

International Nuclear Information System (INIS)

Duet, M.; Ajzenberg, C.; Warnet, A.; Mundler, O.

1998-01-01

The receptors of the somatostatin have been localized in a big number of tumors, whom a great number are neuro-endocrine tumors. However, some tumors that have not this differentiation (breast cancer, lymphomas, cerebral tumors) possess them as well. Analogues of somatostatin, labelled with isotopes having a gamma emission, allow from now their detection in vivo. (N.C.)

Technetium-99m labeled somatostatin and analogs: synthesis, characterization and in vivo evaluation

International Nuclear Information System (INIS)

Amartey, J.K.

1993-01-01

Technetium-99m complexes of somatostatin and analogs were synthesized following the introduction of sulfhydryl groups with 2-iminothiolane (Traut's Reagent). In rats the complex was taken up by the liver, kidneys, adrenals, lungs and the pancreas. Analysis of urine samples of treated rats showed that the radiochemicals have reasonably good in vivo stability. This implies that the complexes may be potentially useful for biochemical characterization of somatostatin receptors and also in scintigraphic detection of somatostatin receptor positive tumors, especially for metastatic deposits in patients on somatostatin therapy. (Author)

Structural features of subtype-selective EP receptor modulators.

Science.gov (United States)

Markovič, Tijana; Jakopin, Žiga; Dolenc, Marija Sollner; Mlinarič-Raščan, Irena

2017-01-01

Prostaglandin E2 is a potent endogenous molecule that binds to four different G-protein-coupled receptors: EP1-4. Each of these receptors is a valuable drug target, with distinct tissue localisation and signalling pathways. We review the structural features of EP modulators required for subtype-selective activity, as well as the structural requirements for improved pharmacokinetic parameters. Novel EP receptor subtype selective agonists and antagonists appear to be valuable drug candidates in the therapy of many pathophysiological states, including ulcerative colitis, glaucoma, bone healing, B cell lymphoma, neurological diseases, among others, which have been studied in vitro, in vivo and in early phase clinical trials. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

DEFF Research Database (Denmark)

Lauritsen, Marlene B; Nyegaard, Mette; Betancur, Catalina

2003-01-01

growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine......Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports...... of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased...

Novel Somatostatin Receptor Ligands Therapies for Acromegaly

Directory of Open Access Journals (Sweden)

Rosa Maria Paragliola

2018-03-01

Full Text Available Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs octreotide (OCT, lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients’ compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029, delivered via prefilled syringes and oral OCT that uses a “transient permeability enhancer” technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003, which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.

Ga-66 labeled somatostatin analogue DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

Energy Technology Data Exchange (ETDEWEB)

Ugur, Oemer E-mail: ougur@hacettepe.edu.tr; Kothari, Paresh J.; Finn, Ronald D.; Zanzonico, Pat; Ruan, Shutian; Guenther, Ilonka; Maecke, Helmut R.; Larson, Steven M

2002-02-01

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T{sub 1/2} =9.5 hr; {beta}{sup +}=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of {sup 66}Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with {sup 67}Ga- and {sup 68}Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was >95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET{sup TM} images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0{+-}0.7, 13.2{+-}2.1 and 9.8{+-}1.5 for {sup 66}Ga-, {sup 67}Ga-, and {sup 68}Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for {sup 66}Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively. We conclude that {sup 66}Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. {sup 66}Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the

Preparation, formulation and quality control of one step kit 99m Tc - EDDA/HYNIC-Tyr3-Octreotide as a peptide radiopharmaceutical for imaging somatostatin receptor positive tumors

International Nuclear Information System (INIS)

Gandomkar, M.; Najafi, R.; Sadat-Ebrahimi, E.; Babaei, M.H.

2004-01-01

The high expression of somatostatin receptors in many tumours, have made receptor scintigraphy with 11I n-DTPA-Octreotide a widely used procedure in nuclear medicine. Despite its clinical success, some limitation and drawbacks of radiolabelling with 11I n remain, especially those concerned with the cost, availability and physical decay properties of this radionuclide. 99m Tc - EDDA/HYNIC-Tyr 3 -Octreotide was studied as a new agent with the potential to replace octreoscan in somatostatin receptor scintigraphy. This hydrazino nicotinic acid derivatized somatostatin complex contains ethylenediamine N, N diacetic acid as a co-ligand resulting in a high in vitro and in vivo stability. High labeling yields (>90%) were achieved at high specific activities. Characterization via HPLC, biodistribution and receptor binding of the resulting complex are described. The formulation developed enables rapid and simple labeling of 99m Tc - EDDA/HYNIC-TOC in a manner suitable for clinical setting

Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung

International Nuclear Information System (INIS)

Mak, J.C.; Barnes, P.J.

1990-01-01

Muscarinic receptor subtypes have been localized in human and guinea pig lung sections by an autoradiographic technique, using [3H](-)quinuclidinyl benzilate [( 3H]QNB) and selective muscarinic antagonists. [3H]QNB was incubated with tissue sections for 90 min at 25 degrees C, and nonspecific binding was determined by incubating adjacent serial sections in the presence of 1 microM atropine. Binding to lung sections had the characterization expected for muscarinic receptors. Autoradiography revealed that muscarinic receptors were widely distributed in human lung, with dense labeling over submucosal glands and airway ganglia, and moderate labeling over nerves in intrapulmonary bronchi and of airway smooth muscle of large and small airways. In addition, alveolar walls were uniformly labeled. In guinea pig lung, labeling of airway smooth muscle was similar, but in contrast to human airways, epithelium was labeled but alveolar walls were not. The muscarinic receptors of human airway smooth muscle from large to small airways were entirely of the M3-subtype, whereas in guinea pig airway smooth muscle, the majority were the M3-subtype with a very small population of the M2-subtype present. In human bronchial submucosal glands, M1- and M3-subtypes appeared to coexist in the proportions of 36 and 64%, respectively. In human alveolar walls the muscarinic receptors were entirely of the M1-subtype, which is absent from the guinea pig lung. No M2-receptors were demonstrated in human lung. The localization of M1-receptors was confirmed by direct labeling with [3H]pirenzepine. With the exception of the alveolar walls in human lung, the localization of muscarinic receptor subtypes on structures in the lung is consistent with known functional studies

Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?

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Constantin Lapa

Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68, proliferative activity (Ki67 as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.The amount of microglia/macrophages ranged from 50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.

Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

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Rishi K. Somvanshi

2012-04-01

Full Text Available G-protein coupled receptors (GPCRs are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs in pathophysiology of diseases and as the potential candidate for drug discovery.

Synthesis of a Fluorescently Labeled 68Ga-DOTA-TOC Analog for Somatostatin Receptor Targeting.

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Ghosh, Sukhen C; Hernandez Vargas, Servando; Rodriguez, Melissa; Kossatz, Susanne; Voss, Julie; Carmon, Kendra S; Reiner, Thomas; Schonbrunn, Agnes; Azhdarinia, Ali

2017-07-13

Fluorescently labeled imaging agents can identify surgical margins in real-time to help achieve complete resections and minimize the likelihood of local recurrence. However, photon attenuation limits fluorescence-based imaging to superficial lesions or lesions that are a few millimeters beneath the tissue surface. Contrast agents that are dual-labeled with a radionuclide and fluorescent dye can overcome this limitation and combine quantitative, whole-body nuclear imaging with intraoperative fluorescence imaging. Using a multimodality chelation (MMC) scaffold, IRDye 800CW was conjugated to the clinically used somatostatin analog, 68 Ga-DOTA-TOC, to produce the dual-labeled analog, 68 Ga-MMC(IRDye 800CW)-TOC, with high yield and specific activity. In vitro pharmacological assays demonstrated retention of receptor-targeting properties for the dual-labeled compound with robust internalization that was somatostatin receptor (SSTR) 2-mediated. Biodistribution studies in mice identified the kidneys as the primary excretion route for 68 Ga-MMC(IRDye 800CW)-TOC, along with clearance via the reticuloendothelial system. Higher uptake was observed in most tissues compared to 68 Ga-DOTA-TOC but decreased as a function of time. The combination of excellent specificity for SSTR2-expressing cells and suitable biodistribution indicate potential application of 68 Ga-MMC(IRDye 800CW)-TOC for intraoperative detection of SSTR2-expressing tumors.

Multiple estrogen receptor subtypes influence ingestive behavior in female rodents.

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Santollo, Jessica; Daniels, Derek

2015-12-01

Postmenopausal women are at an increased risk of obesity and cardiovascular-related diseases. This is attributable, at least in part, to loss of the ovarian hormone estradiol, which inhibits food and fluid intake in humans and laboratory animal models. Although the hypophagic and anti-dipsogenic effects of estradiol have been well documented for decades, the precise mechanisms underlying these effects are not fully understood. An obvious step toward addressing this open question is identifying which estrogen receptor subtypes are involved and what intracellular processes are involved. This question, however, is complicated not only by the variety of estrogen receptor subtypes that exist, but also because many subtypes have multiple locations of action (i.e. in the nucleus or in the plasma membrane). This review will highlight our current understanding of the roles that specific estrogen receptor subtypes play in mediating estradiol's anorexigenic and anti-dipsogenic effects along with highlighting the many open questions that remain. This review will also describe recent work being performed by our laboratory aimed at answering these open questions. Copyright © 2015 Elsevier Inc. All rights reserved.

Preparation and biological evaluation of [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide for somatostatin receptor-positive tumor imaging.

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Erfani, Mostafa; Shafiei, Mohammad; Mazidi, Mohammad; Goudarzi, Mostafa

2013-04-01

Somatostatin-derived analogues play an important role in the diagnosis and treatment of neuroendocrine tumors. The aim of this study was to evaluate a new somatostatin analogue designed for labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), β-(3-benzothienyl)-Ala (BzThi(3))]-octreotide ([HYNIC]-BOC), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was performed on a solid phase using a standard Fmoc strategy. The HYNIC-peptide conjugate was radiolabeled with (99m)Tc and characterized by ITLC and high-performance liquid chromatography (HPLC). In vitro studies were carried out in sstr2 expressing AR4-2J cell lines. In vivo distribution studies were performed in rats bearing the AR4-2J tumor. The radiolabeled complex could be prepared at high-specific activities and >95% radiochemical yield as determined by HPLC. The peptide conjugate showed high-affinity binding for sstr2. The radioligand showed high and specific internalization into AR4-2J cells (18.19%±0.21% at 4 hours). In vivo distribution studies in rats bearing tumor have shown a receptor-specific uptake of radioactivity in somatostatin receptor-positive organs. After 4 hours, uptake in the AR4-2J tumor was 1.71%±0.36% injected dose per gram tissue (%ID/g). These data show that [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies.

NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia

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Fatemah Alherz

2017-06-01

Full Text Available This review investigates the association between N-methyl-d-Aspartate receptor (NMDAR hypofunction and somatostatin-expressing GABAergic interneurons (SST+ and how it contributes to the cognitive deficits observed in schizophrenia (SZ. This is based on evidence that NMDAR antagonists caused symptoms resembling SZ in healthy individuals. NMDAR hypofunction in GABAergic interneurons results in the modulation of the cortical network oscillation, particularly in the gamma range (30–80 Hz. These gamma-band oscillation (GBO abnormalities were found to lead to the cognitive deficits observed in the disorder. Postmortem mRNA studies have shown that SST decreased more significantly than any other biomarker in schizophrenic subjects. The functional role of Somatostatin (SST in the aetiology of SZ can be studied through its receptors. Genetic knockout studies in animal models in Huntington's disease (HD have shown that a specific SST receptor, SSTR2, is increased along with the increased NMDAR activity, with opposing patterns observed in SZ. A direct correlation between SSTR and NMDAR is hence inferred in this review with the hope of finding a potential new therapeutic target for the treatment of SZ and related neurological conditions.

Detecting somatostatin receptor in breast tumor tissue and its clinical significance

International Nuclear Information System (INIS)

Zhang Yongjian; Yu Xian; Lin Wei; Ding Xuan; Huang Shizhang; Lu Guangming

2002-01-01

The authors observe the difference of somatostatin receptor (SSR) between benign and malignant breast tumor and the relation between SSR and estrogen receptor (ER) or progesterone receptor (PR) in breast tumor tissue, and to predict the clinical value of detecting breast tumor by SSR receptor imaging. These tissues excised from operation in breast tumor were divided into 4 groups: breast malignant tumor group (BMTG) and its control group (C1G), breast benign tumor group (BBTG) and its control group (C2G). SSR was detected by radioligand binding assay (RBA) and ER, PR by LsAB method in these groups. Results is: (1) The SSR express quantity is 108.6 +- 67.3 fmol/mg pr, 37.2 +- 9.6 fmol/mg pr, 43.4 +- 12.6 fmol/mg pr 33.9 +- 10.2 fmol/mg pr respectively in BMTG, C1G, BBTG, C2G. The SSR of BMTG is the most among these groups, the difference is obvious, P 0.05); (2) The correlation coefficient of SSR and ER is 0.859, SSR and PR is 0.750. Most breast tumor tissues express high density SSR, the authors suppose that malignant tumor can been distinguished from benign tumor preliminarily by SSR receptor imaging. There is a good correlation between SSR and ER, PR, detecting SSR may predict the quality of tumor and the prognosis of the patient

Multiparametric PET imaging in thyroid malignancy characterizing tumour heterogeneity: somatostatin receptors and glucose metabolism

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Traub-Weidinger, Tatjana [Medical University of Vienna, Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Putzer, Daniel; Bale, Reto [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Guggenberg, Elisabeth von; Dobrozemsky, Georg; Nilica, Bernhard; Kendler, Dorota; Virgolini, Irene Johanna [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

2015-12-15

Radiolabelled somatostatin (SST) analogues have proven useful in diagnosing tumours positive for SST receptor (SSTR). As different subtypes of SSTR are expressed on the tumour cell surface, the choice of appropriate therapeutic SST analogue is crucial. We evaluated the SSTR status of thyroid cancer patients who had signs of progressive disease comparing different SSTR ligands for PET imaging to evaluate possible further therapeutic options. PET with {sup 68}Ga-radiolabelled SSTR ligands DOTA lanreotide (DOTA-LAN), DOTA-Tyr{sup 3} octreotide (DOTA-TOC) and {sup 18}F-FDG was performed in 31 patients with thyroid cancer (TC). These 31 patients comprised 18 with radioiodine non-avid differentiated TC (DTC) including 6 papillary TC (PTC), 8 follicular TC (FTC) and 4 oxyphilic TC (oxyTC), 5 with anaplastic TC (ATC), and 8 with medullary TC (MTC). The PET results were compared in a region-based evaluation. All patients underwent a PET study with {sup 68}Ga-DOTA-LAN, 28 patients with {sup 68}Ga-DOTA-TOC and 28 patients with {sup 18}F-FDG. A lack of SSTR expression was found in 13 of the 31 patients (42 %) with negative results with both SSTR tracers in 12 patients. Ambiguous results with both SSTR tracers were observed in one patient. High tracer uptake in SSTR PET images was seen in seven DTC patients (39 %; two PTC, three FTC, two oxyTC), in four ATC patients (80 %) and in six MTC patients (75 %). Lesions showing aerobic glycolysis on {sup 18}F-FDG PET were found in 24 of 28 patients (86 %) with corresponding positive results with {sup 68}Ga-DOTA-LAN in 35 % and with {sup 68}Ga-DOTA-TOC in 29 %. The heterogeneous SSTR profile of TC tumour lesions needs to be evaluated using different SSTR PET tracers to characterize more closely the SSTR subtype affinities in patients with progressive TC in order to further stratify therapy with SSTR therapeutics. (orig.)

“In-house” preparation of 99mTc-EDDA/HYNIC-TOC, a specific targeting agent for somatostatin receptor scintigraphy

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Sonja Kuzmanovska

2012-01-01

Full Text Available The use of radiolabeled peptide ligands as diagnostics and therapeutics in nuclear oncology has increased recently. One of the most frequently used radiopharmaceutical is 99mTc-EDDA/HYNIC-TOC, a somatostatin analog with affinity for certain types of somatostatin receptors, overexpressed in tumors of neuroendocrine origin. The radiopharmaceutical is not readily available; therefore we introduced its “in house” preparation within project activities supported by the International Atomic Energy Agency (IAEA. We optimized the radiolabeling protocol, prepared a small batch of frozen kits, performed ITLC quality control and animal biodistribution during the preclinical evaluation procedures. The co-ligand exchange labeling procedure was carried out at 100°C during 10 min, resulting in radiochemical purity >90%. The biodistribution scintigrams in normal Wistar rats showed rapid blood clearance after 15 min and predominant kidney accumulation after 4 h, in accordance with the data reported by other authors. Storage stability of the formulated small batch frozen kit (-20°C was evaluated within 6 months, with radiolabeling yield ranging between 94,3% and 96,9%. We conclude that frozen kit can be a safe alternative to the freeze-dried for small batch in house production, and after the satisfactory preclinical evaluation, the “in house” prepared 99mTc-EDDA/ HYNIC-TOC can be introduced in clinical practice as specific targeting agent for somatostatin receptor scintigraphy.

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors.

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Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-08-01

Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), 1-Nal(3), Thr(8)]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with (99m)Tc was performed at 100 degrees C for 10 min using SnCl(2) as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr(2)-expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr(2). The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13+/-0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33+/-0.23%ID/g (percentage of injected dose per gram of tissue). These data show that [(99m)Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies.

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors

International Nuclear Information System (INIS)

Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-01-01

Purpose: Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with 99m Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC 0 ), 1-Nal 3 , Thr 8 ]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Methods: Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with 99m Tc was performed at 100 o C for 10 min using SnCl 2 as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr 2 -expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Results: Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr 2 . The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13±0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33±0.23%ID/g (percentage of injected dose per gram of tissue). Conclusion: These data show that [ 99m Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies

NCBI nr-aa BLAST: CBRC-TSYR-01-0849 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-TSYR-01-0849 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 87% ...

NCBI nr-aa BLAST: CBRC-PVAM-01-1207 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PVAM-01-1207 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 87% ...

NCBI nr-aa BLAST: CBRC-PHAM-01-1593 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PHAM-01-1593 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 86% ...

99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors.

Science.gov (United States)

Trogrlic, Mate; Tezak, Stanko

2016-01-01

Aim of this study was to determine the value of technetium-99m-hydrazinonicotinyl-Tyr3-octreotide (99mTc-ED-DA/HYNIC-TOC) in patients with somatostatin receptor (SSR) positive tumors of head and neck region. A total number of 16 patients were enrolled in this study. Planar whole body (WB) and single photon emission computed tomography (SPECT) images were acquired at 2 and 4 hours after the injection of approximately 670 MBq of 99mTc-EDDA/HYNIC-TOC. Additional single photon emission computed tomography/computed tomography (SPECT/CT) images of the head and neck region were acquired at 4h post tracer injection. Clinical and imaging follow up were taken as the reference standard. There were 10 female and 6 male patients of age 57.7 ± 12.9 years (58.5; 32-78) years. 99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy (SRS) was TP in 13 patients, TN in two and FP in one. Follow up period for SRS was 31.1 ± 19.4 (29; 2-63) months. 99mTc-EDDA/HYNIC-TOC scintigraphy provided additional information in 50% of patients, with impact on patient management in the same percentage of patients. Distant metastases were found in nine out of 16 patients (56%). 99mTc-EDDA/HYNIC-TOC SRS had sensitivity of 100% (75.3-100%), specificity of 66.7% (9.4-99.2%), accuracy of 93.7%, positive predictive value of 92.9% (66.1-99.8%), and negative predictive value of 100% (15.8-100%). Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC is very useful imaging method in the evalu-ation of patients with SSR positive tumors of head and neck region.

NCBI nr-aa BLAST: CBRC-GGOR-01-1250 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-GGOR-01-1250 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-119 80% ...

NCBI nr-aa BLAST: CBRC-MEUG-01-0329 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MEUG-01-0329 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-160 73% ...

NCBI nr-aa BLAST: CBRC-MLUC-01-0637 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MLUC-01-0637 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-165 90% ...

Gene specific actions of thyroid hormone receptor subtypes.

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Jean Z Lin

Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

Characterization of somatostatin receptors and associated signaling pathways in pancreas of R6/2 transgenic mice.

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Somvanshi, Rishi K; Jhajj, Amrit; Heer, Michael; Kumar, Ujendra

2018-02-01

The present study describes the status of somatostatin receptors (SSTRs) and their colocalization with insulin (β), glucagon (α) and somatostatin (δ) producing cells in the pancreatic islets of 11weeks old R6/2 Huntington's Disease transgenic (HD tg) and age-matched wild type (wt) mice. We also determined expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and presynaptic marker synaptophysin (SYP) in addition to signal transduction pathways associated with diabetes. In R6/2 mice, islets are relatively smaller in size, exhibit enhanced expression and nuclear inclusion of mHtt along with the loss of insulin, glucagon and somatostatin expression. In comparison to wt, R6/2 mice display enhanced mRNA for all SSTRs except SSTR2. In the pancreatic lysate, SSTR1, 4 and 5 immunoreactivity decreases whereas SSTR3 immunoreactivity increases with no discernible changes in SSTR2 immunoreactivity. Furthermore, at the cellular level, R6/2 mice exhibit a receptor specific distributional pattern of SSTRs like immunoreactivity and colocalization with β, α and δ cells. While GAD expression is increased, TH and SYP immunoreactivity was decreased in R6/2 mice, anticipating a cross-talk between the CNS and pancreas in diabetes pathophysiology. We also dissected out the changes in signaling pathway and found decreased activation and expression of PKA, AKT, ERK1/2 and STAT3 in R6/2 mice pancreas. These findings suggest that the impaired organization of SSTRs within islets may lead to perturbed hormonal regulation and signaling. These interconnected complex events might shed new light on the pathogenesis of diabetes in neurodegenerative diseases and the role of SSTRs in potential therapeutic intervention. Copyright © 2017 Elsevier B.V. All rights reserved.

Ectopic Expression of α6 and δ GABAA Receptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

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Tong, Xiaoping; Peng, Zechun; Zhang, Nianhui; Cetina, Yliana; Huang, Christine S.; Wallner, Martin; Otis, Thomas S.

2015-01-01

The role of GABAA receptor (GABAAR)-mediated tonic inhibition in interneurons remains unclear and may vary among subgroups. Somatostatin (SOM) interneurons in the hilus of the dentate gyrus show negligible expression of nonsynaptic GABAAR subunits and very low tonic inhibition. To determine the effects of ectopic expression of tonic GABAAR subtypes in these neurons, Cre-dependent viral vectors were used to express GFP-tagged GABAAR subunits (α6 and δ) selectively in hilar SOM neurons in SOM-Cre mice. In single-transfected animals, immunohistochemistry demonstrated strong expression of either the α6 or δ subunit; in cotransfected animals, both subunits were consistently expressed in the same neurons. Electrophysiology revealed a robust increase of tonic current, with progressively larger increases following transfection of δ, α6, and α6/δ subunits, respectively, indicating formation of functional receptors in all conditions and likely coassembly of the subunits in the same receptor following cotransfection. An in vitro model of repetitive bursting was used to determine the effects of increased tonic inhibition in hilar SOM interneurons on circuit activity in the dentate gyrus. Upon cotransfection, the frequency of GABAAR-mediated bursting in granule cells was reduced, consistent with a reduction in synchronous firing among hilar SOM interneurons. Moreover, in vivo studies of Fos expression demonstrated reduced activation of α6/δ-cotransfected neurons following acute seizure induction by pentylenetetrazole. The findings demonstrate that increasing tonic inhibition in hilar SOM interneurons can alter dentate gyrus circuit activity during strong stimulation and suggest that tonic inhibition of interneurons could play a role in regulating excessive synchrony within the network. SIGNIFICANCE STATEMENT In contrast to many hippocampal interneurons, somatostatin (SOM) neurons in the hilus of the dentate gyrus have very low levels of nonsynaptic GABAARs and exhibit

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy

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Kaemmerer, Daniel; Träger, Tina; Hoffmeister, Maike; Sipos, Bence; Hommann, Merten; Sänger, Järg; Schulz, Stefan; Lupp, Amelie

2015-01-01

Introduction Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies. PMID:26259237

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

OpenAIRE

Andreas Stengel; Yvette F. Taché; Yvette F. Taché

2017-01-01

Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a br...

Identification of Receptor Ligands and Receptor Subtypes Using Antagonists in a Capillary Electrophoresis Single-Cell Biosensor Separation System

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Fishman, Harvey A.; Orwar, Owe; Scheller, Richard H.; Zare, Richard N.

1995-08-01

A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3 acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B_2 receptor subtype (B_2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B_2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

Examination of the somatostatin receptor status in non-medullary thyroid cancer; Untersuchungen zum Somatostatinrezeptor-Status bei nicht-medullaeren Schilddruesenkarzinomen

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Goerges, R.; Brandt-Mainz, K.; Bockisch, A. [Essen Univ. (Gesamthochschule) (Germany). Klinik und Poliklinik fuer Nuklearmedizin; Kahaly, G. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Medizin - Endokrinologie und Stoffwechselerkrankungen; Mueller-Brand, J.; Maecke, H. [Kantonsspital Basel (Switzerland). Inst. fuer Nuklearmedizin; Walgenbach, S. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Allgemein- und Abdominalchirurgie; Bruns, C. [Praeklinische Forschung Novartis, Basel (Switzerland); Andreas, J. [Universitaetsklinik Mainz (Germany). Klinik und Poliklinik fuer Nuklearmedizin

1999-06-01

Aim: Recent in-vitro and in-vivo studies demonstrated a somatostatin receptor expression in some non-medullary thyroid carcinomas. In this study we investigated the somatostatin receptor status for this particular tumor entity in a larger patient group. Subject and methods: We compared 131-iodine with 111-In-pentetreotide scans in 24 patients with metastasizing, non-medullary thyroid cancer. The findings were correlated with other imaging modalities. Additionally, we performed receptor autoradiography in one patient, octreotide therapy in another patient and administration of 90-Y- and 111-In-DOTATOC in 2 consecutive patients. Results: In the 15 patients with papillary or follicular carcinoma, 111-In-pentetreotide was inferior to 131-I in 8/15, equal in 1/15, and superior in 6/15 patients. In 8/9 of the patients with Huerthle cell cacinoma, metastases showed a 111-In-pentetreotide accumulation of various intensity, while 131-iodine scans were negative except for one patient. 111-In-pentetreotide was equal or superior compared to 201-Tl or 99m-Tc-sestamibi, but for the most part inferior in comparison with 18-F-FDG-PET. The findings of 111-In-pentetreotide scintigraphy correlated well with the receptor autoradiography and the accumulation of DOTATOC, but not with the therapeutic effect of `cold` octreotide on the thyroid cancer metastases. Conclusions: Several metastases of papillary and follicular carcinoma, and the majority of Huerthle cell cancer metastases can express somatostatin receptors. 111-In-pentetreotide scintigraphy is a promising tool for localization of metastases especially in Huerthle cell cancer or if PET is not available, and may be useful for selection of possible candidates, if therapeutic effective {beta}-emitting somatostatin analogues will be available for routine application. (orig.) [Deutsch] Ziel: in aktuellen In-vitro und In-vivo-Untersuchungen wurde eine Somatostatinrezeptor-Expression bei einigen nicht

Synthesis and evaluation of ligand targeting the somatostatin receptor for drug delivery to tumor cell

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Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-12-15

Most of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells to produce its cytotoxic effect. Either small molecule drugs or monoclonal antibodies are mostly used in targeted therapies. Unfortunately, targeted therapy has a certain degree of unwanted side effect like other cytotoxicity inducing chemotherapies. To overcome and to reduce unwanted side effects during a cancer therapy, recently radiopeptide therapies has got the worlds' attraction for the tumor targeting modalities due to its beneficial effect on less side effect compared to cytotoxic chemotherapies. Among radiopeptide therapies, {sup 177}Lu-DOTATATE is a major modality as an effective one invented so far in treating neuroendocrine tumor (NET) and it has been in clinical trials at least one decade. Although it does have rather effective therapeutic effect on NET, it has less effective in rather large solid tumor. There are many ways to improve or increase therapeutic effect of radiopeptide are a finding the potent small molecules to target the tumor site selectively, or a labeling with radioisotope of emitting high energy, or an improving its biological half-life by introducing different moieties to increase lipophilicity. Present study was focus to increase a biological halflife of radio somatostatin which will target the somatostatin receptor by altering the bifunctional chelator (BFCA) by introducing lipophilic moiety to the somatostatin, which would make the labeled peptide stay longer in the tumor site and thus it can intensify the therapeutic effect on tumor cell itself and around tissues.

Differential Expression of Dopamine D5 Receptors across Neuronal Subtypes in Macaque Frontal Eye Field

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Adrienne Mueller

2018-02-01

Full Text Available Dopamine signaling in the prefrontal cortex (PFC is important for cognitive functions, yet very little is known about the expression of the D5 class of dopamine receptors (D5Rs in this region. To address this, we co-stained for D5Rs, pyramidal neurons (neurogranin+, putative long-range projection pyramidal neurons (SMI-32+, and several classes of inhibitory interneuron (parvalbumin+, calbindin+, calretinin+, somatostatin+ within the frontal eye field (FEF: an area within the PFC involved in the control of visual spatial attention. We then quantified the co-expression of D5Rs with markers of different cell types across different layers of the FEF. We show that: (1 D5Rs are more prevalent on pyramidal neurons than on inhibitory interneurons. (2 D5Rs are disproportionately expressed on putative long-range projecting pyramidal neurons. The disproportionately high expression of D5Rs on long-range projecting pyramidals, compared to interneurons, was particularly pronounced in layers II–III. Together these results indicate that the engagement of D5R-dependent mechanisms in the FEF varies depending on cell type and cortical layer, and suggests that non-locally projecting neurons contribute disproportionately to functions involving the D5R subtype.

Nicotine Receptor Subtype-Specific Effects on Auditory Evoked Oscillations and Potentials

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Featherstone, Robert E.; Phillips, Jennifer M.; Thieu, Tony; Ehrlichman, Richard S.; Halene, Tobias B.; Leiser, Steven C.; Christian, Edward; Johnson, Edwin; Lerman, Caryn; Siegel, Steven J.

2012-01-01

Background Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. Methodology/Principal Findings We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma. Conclusions/Significance These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2

Sensitive radioimmunoassay for somatostatin using N-(/sup 125/I)-tyr-somatostatin as labelled antigen

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Dupont, A [CHUL, Quebec (Canada). Lab. of Molecular Endocrinology and Service of Gastro-Enterology; Coy, D H; Alvarado-Urbina, G; Cote, J; Meyers, C A; McManus, J; Barden, N; De Lean, A; Labrie, F

1979-01-01

A sensitive radioimmunoassay for somatostatin using N-(/sup 125/I)-Tyr-somatostatin is described and compared with using (/sup 125/I)-Tyr/sup 1/-somatostatin. The minimum detectable amount of somatostatin using N-(/sup 125/I)-Tyr-somatostatin as tracer was 0.1 to 0.5 pg, which is approximately 10-fold lower detection limit of the RIA using (/sup 125/I)-Tyr/sup 1/-somatostatin. Moreover, it was found that the shelf-life of N-(/sup 125/I)-Tyr-somatostatin was prolonged in comparison with labelled Tyr/sup 1/-somatostatin. Human pancreatic and gastric extracts displayed immunological similarity to synthetic somatostatin tetradecapeptide.

Preliminary clinical evaluation of Somatostatin Receptor Scintigraphy (SRS) with 99mTc-EDDA/HYNIC-TATE in comparison to 111In-Octreoscan and 131 I MIBG scans

International Nuclear Information System (INIS)

Hubalewska, A.; Fross, K.; Staszczak, A.; Huszno, B.; Mikolajczak, R.; Gorska, A.

2004-01-01

Full text: Over expression of somatostatin receptors in various neuroendocrine tumours prompted development of somatostatin analogues, which after radioactive labelling, could be used in oncological diagnostics. Somatostatin Receptor Positive Tumour (Spt) imaging with 111In-DTPA-DPhe1- octreotide (111In-Octreoscan) has become a widely used diagnostic procedure in clinical nuclear medicine. However 111In as a radiolabel has several drawbacks, including limited availability, sub optimal gamma energy and high radiation burden to the patient. Technetium (99mTc) labelling of somatostatin analogues is especially attractive due to the ready availability of 99mTc from generators and its well recognised favourable imaging characteristics. HYNIC conjugated Tyr 3 -Octreotate (HYNIC-TATE) prepared in our laboratory in a dry kit form was labelled with technetium-99mTc, with tricine and EDDA used as coligands. Tyr3-octreotate differs from octreotide (OC) by more hydrophilic tyrosine in the third position and the terminal threonine, which replaced threoninol present in OC. In vitro studies using cell lines transfected with somatostatin receptors (SSTR) revealed that octreotate shows 14- 17 times better binding affinity for SSTR type 2 than does OC. It is expected to clear more rapidly from non-target tissues as a result of the carboxylic group at the C-terminal of the peptide. HYNIC has been used as bifunctional chelator in 99mTc-HYNIC-Tyr3-octreotide (TOC) by Maecke and Behe, who reported on its favourable preclinical characteristics when EDDA was used as a co-ligand. These pre-clinical data were confirmed by Decristoforo and Mather and their early clinical studies appeared recently. The new radiopharmaceutical - 99mTc-DDA/HYNICTATE was evaluated in-vitro and in-vivo in an animal model and its potential for SSTR scintigraphy was documented. In the current patient study the diagnostic usefulness of the new radiopharmaceutical was tested for detection of tumours expressing SSTR

Cockroach GABAB receptor subtypes: molecular characterization, pharmacological properties and tissue distribution.

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Blankenburg, S; Balfanz, S; Hayashi, Y; Shigenobu, S; Miura, T; Baumann, O; Baumann, A; Blenau, W

2015-01-01

γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the central nervous system (CNS). Its effects are mediated by either ionotropic GABAA receptors or metabotropic GABAB receptors. GABAB receptors regulate, via Gi/o G-proteins, ion channels, and adenylyl cyclases. In humans, GABAB receptor subtypes are involved in the etiology of neurologic and psychiatric disorders. In arthropods, however, these members of the G-protein-coupled receptor family are only inadequately characterized. Interestingly, physiological data have revealed important functions of GABAB receptors in the American cockroach, Periplaneta americana. We have cloned cDNAs coding for putative GABAB receptor subtypes 1 and 2 of P. americana (PeaGB1 and PeaGB2). When both receptor proteins are co-expressed in mammalian cells, activation of the receptor heteromer with GABA leads to a dose-dependent decrease in cAMP production. The pharmacological profile differs from that of mammalian and Drosophila GABAB receptors. Western blot analyses with polyclonal antibodies have revealed the expression of PeaGB1 and PeaGB2 in the CNS of the American cockroach. In addition to the widespread distribution in the brain, PeaGB1 is expressed in salivary glands and male accessory glands. Notably, PeaGB1-like immunoreactivity has been detected in the GABAergic salivary neuron 2, suggesting that GABAB receptors act as autoreceptors in this neuron. Copyright © 2014 Elsevier Ltd. All rights reserved.

Normal uptake of 68Ga-DOTA-TOC by the pancreas uncinate process mimicking malignancy at somatostatin receptor PET.

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Jacobsson, Hans; Larsson, Patricia; Jonsson, Cathrine; Jussing, Emma; Grybäck, Per

2012-04-01

To characterize a commonly occurring increased uptake by the uncinate process of the pancreas at PET/CT using 68Ga-DOTA-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC). This tracer has replaced In pentetreotide (OctreoScan®) for somatostatin receptor scintigraphy at our laboratory. Fifty of our first 74 PET/CT examinations with 68Ga-DOTA-TOC could be evaluated in retrospect. None of these patients had surgery or showed any pathology in the pancreas head at the concomitant CT. Thirty-five of the 50 examinations (70%) showed an uptake by the uncinate process sufficiently intense to be interpreted as pathologic and simulating a tumor. Mean SUVmax was 9.2. Mean SUVmean using an isoactivity cut-off of >75% and >50% was 7.8 and 6.0, respectively. Volume calculations of the uncinate process activity using these definitions gave 0.9 mL and 4.2 mL, respectively. There is a frequent physiological uptake of 68Ga-DOTA-TOC by the pancreas uncinate process. This may be caused by an accumulation of pancreatic polypeptide-containing cells expressing somatostatin receptors. If there is a normal finding at concomitant diagnostic CT, this uptake should be regarded as physiological.

Characterization of muscarinic receptor subtypes in human tissues

International Nuclear Information System (INIS)

Giraldo, E.; Martos, F.; Gomez, A.; Garcia, A.; Vigano, M.A.; Ladinsky, H.; Sanchez de La Cuesta, F.

1988-01-01

The affinities of selective, pirenzepine and AF-DX 116, and classical, N-methylscopolamine and atropine, muscarinic cholinergic receptor antagonists were investigated in displacement binding experiments with [ 3 H]Pirenzepine and [ 3 H]N-methylscopolamine in membranes from human autoptic tissues (forebrain, cerebellum, atria, ventricle and submaxillary salivary glands). Affinity estimates of N-methylscopolamine and atropine indicated a non-selective profile. Pirenzepine showed differentiation between the M 1 neuronal receptor of the forebrain and the receptors in other tissues while AF-DX 116 clearly discriminated between muscarinic receptors of heart and glands. The results in human tissues confirm the previously described selectivity profiles of pirenzepine and AF-DX 116 in rat tissues. These findings thus reveal the presence also in man of three distinct muscarinic receptor subtypes: the neuronal M 1 , the cardiac M 2 and the glandular M 3

Histamine receptors in human detrusor smooth muscle cells: physiological properties and immunohistochemical representation of subtypes.

Science.gov (United States)

Neuhaus, Jochen; Weimann, Annett; Stolzenburg, Jens-Uwe; Dawood, Waled; Schwalenberg, Thilo; Dorschner, Wolfgang

2006-06-01

The potent inflammatory mediator histamine is released from activated mast cells in interstitial cystitis (IC). Here, we report on the histamine receptor subtypes involved in the intracellular calcium response of cultured smooth muscle cells (cSMC). Fura-2 was used to monitor the calcium response in cSMC, cultured from human detrusor biopsies. The distribution of histamine receptor subtypes was addressed by immunocytochemistry in situ and in vitro. Histamine stimulated a maximum of 92% of the cells (n=335), being more effective than carbachol (70%, n=920). HTMT (H1R-agonist), dimaprit (H2R) and MTH (H3R) lead to significant lower numbers of reacting cells (60, 48 and 54%). Histamine receptor immunoreactivity (H1R, H2R, H3R, H4R) was found in situ and in vitro. Histamine-induced calcium increase is mediated by distinct histamine receptors. Thus, pre-therapeutic evaluation of histamine receptor expression in IC patients may help to optimize therapy by using a patient-specific cocktail of subtype-specific histamine receptor antagonists.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

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Zhang, Libo; Vines, Douglass C; Scollard, Deborah A; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68 Ga-DOTA-TATE uptake and 177 Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68 Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68 Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177 Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro , NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131 I-MIBG therapy, low 123 I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68 Ga-DOTA-TATE uptake and antitumor efficacy of 177 Lu-DOTA-TATE. 68 Ga-DOTA-TATE PET is superior to 123 I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177 Lu-DOTA-TATE therapy.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

Directory of Open Access Journals (Sweden)

Libo Zhang

2017-01-01

Full Text Available Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2 expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15 compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2. Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal, tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET, a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

Quantitative Assessment of 99mTc-Depreotide Uptake in Oesophageal Cancer and Precursor Conditions and Its Reflection in Immunohistochemically Detected Somatostatin Receptors

International Nuclear Information System (INIS)

Herlin, G.; Aspelin, P.; Axelsson, R.; Herlin, G.; Aspelin, P.; Axelsson, R.; Lundell, L.; Ost, A.; Svensson, L.

2012-01-01

Background. Somatostatin receptors (SSTRs) are over-expressed in several tumors making it possible for imaging with labelled SSTR. A previous study showed feasibility to image oesophageal cancer with SSTR analogue 99m Tc-depreotide. Purpose. (1) To investigate expression of the SSTRs in different types of esophageal carcinoma and (2) to correlate such an expression with 99m Tc-depreotide uptake in these lesions. Material and Methods. Total 28 patients (17 with esophageal cancer and 11 with Barrett’s esophagus) were examined with 99m Tc-depreotide scintigraphy. The SSTR2A, SSTR2B, SSTR3, and SSTR5 were analyzed immunohistochemically in the lesion samples. Results. Among the patients with adenocarcinoma 10/11 expressed different amounts of SSTRs, while SSTRs were absent in 5/6 patients with Squamous cell carcinoma (Sqcc). There was no correlation neither between the 99m Tc-depreotide uptake and the amount of SSTRs nor between the amount of SSTRs and differentiation grade of the tumor. Conclusions. (1) SSTRs are expressed in esophageal carcinoma and more abundantly so in adenocancer specimens; (2) in vivo 99m Tc-depreotide uptake does not obviously correlate with the immunohistochemically detection of SSTRs of different subtypes in esophageal carcinoma.

Quantitative Assessment of 99mTc-Depreotide Uptake in Oesophageal Cancer and Precursor Conditions and Its Reflection in Immunohistochemically Detected Somatostatin Receptors

International Nuclear Information System (INIS)

Herlin, Gunnar; Lundell, Lars; Öst, Åke; Aspelin, Peter; Svensson, Leif; Axelsson, Rimma

2012-01-01

Background. Somatostatin receptors (SSTRs) are over-expressed in several tumors making it possible for imaging with labelled SSTR. A previous study showed feasibility to image oesophageal cancer with SSTR analogue 99m Tc-depreotide. Purpose. (1) To investigate expression of the SSTRs in different types of esophageal carcinoma and (2) to correlate such an expression with 99m Tc-depreotide uptake in these lesions. Material and Methods. Total 28 patients (17 with esophageal cancer and 11 with Barrett's esophagus) were examined with 99m Tc-depreotide scintigraphy. The SSTR2A, SSTR2B, SSTR3, and SSTR5 were analyzed immunohistochemically in the lesion samples. Results. Among the patients with adenocarcinoma 10/11 expressed different amounts of SSTRs, while SSTRs were absent in 5/6 patients with Squamous cell carcinoma (Sqcc). There was no correlation neither between the 99m Tc-depreotide uptake and the amount of SSTRs nor between the amount of SSTRs and differentiation grade of the tumor. Conclusions. (1) SSTRs are expressed in esophageal carcinoma and more abundantly so in adenocancer specimens; (2) in vivo 99m Tc-depreotide uptake does not obviously correlate with the immunohistochemically detection of SSTRs of different subtypes in esophageal carcinoma

Impact of the scintigraphy of somatostatin receptors upon the therapeutic strategy in patients bearing digestive endocrine tumors

International Nuclear Information System (INIS)

Lebtahi, R.; Cadiot, G.; Genin, R.; Delahaye, N.; Faraggi, M.; Daou, D.; Peker, C.; Migon, M.; Le Guludec, D.

1997-01-01

The scintigraphy of somatostatin receptors (SSR) is a sensible method for detecting the gastroenteric-pancreatic endocrine tumors and their metastases. The aim of this study is to evaluate the clinical impact of the results of SSR in taking patients in therapeutic charge. A hundred and sixty patients bearing biologically and/or histologically proved digestive endocrine tumors were prospectively studied. The patients were classified in 3 groups: group I - 90 patients with no known metastases; group II - 59 patients with liver metastases and group III - 11 patients with known extra-hepatic metastases. The results of the scintigraphy were compared with those of conventional imaging. The following results were obtained: in group 1 (90 patients) the conventional imaging has allowed detecting 53 primitive tumors in 44 patients. The SSR visualized 68% of these sites and has detected 26 supplementary primitive sites in 20 patients and 29 metastatic sites in 25 patients. In group II the scintigraphy has detected 95% of hepatic metastases and revealed 23 new metastasis sites and 18/59 patients. In group III the scintigraphy has detected 11 new sites in 7 patients. The results of scintigraphy modified the patient's classification in 38 cases (24%). The therapeutic strategy was modified for 40 patients (25%). In conclusion, the scintigraphy of somatostatin receptors is able to detect a significant number of digestive endocrine tumors what has important implications for therapeutical planning of the treatment of patients. It must be carried out during pre-therapeutic extension examination of these tumors

Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions.

Science.gov (United States)

Perianes-Cachero, A; Burgos-Ramos, E; Puebla-Jiménez, L; Canelles, S; Frago, L M; Hervás-Aguilar, A; de Frutos, S; Toledo-Lobo, M V; Mela, V; Viveros, M P; Argente, J; Chowen, J A; Arilla-Ferreiro, E; Barrios, V

2013-11-12

Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain

Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

Science.gov (United States)

Nutt, David J; Besson, Marie; Wilson, Susan J; Dawson, Gerard R; Lingford-Hughes, Anne R

2007-12-01

Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.

Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjögren's syndrome treated with Infliximab: a pilot study.

Science.gov (United States)

Anzola-Fuentes, L K; Chianelli, M; Galli, F; Glaudemans, A W J M; Martin Martin, L; Todino, V; Migliore, A; Signore, A

2016-12-01

Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue ((99m)Tc-EDDA/tricine-HYNIC-tyr(3)-octreotide ((99m)Tc-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjögren's syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment. Eighteen patients with rheumatoid arthritis and secondary Sjögren's syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-α. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer's test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3-6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of (99m)Tc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively. All patients showed uptake of (99m)Tc-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands. SRS using (99m)Tc-EDDA/HYNIC-TOC may be a useful imaging tool to assess

Subtype-dependent postnatal development of taste receptor cells in mouse fungiform taste buds.

Science.gov (United States)

Ohtubo, Yoshitaka; Iwamoto, Masafumi; Yoshii, Kiyonori

2012-06-01

Taste buds contain two types of taste receptor cells, inositol 1,4,5-triphosphate receptor type 3-immunoreactive cells (type II cells) and synaptosomal-associating protein-25-immunoreactive cells (type III cells). We investigated their postnatal development in mouse fungiform taste buds immunohistochemically and electrophysiologically. The cell density, i.e. the number of cells per taste bud divided by the maximal area of the horizontal cross-section of the taste bud, of type II cells increased by postnatal day (PD)49, where as that of type III cells was unchanged throughout the postnatal observation period and was equal to that of the adult cells at PD1. The immunoreactivity of taste bud cell subtypes was the same as that of their respective subtypes in adult mice throughout the postnatal observation period. Almost all type II cells were immunoreactive to gustducin at PD1, and then the ratio of gustducin-immunoreactive type II cells to all type II cells decreased to a saturation level, ∼60% of all type II cells, by PD15. Type II and III cells generated voltage-gated currents similar to their respective adult cells even at PD3. These results show that infant taste receptor cells are as excitable as those of adults and propagate in a subtype-dependent manner. The relationship between the ratio of each taste receptor cell subtype to all cells and taste nerve responses are discussed. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

Energy Technology Data Exchange (ETDEWEB)

Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)

2013-12-06

Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma.

Science.gov (United States)

Czepczyński, Rafał; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikołajczak, Renata; Ziemnicka, Katarzyna; Gryczyńska, Maria; Sowiński, Jerzy; Signore, Alberto

2007-10-01

Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue (99m)Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using (99m)Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, (99m)Tc(V)-DMSA, (131)I-MIBG, (99m)Tc-MDP, (111)In-DTPA-octreotide and (18)F-FDG-PET) and compared with (99m)Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using (99m)Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. (99m)Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making.

Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

International Nuclear Information System (INIS)

Czepczynski, Rafal; Kosowicz, Jerzy; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Parisella, Maria G.; Mikolajczak, Renata; Signore, Alberto

2007-01-01

Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue 99m Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using 99m Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, 99m Tc(V)-DMSA, 131 I-MIBG, 99m Tc-MDP, 111 In-DTPA-octreotide and 18 F-FDG-PET) and compared with 99m Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using 99m Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. 99m Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making. (orig.)

Breast cancer imaging using radiolabelled somatostatin analogues

International Nuclear Information System (INIS)

Dalm, Simone U.; Melis, Marleen; Emmering, Jasper; Kwekkeboom, Dik J.; Jong, Marion de

2016-01-01

Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Since these techniques were first introduced, many improvements have been made. SSTR expression has also been reported on breast cancer (BC). Currently mammography, magnetic resonance imaging and ultrasound are the most frequent methods used for BC imaging. Since SSTR expression on BC was demonstrated, clinical studies examining the feasibility of visualizing primary BC using SSTR radioligands have been performed. However, to date SSTR-mediated nuclear imaging is not used clinically in BC patients. The aim of this review is to assess whether recent improvements made within nuclear medicine may enable SSTR-mediated imaging to play a role in BC management. For this we critically analysed results of past studies and discussed the potential of the improvements made within nuclear medicine on SSTR-mediated nuclear imaging of BC. Seven databases were searched for publications on BC imaging with SSTR radioligands. The papers found were analysed by 3 individual observers to identify whether the studies met the pre-set inclusion criteria defined as studies in which nuclear imaging using radiolabelled SST analogues was performed in patients with breast lesions. Twenty-four papers were selected for this review including studies on SSTR-mediated nuclear imaging in BC, neuroendocrine BC and other breast lesions. The analysed studies were heterogeneous with respect to the imaging method, imaging protocol, patient groups and the radiolabelled SST analogues used. Despite the fact that the analysed studies were heterogeneous, sensitivity for primary BC ranged from 36–100%. In a subset of the studies LN lesions were visualized, but sensitivity was lower compared to that for primary tumours. A part of the studies included benign lesions and specificity ranged from 22–100%. Furthermore, false negatives and

Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome

International Nuclear Information System (INIS)

Joshi, Prathamesh; Lele, Vikram

2013-01-01

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20%-50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of 123 I/ 131 I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with 68 Gallium- DOTA-DPhe 1 , Tyr 3 -octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA

Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome.

Science.gov (United States)

Joshi, Prathamesh; Lele, Vikram

2013-04-01

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20%-50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of (123)I/(131)I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with (68)Gallium- DOTA-DPhe(1), Tyr(3)-octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA.

Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles.

Science.gov (United States)

Ikemoto, Tadahiro; Park, Min Kyun

2007-02-01

GnRH regulates reproductive functions through interaction with its pituitary receptor in vertebrates. The present study demonstrated that the leopard gecko possessed two and three genes for GnRH ligands and receptors, respectively, though one of the three receptor subtypes had long been thought not to exist in reptiles. Each receptor subtype showed a distinct pharmacology. All types of ligands and receptors showed different expression patterns, and were widely expressed both inside and outside the brain. This report also shows a comparison of the pituitary and ovarian GnRH systems in the leopard gecko during and after the egg-laying season. All three receptor subtypes were expressed in both the whole pituitary and ovary; however, only one receptor subtype could be detected in the anterior pituitary gland. In situ hybridization showed spatial expression patterns of ovarian receptors, and suggested co-expression of multiple receptor subtypes in granulosa cells of larger follicles. Co-transfection of receptor subtypes showed a distinct pharmacology in COS-7 cells compared with those of single transfections. These results suggest that distinct signaling mechanisms are involved in the pituitary and ovarian GnRH systems. Seasonal and developmental variations in receptor expression in the anterior pituitary gland and ovarian follicles may contribute to the seasonal breeding of this animal.

99mTc-N4-[Tyr3]Octreotate Versus 99mTc-EDDA/HYNIC-[Tyr3]Octreotide: an intrapatient comparison of two novel Technetium-99m labeled tracers for somatostatin receptor scintigraphy.

Science.gov (United States)

Gabriel, Michael; Decristoforo, Clemens; Maina, Theodosia; Nock, Berthold; vonGuggenberg, Elisabeth; Cordopatis, Paul; Moncayo, Roy

2004-02-01

Tetraamine-[Tyr3]octreotate (Demotate) is a somatostatin (SST) analogue that can be easily labeled with 99mTc at high specific activities and showed promising preclinical properties for SST receptor scintigraphy. This study reports on the first intra-patient comparison of 99mTc-Demotate and another 99mTc-labeled SST analogue, 99mTc-EDDA/HYNIC-TOC (HYNIC-TOC). Five patients with carcinoid tumors (n = 2) and endocrine pancreatic tumors (n = 3) were investigated with both radiopharmaceuticals. 99mTc-Demotate rapidly visualized somatostatin receptor positive tumors as early as 15 minutes post-injection (p.i.) with maximum tumor uptake and tumor/organ ratios already 1 hour p.i. Organs of predominant physiological uptake were the spleen and the kidneys with no intestinal excretion detectable up to 24 hours. 99mTc-Demotate exhibited faster pharmacokinetic properties compared to HYNIC-TOC. Tumor/organ ratios at equivalent time points were higher or comparable for 99mTc-Demotate in three patients with a matching scan result. Equivocal findings were observed in two patients, i.e. comparable uptake behavior in larger lesions with differences in smaller ones. 99mTc-Demotate is a promising agent for somatostatin receptor scintigraphy providing images of excellent quality as early as 1 hour after injection.

Cloning and expression of a human kidney cDNA for an α2-adrenergic receptor subtype

International Nuclear Information System (INIS)

Regan, J.W.; Kobilka, T.S.; Yang-Feng, T.L.; Caron, M.G.; Lefkowitz, R.J.; Kobilka, B.K.

1988-01-01

An α 2 -adrenergic receptor subtype has been cloned from a human kidney cDNA library using the gene for the human platelet α 2 -adrenergic receptor as a probe. The deduced amino acid sequence resembles the human platelet α 2 -adrenergic receptor and is consistent with the structure of other members of he family of guanine nucleotide-binding protein-coupled receptors. The cDNA was expressed in a mammalian cell line (COS-7), and the α 2 -adrenergic ligand [ 3 H]rauwolscine was bound. Competition curve analysis with a variety of adrenergic ligands suggests that this cDNA clone represents the α 2 B-adrenergic receptor. The gene for this receptor is on human chromosome 4, whereas the gene for the human platelet α 2 -adrenergic receptor (α 2 A) lies on chromosome 10. This ability to express the receptor in mammalian cells, free of other adrenergic receptor subtypes, should help in developing more selective α-adrenergic ligands

Experience with indium-111 and yttrium-90-labeled somatostatin analogs.

Science.gov (United States)

Virgolini, I; Traub, T; Novotny, C; Leimer, M; Füger, B; Li, S R; Patri, P; Pangerl, T; Angelberger, P; Raderer, M; Burggasser, G; Andreae, F; Kurtaran, A; Dudczak, R

2002-01-01

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide / lanreotide analogs as tumor tracers in nuclear medicine. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or immunologic diseases such as thyroid-associated ophthalmology. The vast majority of human tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-DTPA-DPhe(1)-octreotide (OctreoScan(R)) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (K(d) 10-100 nM) and does not bind to hSSTR1 and hSSTR4, (111)In / (90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d) 200 nM). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to (111)In-DTPA-DPhe(1)-octreotide and (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higherrdquuo; high-affinity binding of (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide to hSSTR2 (K(d) 0.1-1 nM). Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as (99m)Tc-depreotide (NeoSpect(R); NeoTect(R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or nonsmall cell

Evaluation of somatostatin receptors in large cell pulmonary neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy.

Science.gov (United States)

Nocuń, Anna; Chrapko, Beata; Gołębiewska, Renata; Stefaniak, Bogusław; Czekajska-Chehab, Elżbieta

2011-06-01

Large cell pulmonary neuroendocrine carcinoma (LCNEC) is a poorly differentiated and high-grade neoplasm. It is positioned between an atypical carcinoid and small cell neuroendocrine carcinoma of the lung in a distinct family of pulmonary neuroendocrine tumors. The aim of our study was to detect somatostatin receptors in this uncommon malignancy and to evaluate the sensitivity of somatostatin receptor scintigraphy (SRS) in LCNEC staging. We analyzed data of 26 patients (mean age: 61.5±7.9 years) with histologically confirmed diagnosis of LCNEC, including 18 cases not treated surgically and eight patients after the resection of the primary tumor. SRS was carried out with technetium-99m ethylene diamine-diacetic acid/hydrazinonicotinyl-Tyr3-octreotide (Tc-TOC). A visual analysis of scintigraphic images was done with reference to conventional imaging modalities (computed tomography and bone sicintigraphy). SRS sensitivity for the detection of primary lesions, supradiaphragmatic metastases, and infradiaphragmatic metastases was 100, 83.3%, and 0%, respectively. Five out of 13 metastases to the liver appeared on SRS as photopenic foci, visible on the background of physiological hepatic activity. Only one of the nine metastases to the skeletal system was found by SRS with sensitivity as low as 11.1%. The overall SRS sensitivity for the detection of secondary lesions and of all lesions was 54.8 and 62.2%, respectively. Within a rather large series of LCNEC, the primary tumor showed an uptake of Tc-TOC in all cases, whereas some metastases did show Tc-TOC uptake and some others did not.

Unicentric Castleman's Disease Revealed by 18F-FDG PET/CT and Somatostatin Receptor Scintigraphy With 99mTc-HYNIC-TOC.

Science.gov (United States)

Luo, Yaping; Wang, Ling; Pan, Qingqing; Ma, Yanru; Li, Fang

2018-07-01

A 51-year-old woman with a history of hypertension and abdominal pain was found with a retroperitoneal mass. The mass had intense enhancement in contrast-enhanced CT, and it showed a moderate degree of increased FDG uptake in PET/CT. The mass was also positive in somatostatin receptor scintigraphy with Tc-HYNIC-TOC, but it was negative in I-MIBG scan. The histopathological result after surgical resection of the mass confirmed the diagnosis of Castleman's disease, the hyaline vascular variant.

Guideline for PET/CT imaging of neuroendocrine neoplasms withGa-DOTA-conjugated somatostatin receptor targeting peptides andF-DOPA

DEFF Research Database (Denmark)

Bozkurt, Murat Fani; Virgolini, Irene; Balogova, Sona

2017-01-01

PURPOSE & METHODS: Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing......, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using68Ga-DOTA-conjugated peptides, as well as18F-DOPA imaging for various neuroendocrine neoplasms. RESULTS & CONCLUSION: The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with68Ga...

An evaluation of the effects of somatostatin analogue therapy in non-functioning pituitary adenomas in comparison to acromegaly.

Science.gov (United States)

Zawada, Natalia Bożena; Kunert-Radek, Jolanta; Pawlikowski, Marek; Pisarek, Hanna; Radek, Maciej

2016-01-01

Non-functioning pituitary adenomas (NFPA) are often diagnosed late as invasive macroadenomas. The surgical resection is usually incomplete and about 50% of patients require additional surgery. Recent data suggest that somatostatin analogues (SSA), so important in the pharmacotherapy of acromegaly, can also be effective in the management of NFPA. We analysed data of patients who had been treated up to 10 years previously with SSA: 40 with acromegaly (23 - primary, 17 - recurrent tumours) and 22 with NFPA (4 - primary, 18 - recurrent tumours). Hormonal profile, dynamics of tumour size change, ophthalmic syndromes, somatostatin receptor (SSTR) scintigraphy, and immunohistochemistry of SSTR subtypes of operated tumours as well as side effects were investigated. Biochemical cure of acromegaly was achieved in 57.5% of patients, while reduction of tumour size was observed in 37% of patients and it was more frequent in not-operated cases. Regarding NFPA, stabilisation of tumour size was noticed in 68% of patients. Tumour shrinkage was reported in 9% of cases, but in 23% of the study group the adenoma size increased with indication for reoperation. The efficacy of SSA in NFPA is much lower in comparison to their well-established effects in the treatment of acromegaly. Stabilisation of tumour size, which is observed in the majority of NFPA, is significantly more frequent in comparison to the natural history of untreated NFPA and our previous studies as well. Analysis of SSTR subtypes is an argument in favour of introduction of novel broad-spectrum SSA that may be more effective in the treatment of NFPA. Referring to acromegaly, adenoma size decrease was reported more frequently in primary therapy. Considering recurrent tumours better outcomes were achieved in patients who were pre-treated with SSA before planned surgery. (Endokrynol Pol 2016; 67 (3): 292-298).

Pharmacological identification of cholinergic receptor subtypes on Drosophila melanogaster larval heart.

Science.gov (United States)

Malloy, Cole A; Ritter, Kyle; Robinson, Jonathan; English, Connor; Cooper, Robin L

2016-01-01

The Drosophila melanogaster heart is a popular model in which to study cardiac physiology and development. Progress has been made in understanding the role of endogenous compounds in regulating cardiac function in this model. It is well characterized that common neurotransmitters act on many peripheral and non-neuronal tissues as they flow through the hemolymph of insects. Many of these neuromodulators, including acetylcholine (ACh), have been shown to act directly on the D. melanogaster larval heart. ACh is a primary neurotransmitter in the central nervous system (CNS) of vertebrates and at the neuromuscular junctions on skeletal and cardiac tissue. In insects, ACh is the primary excitatory neurotransmitter of sensory neurons and is also prominent in the CNS. A full understanding regarding the regulation of the Drosophila cardiac physiology by the cholinergic system remains poorly understood. Here we use semi-intact D. melanogaster larvae to study the pharmacological profile of cholinergic receptor subtypes, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), in modulating heart rate (HR). Cholinergic receptor agonists, nicotine and muscarine both increase HR, while nAChR agonist clothianidin exhibits no significant effect when exposed to an open preparation at concentrations as low as 100 nM. In addition, both nAChR and mAChR antagonists increase HR as well but also display capabilities of blocking agonist actions. These results provide evidence that both of these receptor subtypes display functional significance in regulating the larval heart's pacemaker activity.

Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

International Nuclear Information System (INIS)

Kwekkeboom, D.J.; Krenning, E.P.

1997-01-01

[ 111 In-DTPA-D-Phe 1 [-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established. (orig.). With 4 figs., 1 tab

Pattern of somatostatin receptors expression in normal and bladder cancer tissue samples.

Science.gov (United States)

Karavitakis, Markos; Msaouel, Pavlos; Michalopoulos, Vassilis; Koutsilieris, Michael

2014-06-01

Known risks factors for bladder cancer progression and recurrence are limited regarding their prognostic ability. Therefore identification of molecular determinants of disease progression could provide with more specific prognostic information and could be translated into new approaches for biomarker development. In the present study we evaluated, the expression patterns of somatostatin receptors 1-5 (SSTRs) in normal and tumor bladder tissues. The expression of SSTR1-5 was characterized in 45 normal and bladder cancer tissue samples using reverse transcriptase-polymerase chain reaction (RT-PCR). SSTR1 was expressed in 24 samples, SSTR2 in 15, SSTR3 in 23, SSTR4 in 16 and SSTR5 in all but one sample. Bladder cancer tissue samples expressed lower levels of SSTR3. Co-expression of SSTRs was associated with superficial disease. Our results demonstrate, for the first time, that there is expression of SSTR in normal and bladder cancer urothelium. Further studies are required to evaluate the prognostic and therapeutic significance of these findings. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study.

Science.gov (United States)

Pivonello, Claudia; Rousaki, Panagoula; Negri, Mariarosaria; Sarnataro, Maddalena; Napolitano, Maria; Marino, Federica Zito; Patalano, Roberta; De Martino, Maria Cristina; Sciammarella, Concetta; Faggiano, Antongiulio; Rocco, Gaetano; Franco, Renato; Kaltsas, Gregory A; Colao, Annamaria; Pivonello, Rosario

2017-06-01

Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors

In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ((123I)SDZ 204-090)

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Faglia, G.; Bazzoni, N.; Spada, A.; Arosio, M.; Ambrosi, B.; Spinelli, F.; Sara, R.; Bonino, C.; Lunghi, F. (Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS (Italy))

1991-10-01

The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of (125I)Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, (123I)Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

Receptor-mediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group.

Science.gov (United States)

Chinol, Marco; Bodei, Lisa; Cremonesi, Marta; Paganelli, Giovanni

2002-04-01

High concentrations of subtype 2 somatostatin tumor receptors (sst(2)) are expressed in numerous tumors, enabling primary and metastatic masses to be localized by scintigraphy after injecting (111)In-labeled somatostatin analogue octreotide. In addition to neuroendocrine tumors, somatostatin receptors have been identified on cancers of the central nervous system, breast, lung, and lymphatic tissue, and the use of radionuclide-labeled somatostatin analogues appeared promising for therapy as well as for diagnosis of such malignancies. The somatostatin analogue [DOTA-(D)Phe(1)-Tyr(3)] octreotide (DOTATOC) possesses favorable characteristics for its potential therapeutic use in that it shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3), high hydrophilicity, stable and facile labeling with (111)In and (90)Y. We began to investigate the potential therapeutic applications of (90)Y DOTATOC in 1997 by performing a thorough dosimetric study in 18 patients who were administered (111)In DOTATOC to estimate the absorbed doses during(90)Y-DOTATOC therapy. Then, we moved on and treated an overall number of 256 patients, mostly recruited in 2 distinct protocols with and without the administration of kidney protecting agents, with (90)Y DOTATOC. No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The MTD per cycle was defined as 5.18 GBq. Objective therapeutic responses were documented in more than 20% of patients in terms of partial and complete responses. The present article reports in details our clinical experience (still ongoing) and outcomes with the use of (90)Y DOTATOC. Copyright 2002, Elsevier Science (USA). All rights reserved.

Influence of PET/CT 68Ga somatostatin receptor imaging on proceeding with patients, who were previously diagnosed with 99mTc-EDDA/HYNIC-TOC SPECT.

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Madrzak, Dorota; Mikołajczak, Renata; Kamiński, Grzegorz

2016-01-01

The aim of this study was the assessment of utility of somatostatin receptor scintigraphy (SRS) by SPECT imaging using 99mTc-EDDA/HYNIC-Tyr3-octreotide (99mTc-EDDA/HYNIC-TOC) in patients with neuroendocrine neoplasm (NEN) or suspected NEN, referred to Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The selected group of patients was referred also to 68Ga PET/CT. The posed question was the ratio of patients for whom PET/CT with 68Ga would change their management. The distribution of somatostatin receptors was imaged using 99mTc-EDDA/HYNIC-TOC in 61 planar and SPECT studies between 13/05/2010 and 04/02/2013 in Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The patient age was within a range of 17-80, with the average age of 57.6. The average age of women (65% of patients over-all) was 55.6 and the average age of men (35% of patients overall) was 61.4. In 46 participants (75% of the study group), that underwent SRS, NEN was documented using pathology tests. Selected patients were referred to PET/CT with 68Ga labeled somatostatin analogs, DOTATATE or DOTANOC. This study group consisted of 14 female and 10 male participants with age range of 35-77 and average age of 55.5 years. Patients were classified into 3 groups, as follows: detection - referral due to clinical symptoms and/or biochemical markers (CgA-Chromogranin A, IAA-indoleacetic acid) with the aim of primary diagnosis, staging - referral with the aim of assessment of tumor spread, and follow-up - assessment of the therapy. Out of 61 patients, 24 underwent both 99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT and 68Ga PET/CT. The result of PET/CT was used as a basis for further evaluation. Therefore, the patients were divided into groups; true positive TP (confirmed presence of tissue somatostatin receptors with 68Ga PET/CT) and TN (68Ga PET/CT did not detect any changes and the results were comparable and had the same influence on treatment protocol). In case of SPECT, the results

Effects of LHRH and ANG II on prolactin stimulation are mediated by hypophysial AT1 receptor subtype.

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Becú-Villalobos, D; Lacau-Mengido, I M; Thyssen, S M; Díaz-Torga, G S; Libertun, C

1994-02-01

We have used the nonpeptide angiotensin II (ANG II) receptor antagonists losartan (receptor subtype AT1) and PD-123319 (AT2) to determine the participation of ANG II receptor subtypes in luteinizing hormone-releasing hormone (LHRH)-induced prolactin release in a perifusion study using intact pituitaries in vitro. LHRH (1.85 x 10(-7) M) released prolactin consistently, whereas losartan (10(-5) M) abolished prolactin response without modifying basal prolactin or luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release. PD-123319 (10(-5) M) had no effect on basal or LHRH-induced prolactin, LH, or FSH release. We also determined that the effect of ANG II on prolactin release was mediated by the same receptor subtype. In adenohypophysial cells dispersed in vitro ANG II (10(-8) M) released prolactin. Losartan (10(-7) and 10(-6) M), but not PD-123319, inhibited this effect. We conclude that in intact hypophyses of 15-day-old female rats the effect of LHRH on prolactin release is readily demonstrated. LHRH-induced prolactin release appears to be mediated by ANG II acting in a paracrine manner on AT1 receptors located on lactotrophs.

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: a potential PET tracer for beta cell mass measurement.

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Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

2013-12-06

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM. Copyright © 2013 Elsevier Inc. All rights reserved.

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

International Nuclear Information System (INIS)

Boy, Christian; Poeppel, Thorsten D.; Jentzen, Walter; Brandau, Wolfgang; Bockisch, Andreas; Heusner, Till A.; Antoch, Gerald; Redmann-Bischofs, Anja; Unger, Nicole; Mann, Klaus; Petersenn, Stephan

2011-01-01

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. A total of 120 patients were subjected to diagnostic 68 Ga-DOTATOC positron emission tomography (PET)/CT (age range 19-83 years). SUV max values were measured in physiologically normal tissues defined by normal morphology, absence of surgical intervention and absence of metastatic spread during clinical follow-up. Expression of sst subtypes (sst1-sst5) was measured independently in pooled adult normal human tissue by real-time reverse transcriptase polymerase chain reaction (RT-PCR). SUV max revealed a region-specific pattern (e.g., mean ± SD, spleen 31.1 ± 10.9, kidney 16.9 ± 5.3, liver 12.8 ± 3.6, stomach 7.0 ± 3.1, head of pancreas 6.2 ± 2.3, small bowel 4.8 ± 1.8, thyroid 4.7 ± 2.2, bone 3.9 ± 1.3, large bowel 2.9 ± 0.8, muscle 2.1 ± 0.5, parotid gland 1.9 ± 0.6, axillary lymph node 0.8 ± 0.3 and lung 0.7 ± 0.3). SUV max was age independent. Gender differences were evident within the thyroid (female/male: 3.7 ± 1.6/5.5 ± 2.4, p max values exclusively correlated with sst2 expression (r = 0.846, p max with the expression of the other four subtypes. In normal human tissues 68 Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis. (orig.)

Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype

International Nuclear Information System (INIS)

Wilson, A.L.; Seibert, K.; Brandon, S.; Cragoe, E.J. Jr.; Limbird, L.E.

1991-01-01

The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation

Synthesis, radiochemistry and biological evaluation of a new somatostatin analogue (SDZ 219-387) labelled with technetium-99m

International Nuclear Information System (INIS)

Maina, T.; Stolz, B.; Albert, R.; Bruns, C.; Koch, P.; Maecke, H.

1994-01-01

A new derivative of octreotide SDZ 219-387 [PnAO-(D)Phe 1 -octreotide] was synthesized, which binds specifically and with high affinity to somatostatin receptors in vitro (pK i =9.79±0.16). This new somatostatin analogue chelates technetium-99m under mild labelling conditions in good yields. The resulting [ 99m Tc]SDZ 219-387 was stable up to 6 h after labelling and could be isolated in a pure radiochemical and chemical form by high-perfomance liquid chromatographic purification. The intravenous administration of purified [ 99m Tc]SDZ 219-387 revealed that the radioligand was rapidly cleared from circulation, and tumour uptake of 0.38% ID/g was observed at 1.5 h post injection. [ 99m Tc]SDZ 219-387 specifically interacted with somatostatin binding sites on the tumour. However, the radioligand is highly lipophilic and excreted mainly through the hepatobiliary system. As a consequence, [ 99m Tc]SDZ 219-387 exhibits increased background activity and therefore is not appropriate for the in vivo visualization of somatostatin receptor-positive tumours and/or their metastases in the abdomen. (orig.)

Tumour uptake of the radiolabelled somatostatin analogue [DOTA0,TYR3]octreotide is dependent on the peptide amount

International Nuclear Information System (INIS)

Jong, M. de; Breeman, W.A.P.; Bernard, B.F.; Gameren, A. van; Bruin, E. de; Bakker, W.H.; Van der Pluijm, M.E.; Krenning, E.P.; Visser, T.J.; Maecke, H.R.

1999-01-01

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr 3 ]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in somatostatin receptor subtype 2 (sst 2 )-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111 In-labelled [DOTA 0 ,Tyr 3 ]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in sst 2 -positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pancreas) μg. Uptake in the tumour was highest at 0.5 μg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [ 111 In-DTPA 0 ]octreotide (d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound

Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR

Science.gov (United States)

Grace, Christy Rani R.; Erchegyi, Judit; Koerber, Steven C.; Reubi, Jean Claude; Rivier, Jean; Riek, Roland

2008-01-01

The three-dimensional NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II’ β-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8 and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is therefore different from that proposed by others for sst2/3/5 analogues. PMID:16854054

Anxiety and Depression: Mouse Genetics and Pharmacological Approaches to the Role of GABAA Receptor Subtypes

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Smith, Kiersten S.; Rudolph, Uwe

2012-01-01

GABAA receptors mediate fast synaptic inhibitory neurotransmission throughout the central nervous system. Recent work indicates a role for GABAA receptors in physiologically modulating anxiety and depression levels. In this review, we summarize research that led to the identification of the essential role of GABAA receptors in counteracting trait anxiety and depression-related behaviors, and research aimed at identifying individual GABAA receptor subtypes involved in physiological and pharmacological modulation of emotions. PMID:21810433

Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging

International Nuclear Information System (INIS)

Buder, Kristina; Becker, Jürgen C; Lapa, Constantin; Kreissl, Michael C; Schirbel, Andreas; Herrmann, Ken; Schnack, Alexander; Bröcker, Eva-Bettina; Goebeler, Matthias; Buck, Andreas K

2014-01-01

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. To non-invasively assess SSTR expression in MCC using PET and the radiotracers [ 68 Ga]DOTA-D-Phe 1 -Tyr 3 -octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%). SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management

IMMUNOHISTOCHEMICAL DETERMINATION OF EXPRESSION OF SOMATOSTATIN RECEPTORS TYPES 1, 2A, 3 AND 5 IN NEUROENDOCRINE TUMORS OF VARIOUS LOCALIZATION AND GRADE

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L. E. Gurevich

2016-01-01

Full Text Available Background: Prediction of clinical benefits of somatostatin analogues in patients with neuroendocrine tumors (NET is very important prior to their administration. Data on immunohistochemical assessment of the expression of somatostatin receptors (SSR of various types, obtained from large samples of NET with various localization, functional activity and degree of malignancy, are scarce; therefore, the study was aimed at assessment of the latter.Materials and methods: We performed an immunohistochemical study with antibodies to SSR1, 2A, 3 and 5  types on tissue samples obtained during diagnostic and intra-operative biopsies from 399 NETs: 168 from pancreas, 120 from gastrointestinal tract (stomach, 48, from small intestine, 39, 14 of which being from duodenum; appendix, 6, colon and the rectum, 15 and 12, respectively, 84 from lung, 6 from thymus/mediastinum, and 21 from NET metastases of unknown primary localization.Results: Very high levels expression of receptors SSR2A preferentially binding to somatostatin analogues, which are currently used in clinical practice, were detected in the small intestine NETs (22/25, 88%, appendix (5/6, 83.3%, colon (10/15, 66.7%, thymus (4/6, 66.7%, atypical carcinoids of the lung (10/15, 66.7%, stomach (27/41, 65.8% and pancreas (105/165, 63.6%. The lowest expression was found in rectal NETs (5/12, 41.7% and small and large cell neuroendocrine lung carcinomas (20, 11.1%. Among functioning NETs, the highest level of SSR2A was found in gastrinomas (18/19, 94.7%, glucagonomas (15/16, 93.8%, small intestine carcinoids (31/35, 88.6%, and somatostatinomas (2/3, 66.7%. The lowest expression was detected in ACTH secreting tumors with Cushing's syndrome (11/12, 50%, and in insulinomas (34/69, 49.3%. SSR2A expression in functionally inactive pancreatic NETs was significantly higher than in insulinomas (57/82, 34/69 vs 69.5 and 49.3%, respectively. SSR2A expression was associated with the degree of malignancy and is

Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients.

Science.gov (United States)

Faggiano, Antongiulio; Tavares, Lidice Brandao; Tauchmanova, Libuse; Milone, Francesco; Mansueto, Gelsomina; Ramundo, Valeria; De Caro, Maria Laura Del Basso; Lombardi, Gaetano; De Rosa, Gaetano; Colao, Annamaria

2008-11-01

In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated. To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP. Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled. The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy. Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR. After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%). Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.

The prognostic value of age for invasive lobular breast cancer depending on estrogen receptor and progesterone receptor-defined subtypes: A NCDB analysis.

Science.gov (United States)

Liu, Jieqiong; Chen, Kai; Mao, Kai; Su, Fengxi; Liu, Qiang; Jacobs, Lisa K

2016-02-02

We aimed to assess the effect of age on survival according to estrogen receptor (ER) and progesterone receptor (PR)-defined lobular breast cancer subtype in a wide age range. 43,230 invasive lobular breast cancer women without comorbidities diagnosed between 2004 and 2011 in the National Cancer Database (NCDB) were analyzed. The effects of age on overall survival (OS) among different age groups were evaluated by log-rank test and Cox proportional model. Multivariate analysis showed that patients diagnosed at both young ( 0.1); and in ER-PR+ subgroup, the HRs were similar in patients younger than 70 (P > 0.1); thus, the plots of HRs in these three subtypes remained steady until the age of 60 or 70. Our findings identified that the effect of age on OS in lobular breast cancer varied with ER/PR-defined subtypes. Personalized treatment strategies should be developed to improve outcomes of breast cancer patients with different ages and ER/PR statuses.

Iodine-131 labelled octreotide: not an option for somatostatin receptor therapy

International Nuclear Information System (INIS)

Bakker, W.H.; Breeman, W.A.P.; Pluijm, M.E. van der; Jong, M. de; Visser, T.J.; Krenning, E.P.

1996-01-01

This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from 131 I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of 131 I in cancer treatment and out previous experience with [ 111 In-DTPA-D-Phe 1 ]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq 131 I has to be coupled to a maximum of ∼100 μg peptide, representing only a slight excess of peptide over 131 I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated form unreacted iodide, and from di-iodinated and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 μg unlabelled peptide with 370 MBq 131 I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher β-flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated 131 I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain. (orig./VHE)

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

International Nuclear Information System (INIS)

Trejtnar, F.; Novy, Z.; Petrik, M.; Laznickova, A.; Melicharova, L.; Vankova, M.; Laznicek, M.

2008-01-01

Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA 0 , Tyr 3 , Thr 8 ]-octreotide (DOTA-TATE) and [DOTA 0 , 1-Nal 3 ]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods. The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells. The renal clearance of 111 In-DOTA-NOC in the perfused rat kidney was significantly lower than that of 111 In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. 111 In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than 111 In-DOTA-TATE (ratio 3:1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin

PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy

International Nuclear Information System (INIS)

Hofmann, M.; Gazdhar, A.; Weitzel, T.; Schmid, R.; Krause, T.

2006-01-01

Localized information on region-selective gene expression in small animals is widely obtained by use of reporter genes inducing light emission. Using these reporter genes for imaging deep inside the human body fluorescent probes are hindered by attenuation, scattering and possible fluorescence quenching. This can be overcome by use of radio-peptide receptors as reporter genes. Therefore, the feasibility of the somatostatin receptor 2 expression vector system for expression imaging was checked against a control vector containing luciferase gene. For in vivo transduction of vector DNA into the rat forelimb muscles the in vivo electroporation technique was chosen because of its high regio-selectivity. The gene expression was imaged by high-sensitive CCD camera (luciferase activity) and by PET/CT using a Ga-68-DOTATOC as radio peptide probe. The relative sstr2 expression was enhanced by gene transduction at maximum to a factor of 15. The PET/CT images could be fully quantified. The above demonstrated feasibility of radio-peptide PET/CT reporter gene imaging may serve in the future as a tool for full quantitative understanding of regional gene expression, especially in large animals and humans

PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy

Energy Technology Data Exchange (ETDEWEB)

Hofmann, M. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland)]. E-mail: Michael.Hofmann@insel.ch; Gazdhar, A. [Division of Pulmonary Medicine, University Hospital Bern (Switzerland); Weitzel, T. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland); Schmid, R. [Division of Thoracic Surgery, University Hospital Bern (Switzerland); Krause, T. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland)

2006-12-20

Localized information on region-selective gene expression in small animals is widely obtained by use of reporter genes inducing light emission. Using these reporter genes for imaging deep inside the human body fluorescent probes are hindered by attenuation, scattering and possible fluorescence quenching. This can be overcome by use of radio-peptide receptors as reporter genes. Therefore, the feasibility of the somatostatin receptor 2 expression vector system for expression imaging was checked against a control vector containing luciferase gene. For in vivo transduction of vector DNA into the rat forelimb muscles the in vivo electroporation technique was chosen because of its high regio-selectivity. The gene expression was imaged by high-sensitive CCD camera (luciferase activity) and by PET/CT using a Ga-68-DOTATOC as radio peptide probe. The relative sstr2 expression was enhanced by gene transduction at maximum to a factor of 15. The PET/CT images could be fully quantified. The above demonstrated feasibility of radio-peptide PET/CT reporter gene imaging may serve in the future as a tool for full quantitative understanding of regional gene expression, especially in large animals and human000.

Evaluation of (64)Cu-labeled DOTA-D-Phe(1)-Tyr (3)-octreotide ((64)Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors.

Science.gov (United States)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich; Paudyal, Pramila; Iida, Yasuhiko; Watanabe, Shigeki; Paudyal, Bishnuhari; Higuchi, Tetsuya; Oriuchi, Noboru; Endo, Keigo

2009-08-01

In-111 ((111)In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ((64)Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a (64)Cu-labeled octreotide analog, (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D: -Phe(1)-Tyr(3)-octreotide ((64)Cu-DOTA-TOC). (64)Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 degrees C. The stability of (64)Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of (64)Cu-DOTA-TOC and (111)In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of (64)Cu-DOTA-TOC or (64)Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC). The tumor was imaged using (64)Cu-DOTA-TOC, (64)Cu-TETA-OC, and FDG with an animal PET scanner. (64)Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. (64)Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of (64)Cu was higher than that of (111)In in all organs except kidney. In tumor-bearing mice, (64)Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 +/- 1.17 at 6 h after administration. (64)Cu-DOTA-TOC showed significantly higher accumulation in the tumor than (64)Cu-TETA-OC. (64)Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of (18)F-FDG PET and very similar to that of (64)Cu

Evaluation of 64Cu-labeled DOTA-D-Phe1-Tyr3-octreotide (64Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors

International Nuclear Information System (INIS)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich

2009-01-01

In-111 ( 111 In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ( 64 Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a 64 Cu-labeled octreotide analog, 64 Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D-Phe 1 -Tyr 3 -octreotide ( 64 Cu-DOTA-TOC). 64 Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 deg C. The stability of 64 Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by high performance liquid chromatography (HPLC) analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of 64 Cu-DOTA-TOC and 111 In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of 64 Cu-DOTA-TOC or 64 Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ( 64 Cu-TETA-OC). The tumor was imaged using 64 Cu-DOTA-TOC, 64 Cu-TETA-OC, and fluorodeoxyglucose (FDG) with an animal PET scanner. 64 Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. 64 Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of 64 Cu was higher than that of 111 In in all organs except kidney. In tumor-bearing mice, 64 Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81±1.17 at 6 h after administration. 64 Cu-DOTA-TOC showed significantly higher accumulation in the tumor than 64 Cu-TETA-OC. 64 Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of 18 F-FDG PET and

Establishment of a normal-derived estrogen receptor-positive cell line comparable to the prevailing human breast cancer subtype

DEFF Research Database (Denmark)

Hopkinson, Branden Michael; Klitgaard, Marie Christine; Petersen, Ole William

2017-01-01

Understanding human cancer increasingly relies on insight gained from subtype specific comparisons between malignant and non-malignant cells. The most frequent subtype in breast cancer is the luminal. By far the most frequently used model for luminal breast cancer is the iconic estrogen receptor-...

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes (''chimney sign'') in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

International Nuclear Information System (INIS)

Behr, T.M.; Gratz, S.; Markus, P.M.; Dunn, R.M.; Huefner, M.; Becker, H.; Becker, W.

1997-01-01

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the ''chimney sign'' may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis. (orig.). With 2 figs., 1 tab

Autoradiography after incubation of tissue slices in 111 In-pentetreotide. Demonstration of the feasibility of the technique on rat brain slices. Application in two cases of human renal cell carcinoma

International Nuclear Information System (INIS)

Montravers, F.; Allard, S.; Fouret, P.; Daty, N.; Talbot, J.N.; Bernaudin, J.F.

1996-01-01

We report on a macroscopic autoradiographic technique using 111 In-pentetreotide after in vitro incubation of the slices. The feasibility of this technique has been demonstrated by the actual labeling of the deeper layers of the rat cerebral cortex, corresponding to the known cerebral distribution of somatostatin subtype 2 receptor. This technique has subsequently been applied in two of human renal cell carcinoma and has proven the presence of somatostatin receptors in both tumours. In one of these cases, a preoperative scintigraphy using 111 In-pentetreotide showed the absence of tumour visualization. The mechanism proposed to explain this discrepancy between scintigraphic and autoradiographic results is a lack of accessibility of the somatostatin analog to the receptor in case of voluminous renal tumour. (authors). 19 refs., 2 figs

GABA regulates the rat hypothalamic-pituitary-adrenocortical axis via different GABA-A receptor alpha-subtypes

DEFF Research Database (Denmark)

Mikkelsen, Jens D; Bundzikova, Jana; Larsen, Marianne Hald

2008-01-01

dependent on the composition of the GABA-A receptor subunits through which they act. We show here that positive modulators of alpha(1)-subtype containing GABA-A receptors with zolpidem (10 mg/kg) increase HPA activity in terms of increase in plasma corticosterone and induction of Fos in the PVN, whereas...... after positive modulation of GABA-A receptors composed of alpha(1)-subunit(s) affects a selective afferent system than the PVN, which is distinct from another afferent system(s) activated by non alpha(1)-containing GABA-A receptors....

Ectopic ACTH secretion due to a bronchopulmonary carcinoid localized by somatostatin receptor scintigraphy.

Science.gov (United States)

Iser, G; Pfohl, M; Dörr, U; Weiss, E M; Seif, F J

1994-11-01

We present the case of a 65-year-old woman with an adrenocorticotropic hormone (ACTH) secreting bronchopulmonary carcinoid. This patient showed the typical long history of Cushing's syndrome, including hypokaliemia, impaired glucose tolerance, high levels of ACTH and beta-endorphin, and coproduction of other peptides. At the onset of clinical symptoms in 1979 an adrenal adenoma was suspected, and left-sided adrenalectomy was performed. The symptoms soon recurred, and the diagnosis of ACTH-dependent Cushing's syndrome was made. As no ACTH-secreting tumor was found, the right adrenal was resected, and the patient was followed up regularly. Fourteen years later chest roentgenography and computed tomography revealed a para-aortic pulmonary lesion, which was suspicious for a bronchopulmonary carcinoid. ACTH and beta-endorphin were excessively, pancreatic polypeptide slightly elevated at that time. The final diagnosis was made using somatostatin receptor scintigraphy which confirmed the hormonal activity of the suspicious lesion; no additional focus was found. This method turned out to be not only a useful additional localization technique but also a promising tool for characterization and staging of a suspected ACTH-producing carcinoid. The tumor was resected curatively, and the diagnosis was confirmed histologically.

Current knowledge on the sensitivity of the 68Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours

OpenAIRE

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; von Guggenberg, Elisabeth; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, llanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-01-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three 68Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these 68Ga-sstr-binding peptides in the imaging setting. On 68Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake val...

Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location.

Science.gov (United States)

Faisal, Farzana A; Sundi, Debasish; Tosoian, Jeffrey J; Choeurng, Voleak; Alshalalfa, Mohammed; Ross, Ashley E; Klein, Eric; Den, Robert; Dicker, Adam; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L; Schaeffer, Edward M

2016-07-01

Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, pprostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. Copyright © 2015. Published by Elsevier B.V.

Peptide receptor radionuclide therapy with {sup 90}Y-DOTATOC in recurrent meningioma

Energy Technology Data Exchange (ETDEWEB)

Bartolomei, Mirco; Bodei, Lisa; De Cicco, Concetta; Grana, Chiara Maria; Baio, Silvia Melania; Arico, Demetrio; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Botteri, Edoardo [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Radiometabolic Medicine Division, Meldola (Italy)

2009-09-15

Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using {sup 90}Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous {sup 90}Y-DOTATOC for 2-6 cycles for a cumulative dose in the range of 5-15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II-III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. PRRT with {sup 90}Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation. (orig.)

Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy. A potential novel treatment based on molecular pathology

International Nuclear Information System (INIS)

Salavati, A.; Prasad, V.; Baum, R.P.; Schneider, C.P.; Herbst, R.

2012-01-01

Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of 177 Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by 18 F-fluorodeoxyglucose ( 18 F-FDG) and 68 gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up positron emission tomography (PET)/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and 68 Ga-somatostatin-receptor PET/CT in the management of MCC. (author)

Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice

Science.gov (United States)

Smith, Kiersten S.; Engin, Elif; Meloni, Edward G.; Rudolph, Uwe

2012-01-01

GABAA receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABAA receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABAA receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABAA receptors are necessary for BZs to exert their effects on conditioned fear responses.. Our findings illustrate both an overlap and a divergence between the GABAA receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABAA receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABAA receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored. PMID:22465203

Quantitative autoradiographic analysis of muscarinic receptor subtypes and their role in representational memory

International Nuclear Information System (INIS)

Messer, W.S.

1986-01-01

Autoradiographic techniques were used to examine the distribution of muscarinic receptors in rat brain slices. Agonist and selective antagonist binding were examined by measuring the ability for unlabeled ligands to inhibit [ 3 H]-1-QNB labeling of muscarinic receptors. The distribution of high affinity pirenzepine binding sites (M 1 subtype) was distinct from the distribution of high affinity carbamylcholine sites, which corresponded to the M 2 subtype. In a separate assay, the binding profile for pirenzepine was shown to differ from the profile for scopolamine, a classical muscarinic antagonist. Muscarinic antagonists, when injected into the Hippocampus, impaired performance of a representational memory task. Pirenzepine, the M 1 selective antagonist, produced representational memory deficits. Scopolamine, a less selective muscarinic antagonist, caused increases in running times in some animals which prevented a definitive interpretation of the nature of the impairment. Pirenzepine displayed a higher affinity for the hippocampus and was more effective in producing a selective impairment of representational memory than scopolamine. The data indicated that cholinergic activity in the hippocampus was necessary for representation memory function

Expression and distribution patterns of Mas-related gene receptor subtypes A-H in the mouse intestine: inflammation-induced changes.

Science.gov (United States)

Avula, Leela Rani; Buckinx, Roeland; Favoreel, Herman; Cox, Eric; Adriaensen, Dirk; Van Nassauw, Luc; Timmermans, Jean-Pierre

2013-05-01

Mas-related gene (Mrg) receptors constitute a subfamily of G protein-coupled receptors that are implicated in nociception, and are as such considered potential targets for pain therapies. Furthermore, some Mrgs have been suggested to play roles in the regulation of inflammatory responses to non-immunological activation of mast cells and in mast cell-neuron communication. Except for MrgD, E and F, whose changed expression has been revealed during inflammation in the mouse intestine in our earlier studies, information concerning the remaining cloned mouse Mrg subtypes in the gastrointestinal tract during (patho) physiological conditions is lacking. Therefore, the present study aimed at identifying the presence and putative function of these remaining cloned Mrg subtypes (n = 19) in the (inflamed) mouse intestine. Using reverse transcriptase-PCR, quantitative-PCR and multiple immunofluorescence staining with commercial and newly custom-developed antibodies, we compared the ileum and the related dorsal root ganglia (DRG) of non-inflamed mice with those of two models of intestinal inflammation, i.e., intestinal schistosomiasis and 2,4,6-trinitrobenzene sulfonic acid-induced ileitis. In the non-inflamed ileum and DRG, the majority of the Mrg subtypes examined were sparsely expressed, showing a neuron-specific expression pattern. However, significant changes in the expression patterns of multiple Mrg subtypes were observed in the inflamed ileum; for instance, MrgA4, MrgB2and MrgB8 were expressed in a clearly increased number of enteric sensory neurons and in nerve fibers in the lamina propria, while de novo expression of MrgB10 was observed in enteric sensory neurons and in newly recruited mucosal mast cells (MMCs). The MrgB10 expressing MMCs were found to be in close contact with nerve fibers in the lamina propria. This is the first report on the expression of all cloned Mrg receptor subtypes in the (inflamed) mouse intestine. The observed changes in the expression and

Role of 68Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study

International Nuclear Information System (INIS)

Prasad, Vikas; Sainz-Esteban, Aurora; Arsenic, Ruza; Ploeckinger, Ursula; Denecke, Timm; Pape, Ulrich-Frank; Pavel, Marianne; Pascher, Andreas; Kuehnen, Peter; Blankenstein, Oliver

2016-01-01

To explore the role of 68 Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. This explorative study suggests that SR PET in combination with CT may play a significant role in the detection

Radioimmunoassay of somatostatin: methodological problems and physiological investigations

International Nuclear Information System (INIS)

Penman, E.; Wass, J.A.H.

1981-01-01

Somatostatin, a tetradecapeptide, has a wide distribution throughout the central nervous system and the gastrointestinal tract and a broad spectrum of biological actions. In order to investigate its various physiological roles in man, a radioimmunoassay was developed for somatostatin in human blood plasma, which is described here. This RIA was used to investigate possible factors influencing somatostatin secretion. Changes in somatin levels produced by changes in insulin, glucagon and growth hormone levels were studied via the response of plasma immunoreactive somatostatin to hormonal stimuli in normal man. The influence of fasting and food consumption was studied; and the site of origin of circulating immunoreactive somatostatin was investigated in patients. (Auth.)

Differential expression of muscarinic acetylcholine receptor subtypes in Jurkat cells and their signaling.

Science.gov (United States)

Alea, Mileidys Perez; Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Fuxe, Kjell; Garriga, Pere

2011-08-15

Muscarinic acetylcholine receptors expression and signaling in the human Jurkat T cell line were investigated. Semiquantitative real-time PCR and radioligand binding studies, using a wide set of antagonist compounds, showed the co-existence of M(3), M(4), and M(5) subtypes. Stimulation of these subpopulations caused a concentration and time- dependent activation of second messengers and ERK signaling pathways, with a major contribution of the M(3) subtype in a G(q/11)-mediated response. In addition, we found that T-cell stimulation leads to increased expression of M(3) and M(5) both at transcriptional and protein levels in a PLC/PKCθ dependent manner. Our data clarifies the functional role of AChR subtypes in Jurkat cells and pave the way to future studies on the potential cross-talk among these subpopulations and their regulation of T lymphocytes immune function. Copyright © 2011 Elsevier B.V. All rights reserved.

Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration

NARCIS (Netherlands)

A.C. Lambooij (Antoinette); R.W.A.M. Kuijpers (Robert); E.G. van Lichtenauer-Kaligis; M. Kliffen (Mike); G.S. Baarsma (Seerp); P.M. van Hagen (Martin); C.M. Mooy (Cornelia)

2000-01-01

textabstractPURPOSE: The growth of ocular neovascularization is regulated by a balance between stimulating and inhibiting growth factors. Somatostatin affects angiogenesis by inhibiting the growth hormone-insulin-like growth factor axis and also has a direct

Immuno-reactive somatostatin in the cerebro-spinal fluid

International Nuclear Information System (INIS)

Kohler, J.

1983-01-01

In the present work the lumbar cerebro-spinal fluid of 178 patients with different neurological affections was examined with the aid of a specific radioimmunoassay for somatostatin. 18 patients without any pathologic neurological findings served as controls. In degenerative diseases of the brain, reduced somatostatin levels in the cerebro-spinal fluid as compared to the controls were measured. In 3 patients with isolated cerebellar atrophy no reduction of the somatostatin content was found; rather the values were highly normal. Huntington-Chorea also is a case apart. In patients with manifest affections, the somatostatin reduction, amounting to 54.6%, was particularly notable as compared to the controls. By contrast, degenerative diseases with predominant medullary and spastic affection are characterized by significantly increased somatostatin levels. Again, in non-spastic patients the values were not significantly different from those of the controls. Patients with inflammations of the brain and meminges as well as with tumors of the nervous system showed somatostatin levels increased by about 60.8% respectively 51.8% as compared to the controls. Epileptic patients normally exhibit a reduced somatostatin level in the cerebro-spinal fluid, but the reduction is not significant. Disseminated encephalomyclitis, whether chromic or acute, is not found to be associated with significant modifications of the somatostatin level in the cerebro-spinal fluid. Strikingly, however, patients in which the disease took a serious or very serious clinical course showed also the lowest somatostatin levels in the cerebro-spinal fluid. In patients exhibiting the roof compression symptom in consequence of a prolapse of the disk, no significant modifications were found. By contrast, in patients with the symptoms of a transverse lesion, significantly increased somatostatin values were measured. (orig./MG) [de

Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P(3))

NARCIS (Netherlands)

Jongsma, M.; van Unen, J.; van Loenen, P. B.; Michel, M. C.; Peters, S. L. M.; Alewijnse, A. E.

2009-01-01

Recently, some ligands targeting the sphingosine-1-phosphate receptor subtype 3 (S1P(3)) have become available. The characterization of these compounds was mainly based on one functional read-out system, although S1P(3) receptors are known to activate different signal transduction pathways.

Characterization of the effect of penehyclidine hydrochloride on muscarinic receptor subtypes mediating the contraction of guinea-pig isolated gastrointestinal smooth muscle.

Science.gov (United States)

Xiao, Hong-Tao; Liao, Zhi; Meng, Xian-Min; Yan, Xiao-Yan; Chen, Shu-Jie; Mo, Zheng-Ji

2009-07-01

The aim was to characterize the effect of penehyclidine hydrochloride, which mediates the relaxation of guinea-pig isolated gastrointestinal smooth muscle, on muscarinic receptor subtypes. Radioimmune assay was used to determine cAMP levels in isolated guinea-pig gastrointestinal smooth muscle to compare the selective effects of penehyclidine hydrochloride on muscarinic receptor subtypes. The results indicated that the relaxing effect of penehyclidine hydrochloride on isolated gastrointestinal smooth muscle contraction induced by acetylcholine was stronger than that of atropine (based on PA2 values). In the radioimmune assay, penehyclidine hydrochloride increased the cAMP content in isolated guinea-pig stomach smooth muscle and decreased the cAMP content in isolated guinea-pig intestinal smooth muscle, but the difference was not statistically significant at a dose of 10 mumol/l. The results suggest that penehyclidine hydrochloride has little or no effect on M2 receptor subtypes in guinea-pig gastrointestinal smooth muscle.

Somatostatin in the caudal spinal cord

DEFF Research Database (Denmark)

Schrøder, H D

1984-01-01

. In all of these regions somatostatin-positive cell bodies were also observed. In the intermediate gray matter stained terminals were present around the central canal in a varying number. The most prominent stainability was found in the lumbosacral transition zone. Many terminals were also observed...... was particularly low in the motoneuron neuropil. However, a dense somatostatin network was found in the sixth lumbar segment in relation to the neurons in Onuf's nucleus X complex, the nucleus that innervates the small pelvic muscles including the striated sphincters. It is concluded that somatostatin, besides...

99m Tc- la bed somatostatin analogs for imaging somatostatin-receptor-positive tumors

International Nuclear Information System (INIS)

Gandomkar, M.; Najafi, R.; Shafiei, A.; Sadat Ebrahimi, E.; Babaie, M.H.; Rabani, M.

2002-01-01

Over the least few years, 111 In-DTPA- Octreotide has found widespread clinical applicability, especially in oncology. However limitation, especially concerning availability, imaging properties, and costs, remain and have stimulated research on radiolabeling with many alternative radionuclides. The purpose of this investigation was to labeling somatostatin analogs with 99 m Tc and evaluate their suitability as an agents for in vivo use. Octreotide and Tyr-3-Octreotide were labeled by 99 mTc with direct and indirect methods. Sodium ascorbate and sodium dithionite were used for reduction of cystine bridge and HYNIC was used as bifunctional agents and different co ligands used for labeling by 99 mTc. Yield of labeling, purity, stability, internalisation, binding affinity and biodistribution of peptide conjugates were studied. Direct labeling of octreotide was simple, rapid, efficient and yield was good (%60). K d for binding affinity as high (10 -9 ) but stability was low. Labeling for HYNIC-Tyr-Octreotide had a high yield (>%90), good stability, internalisation and biodistribution. with more experimental work and some improve this peptide-based radiopharmaceuticals can be employed in all nuclear medicine centers as a useful agent for imaging of tumors

A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype

International Nuclear Information System (INIS)

Gitler, M.S.; Cohen, V.I.; De La Cruz, R.; Boulay, S.F.; Jin, B.; Zeeberg, B.R.; Reba, R.C.

1993-01-01

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, the authors have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [ 3 H](R)-3-quinuclidinylbenzilate ([ 3 H]QNB) and [ 3 H]N-methylscopolamine ([ 3 H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[ 125 I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[ 125 I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. The authors conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system

Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors

Energy Technology Data Exchange (ETDEWEB)

Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.; Schulten, Klaus; Mayer, Mark L. (UIUC); (NIH)

2008-10-27

NR3 subtype glutamate receptors have a unique developmental expression profile, but are the least well-characterized members of the NMDA receptor gene family, which have key roles in synaptic plasticity and brain development. Using ligand binding assays, crystallographic analysis, and all atom MD simulations, we investigate mechanisms underlying the binding by NR3A and NR3B of glycine and D-serine, which are candidate neurotransmitters for NMDA receptors containing NR3 subunits. The ligand binding domains of both NR3 subunits adopt a similar extent of domain closure as found in the corresponding NR1 complexes, but have a unique loop 1 structure distinct from that in all other glutamate receptor ion channels. Within their ligand binding pockets, NR3A and NR3B have strikingly different hydrogen bonding networks and solvent structures from those found in NR1, and fail to undergo a conformational rearrangement observed in NR1 upon binding the partial agonist ACPC. MD simulations revealed numerous interdomain contacts, which stabilize the agonist-bound closed-cleft conformation, and a novel twisting motion for the loop 1 helix that is unique in NR3 subunits.

New octreotide derivatives for in vivo targeting of somatostatin receptor-positive tumors for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET)

International Nuclear Information System (INIS)

Maecke, H.R.; Smith-Jones, P.; Maina, T.; Stolz, B.; Albert, R.; Bruns, C.; Reist, H.

1993-01-01

Two new modifications of the somatostatin analog octreotide, designed to hold the gallium isotopes 67 Ga and 68 Ga (DFO-SMS) and 99m Tc (PnAO-SMS) have been synthesized and evaluated in vitro and in vivo in tumor bearing rats. DFO-SMS can be labeled with 67 Ga 3+ and 68 Ga 3+ with high specific activity within less than 30 minutes in a ''cold kit'' type formulation. The labeled conjugate is stable under physiologgical conditions. Moreover the binding affinity to somatostatin receptors on rat brain cortex membranes was shown to be retained. In vivo fast tumor localization was demonstrated and the pharmacokinetics proved to be favourable as the main excretion route was via the kidneys. First PET studies with [ 68 Ga]-DFO-SMS showed a rapid accumulation in the tumor and a residence half-life at the tumor site of about 6 hours. PnAO-SMS can be labeled with 99m Tc with high radiochemical purity. In vivo the radiotracer accumulates well in the tumor but due to its high lipohilicity, its main excretion route is via the hepatobiliary system. (orig.)

Structure-based prediction of subtype selectivity of histamine H3 receptor selective antagonists in clinical trials.

Science.gov (United States)

Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder; Goddard, William A

2011-12-27

Histamine receptors (HRs) are excellent drug targets for the treatment of diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. Among them, the human H(3) histamine receptor (hH(3)HR) antagonists have been proposed for specific therapeutic applications, including treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity. However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity and activity for such treatments, it would be useful to have the three-dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H(1), H(2), H(3), and H(4)) using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol, sampling ∼35 million combinations of helix packings to predict the 10 most stable packings for each of the four subtypes. Then we used these 10 best protein structures with the DarwinDock Monte Carlo protocol to sample ∼50 000 × 10(20) poses to predict the optimum ligand-protein structures for various agonists and antagonists. We find that E206(5.46) contributes most in binding H(3) selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH(3)HR and hH(4)HR are involved in H(3)/ H(4) subtype selectivity. In addition, we find that M378(6.55) in hH(3)HR provides additional hydrophobic interactions different from hH(4)HR (the corresponding amino acid of T323(6.55) in hH(4)HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH(3)HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2, PF-3654746 3, and BF2.649 (tiprolisant) 4] that suggests critical selectivity directing elements are: the basic proton

Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

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Courtney Premer

2013-01-01

Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

Guideline for PET/CT imaging of neuroendocrine neoplasms with {sup 68}Ga-DOTA-conjugated somatostatin receptor targeting peptides and {sup 18}F-DOPA

Energy Technology Data Exchange (ETDEWEB)

Bozkurt, Murat Fani [Hacettepe University Faculty of Medicine Department of Nuclear Medicine, Ankara (Turkey); Virgolini, Irene; Decristoforo, Clemens [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Balogova, Sona [Comenius University and St. Elisabeth Oncology Institute, Department of Nuclear Medicine, Bratislava (Slovakia); Tenon Hospital AP-HP and Universite Pierre et Marie Curie, Department of Nuclear Medicine, Paris (France); Beheshti, Mohsen [St. Vincent' s Hospital, PET-CT Center, Department of Nuclear Medicine and Endocrinology, Linz (Austria); Paracelsus Medical University, Department of Nuclear Medicine, Salzburg (Austria); Rubello, Domenico [Santa Maria della Misericordia Hospital, Department of Nuclear Medicine, PET Center and Medical Physics and Radiology, Rovigo (Italy); Ambrosini, Valentina; Fanti, Stefano [University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Bologna (Italy); Kjaer, Andreas [National University Hospital and University of Copenhagen, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Delgado-Bolton, Roberto [San Pedro Hospital and Centre for Biomedical Research of La Rioja (CIBIR), Department of Diagnostic Imaging (Radiology) and Nuclear Medicine, Logrono (Spain); Kunikowska, Jolanta [Medical University of Warsaw, Nuclear Medicine, Warsaw (Poland); Oyen, Wim J.G. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London (United Kingdom); Chiti, Arturo [Humanitas University, Nuclear Medicine Department, Rozzano, MI (Italy); Giammarile, Francesco [University of Lyon, Nuclear Medicine, Lyon (France)

2017-08-15

Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using {sup 68}Ga-DOTA-conjugated peptides, as well as {sup 18}F-DOPA imaging for various neuroendocrine neoplasms. The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with {sup 68}Ga-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts. (orig.)

Selective central activation of somatostatin receptor 2 increases food intake, grooming behavior and rectal temperature in rats.

Science.gov (United States)

Stengel, A; Goebel, M; Wang, L; Rivier, J; Kobelt, P; Monnikes, H; Tache, Y

2010-08-01

The consequences of selective activation of brain somatostatin receptor-2 (sst2) were assessed using the sst2 agonist, des-AA(1,4-6,11-13)-[DPhe(2),Aph7(Cbm),DTrp(8)]-Cbm-SST-Thr-NH2. Food intake (FI) was monitored in ad libitum fed rats chronically implanted with an intracerebroventricular (i.c.v.) cannula. The sst(2) agonist injected i.c.v. at 0.1 and 1 microg/rat dose-dependently increased light phase FI from 2 to 6 hours post injection (2.3+/-0.5 and 7.5+/-1.2 respectively vs. vehicle: 0.2+/-0.2 g/300 g bw, P<0.001). Peptide action was reversed by i.c.v. injection of the sst2 antagonist, des-AA(1,4-6,11-13)-[pNO(2)-Phe(2),DCys(3),Tyr(7),DAph(Cbm)8]-SST-2Nal-NH(2) and not reproduced by intraperitoneal injection (30 microg/rat). The sst(2) antagonist alone i.c.v. significantly decreased the cumulative 14-hours dark phase FI by 29.5%. Other behaviors, namely grooming, drinking and locomotor activity were also increased by the sst(2) agonist (1 microg/rat, i.c.v.) as monitored during the 2(nd) hour post injection while gastric emptying of solid food was unaltered. Rectal temperature rose 1 hour after the sst(2) agonist (1 microg/rat, i.c.v.) with a maximal response maintained from 1 to 4 hours post injection. These data show that selective activation of the brain sst(2) receptor induces a feeding response in the light phase not associated with changes in gastric emptying. The food intake reduction following sst(2) receptor blockade suggests a role of this receptor in the orexigenic drive during the dark phase.

Studies in rats on octreotide labelled with Ga-67: A potential radiopharmaceutical agent for the treatment of somatostatin receptor-positive tumours

International Nuclear Information System (INIS)

Lazniekova, A.; Laznieek, M.; Trejtnar, F.; Maecke, H.R.

2001-01-01

The paper presents the preparation, biodistribution and analysis of elimination mechanisms of 67 Ga-[DFO]-octreotide in rats. For labelling of the ligand with 67 Ga, desferrioxamine B (DFO) coupled to octreotide via the succinyl linker has been shown to form a stable chelating agent for binding of 67 Ga. The radiopharmaceutical was prepared by direct chelating of 67 Ga 3+ with [DFO]-octreotide in a slightly acidic reaction medium with high radiochemical purity. Pharmacokinetics of 67 Ga-[DFO]-octreotide of radioactivity in rats has shown relatively rapid elimination of the compound from the body with a long-term retention in the kidney and organs with high somatostatin receptor density. The agent was eliminated mostly by urine predominantly by the mechanism of glomerular filtration. (author)

Change of expression of renal alpha1-adrenergic receptor and angiotensin II receptor subtypes with aging in rats.

Science.gov (United States)

Li, Yan-Fang; Cao, Xiao-Jing; Bai, Xue-Yuan; Lin, Shu-Peng; Shi, Shu-Tian

2010-04-01

It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (page and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (prenal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.

Development of radiotracers for imaging NR2B subtype NMDA receptors with positron emission tomography

International Nuclear Information System (INIS)

Labas, R.

2007-01-01

The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ( 11 C or 18 F)

Regulation of somatostatin release in the nervous system of the rat

International Nuclear Information System (INIS)

Sheppard, M.

1979-08-01

This thesis represents the work done to study the release of somatostatin from the rat central nervous system in vitro, providing some evidence for a physiological role for somatostatin. Somatostatin was measured by a sensitive and specific radioimmunoassay devoloped in the laboratory. Chapter 2 reviews the literature on hypothalamic peptides and control of an anterior pituitary function, somatostatin, other central nervous system peptides and neurosecretion. Chapter 3 describes the central nervous system tissue dissection technique, the radioimmunoassay for somatostatin and the tissue levels of somatostatin immunoreactivity in different areas of the central nervous system. Chapter 4 deals with the release of immunoreactive somatostatin from incubated rat hypothalamus in vitro and the influence of other hormones and neuropeptides on this release. Chapter 5 describes the preparation of isolated nerve endings (synaptosomes) from four different areas of rat brain, the localisation of somatostatin to the synaptosome fraction of brain homogenates and the release of somatostatin from these synaptosomes. Chapter 6 deals with the release of somatostatin from incubated rat spinal cord in vitro. Chapter 7 presents the results of the characterisation of released immunoreactive material, the technique utilised being serial dilution of immunoreactive material and comparison to the standard curve, Sephadex gel chromatography, affinity chromatography, and the effect of released immunoreactive somatostatin on growth hormone release from perifused hemipituitaries in vitro, i.e. biological activity. Chapter 8 provides a summary of the main conclusions reached in this study and is followed by the Appendix describing chemical and biochemical methods, histological techniques, and statistical methods

Union of 99m Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer

International Nuclear Information System (INIS)

Rodriguez C, J.; Ramirez I, M.T.; Ferro F, G.; Pedraza L, M.

2005-01-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide 99m Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with 99m Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The 99m Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide 99m Tc-UBI and the 99m TcO 4 . The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the 99m Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the 99m Tc-UBI and the 99m TcO 4 one doesn

Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells

DEFF Research Database (Denmark)

Egerod, Kristoffer L; Engelstoft, Maja S; Lund, Mari L

2015-01-01

In the stomach, somatostatin (SST) acts as a general paracrine negative regulator of exocrine secretion of gastric acid and pepsinogen and endocrine secretion of gastrin, ghrelin, and histamine. Using reporter mice expressing red fluorescent protein (RFP) under control of the SST promotor, we hav...

Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors.

Science.gov (United States)

Mirzaei, Siroos; Bastati, Brigitte; Lipp, Rainer W; Knoll, Peter; Zojer, Niklas; Ludwig, Heinz

2011-01-01

Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. All patients demonstrated (177)Lu-DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc-EDDA/HYNIC-TOC. Copyright © 2011 S. Karger AG, Basel.

On the role of subtype selective adenosine receptor agonists during proliferation and osteogenic differentiation of human primary bone marrow stromal cells.

Science.gov (United States)

Costa, M Adelina; Barbosa, A; Neto, E; Sá-e-Sousa, A; Freitas, R; Neves, J M; Magalhães-Cardoso, T; Ferreirinha, F; Correia-de-Sá, P

2011-05-01

Purines are important modulators of bone cell biology. ATP is metabolized into adenosine by human primary osteoblast cells (HPOC); due to very low activity of adenosine deaminase, the nucleoside is the end product of the ecto-nucleotidase cascade. We, therefore, investigated the expression and function of adenosine receptor subtypes (A(1) , A(2A) , A(2B) , and A(3) ) during proliferation and osteogenic differentiation of HPOC. Adenosine A(1) (CPA), A(2A) (CGS21680C), A(2B) (NECA), and A(3) (2-Cl-IB-MECA) receptor agonists concentration-dependently increased HPOC proliferation. Agonist-induced HPOC proliferation was prevented by their selective antagonists, DPCPX, SCH442416, PSB603, and MRS1191. CPA and NECA facilitated osteogenic differentiation measured by increases in alkaline phosphatase (ALP) activity. This contrasts with the effect of CGS21680C which delayed HPOC differentiation; 2-Cl-IB-MECA was devoid of effect. Blockade of the A(2B) receptor with PSB603 prevented osteogenic differentiation by NECA. In the presence of the A(1) antagonist, DPCPX, CPA reduced ALP activity at 21 and 28 days in culture. At the same time points, blockade of A(2A) receptors with SCH442416 transformed the inhibitory effect of CGS21680C into facilitation. Inhibition of adenosine uptake with dipyridamole caused a net increase in osteogenic differentiation. The presence of all subtypes of adenosine receptors on HPOC was confirmed by immunocytochemistry. Data show that adenosine is an important regulator of osteogenic cell differentiation through the activation of subtype-specific receptors. The most abundant A(2B) receptor seems to have a consistent role in cell differentiation, which may be balanced through the relative strengths of A(1) or A(2A) receptors determining whether osteoblasts are driven into proliferation or differentiation. Copyright © 2010 Wiley-Liss, Inc.

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide

International Nuclear Information System (INIS)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna; Traub-Weidinger, Tatjana; Widmann, Gerlig

2013-01-01

The aim of this study was to evaluate the impact of 68 Ga-labelled DOTA 0 -lanreotide ( 68 Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or 68 Ga-labelled DOTA 0 ,Tyr 3 -octreotide ( 68 Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or 68 Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent 68 Ga-DOTA-LAN PET to evaluate a treatment option with 90 Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. 68 Ga-DOTA-LAN and 68 Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of 68 Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p 68 Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p 68 Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV max ) regarding the primary tumour in 25 patients (p 68 Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. 68 Ga-DOTA-TOC revealed more tumour sites than 68 Ga-DOTA-LAN (106 vs 53). The tumour to background ratios for tumour and liver calculated from SUV max measurements were significantly higher for 68 Ga-DOTA-TOC than 68 Ga

Morphological Imaging in the Localization of Neuroendocrine Gastroenteropancreatic Tumors Found by Somatostatin Receptor Scintigraphy

International Nuclear Information System (INIS)

Saga, T.; Doi, R.; Endo, K.; Shimatsu, A.; Koizumi, K.; Ichikawa, T.; Yamamoto, K.; Noguchi, S.; Ishibashi, M.; Machinami, R.; Nakamura, K.; Sakahara, H.

2005-01-01

Purpose: To evaluate the necessity of morphological images (MI) in reading somatostatin receptor scintigraphy (SRS) in patients with suspected neuroendocrine gastroenteropancreatic (GEP) tumors. Material and Methods: A Japanese multicenter clinical trial of SRS was conducted in 40 patients with suspected GEP tumors. Three experienced radiologists interpreted the images in three separate sessions in a blinded manner (1: SRS images alone, 2: MI alone, 3: SRS and MI analyzed simultaneously), and the reading results of each session were compared. In addition, the diagnostic abilities of SRS, MI and SRS alone and simultaneous SRS and MI readings were compared for patients where final diagnosis was obtained. Results: SRS detected more suspected lesions (positive or inconclusive uptake) than morphological images did (51 vs 27 lesions), but included many physiological uptakes detected as positive or inconclusive uptakes. Combined reading of SRS and morphological images helped to correctly recognize these physiological uptakes, and also helped in determining the anatomical localization of the abnormal uptakes. Combined reading of SRS and morphological images gave the highest diagnostic impact. Conclusion: The sensitivity of SRS with regard to GEP is high. However the specificity is very low. Morphologic imaging is necessary for the exclusion of physiological uptake and correct anatomic location of an abnormal tracer uptake. The combined reading of SRS and morphologic imaging studies gives the highest diagnostic impact

Structural determinants for selective recognition of peptide ligands for endothelin receptor subtypes ETA and ETB.

Science.gov (United States)

Lättig, Jens; Oksche, Alexander; Beyermann, Michael; Rosenthal, Walter; Krause, Gerd

2009-07-01

The molecular basis for recognition of peptide ligands endothelin-1, -2 and -3 in endothelin receptors is poorly understood. Especially the origin of ligand selectivity for ET(A) or ET(B) is not clearly resolved. We derived sequence-structure-function relationships of peptides and receptors from mutational data and homology modeling. Our major findings are the dissection of peptide ligands into four epitopes and the delineation of four complementary structural portions on receptor side explaining ligand recognition in both endothelin receptor subtypes. In addition, structural determinants for ligand selectivity could be described. As a result, we could improve the selectivity of BQ3020 about 10-fold by a single amino acid substitution, validating our hypothesis for ligand selectivity caused by different entrances to the receptors' transmembrane binding sites. A narrow tunnel shape in ET(A) is restrictive for a selected group of peptide ligands' N-termini, whereas a broad funnel-shaped entrance in ET(B) accepts a variety of different shapes and properties of ligands.

Somatostatin receptor scintigraphy and magnetic resonance imaging in recurrent medullary thyroid carcinoma: A comparative study

International Nuclear Information System (INIS)

Doerr, U.; Wuerstlin, S.; Frank-Raue, K.; Raue, F.; Hehrmann, R.; Iser, G.; Scholz, M.; Guhl, L.; Buhr, H.J.; Bihl, H.

1993-01-01

In a prospective study, 18 patients with recurrent medullary thyroid carcinoma (MTC) underwent magnetic resonance imaging (MRI) of the neck and mediastinum and somatostatin receptor scintigraphy (SRS) with 111 In-labeled pentetreotide. In nine patients with macroscopic MTC, 17 corresponding lesions were found on MRI and SRS; in addition, 13 suspicious lesions were seen on SRS only. Histological confirmation was available for 19 metastatic lesions, showing MRI to be true positive in 13 metastases, SRS in 18. In minimal residual disease (n=10), MRI and SRS were compared with the histological findings in three patients and with selective venous catheterization (SVC) in seven patients. Corresponding findings on MRI and SVC were seen in one of seven, whereas SRS and SVC showed concordant localization of tumor recurrence in five of seven. Histological examination demonstrated MTC tissue in one of three cases; MRI and SRS were false positive in one of three cases, while in the others the interpretation remained uncertain. In conclusion, SRS is a promising imaging modality for localization of MTC recurrence. MRI provides better spatial resolution and thus facilitates the planning of surgery for macroscopic metastases. In minimal residual disease, SRS turned out to be superior in detecting occult MTC recurrence, confirming SVC findings. (orig.)

Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.

Science.gov (United States)

de Fiebre, C M; Meyer, E M; Henry, J C; Muraskin, S I; Kem, W R; Papke, R L

1995-01-01

Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents.

Calcitonin gene-related peptide and somatostatin releases correlated with the area under the lafutidine concentration-time curve in human plasma.

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Ikawa, K; Shimatani, T; Azuma, Y; Inoue, M; Morikawa, N

2006-08-01

To examine the effects of the histamine H(2)-receptor antagonist, lafutidine, at clinical dosage (10 mg tablet after a standardized meal) on plasma levels of the gastrointestinal peptides, calcitonin gene-related peptide (CGRP), somatostatin and gastrin. Six healthy male volunteers ate a standardized meal, and received either lafutidine orally at a dose of 10 mg or water only (control). Blood samples were taken before and up to 4 h after the drug administration. Plasma lafutidine concentrations were determined by high pressure liquid chromatography. Pharmacokinetic analysis of lafutidine was performed using one-compartmental model. The levels of immunoreactive substances of plasma CGRP, somatostatin and gastrin were measured by enzyme immunoassay, and the amount of peptide release was calculated by the trapezoidal method. Lafutidine significantly increased plasma CGRP levels at 1, 1.5, 2.5 and 4 h and the total amount of CGRP release (192 +/- 14.0 pg.h/mL) compared with the control group (128 +/- 21.5 pg.h/mL). Lafutidine significantly increased the plasma somatostatin levels at 1 and 1.5 h, and the total amount of somatostatin released (107 +/- 18.2 pg.h/mL) compared with the control (78.4 +/- 7.70 pg.h/mL). The area under the drug concentration-time curve (AUC) from 0 to 4 h after administration correlated well with the Delta-CGRP and Delta-somatostatin release but not with total amount of gastrin released. However, plasma gastrin levels were significantly elevated at 1.5 h after drug administration. Lafutidine at clinical dosage increases plasma CGRP and the somatostatin. The amounts released correlated with the AUC of lafutidine in humans. These results suggest that the increased release of CGRP and somatostatin may contribute to its gastroprotective and anti-acid secretory effect.

Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes.

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Morrison, R Ray; Teng, Bunyen; Oldenburg, Peter J; Katwa, Laxmansa C; Schnermann, Jurgen B; Mustafa, S Jamal

2006-10-01

To examine ischemic tolerance in the absence of A(1) adenosine receptors (A(1)ARs), isolated wild-type (WT) and A(1)AR knockout (A(1)KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A(1)AR deletion and/or ischemia-reperfusion. A(1)KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A(1)AR deletion. After 20 min of ischemia, CF was attenuated in A(1)KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A(1)KO hearts (54.4 +/- 5.1 vs. WT 81.1 +/- 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A(1)KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A(1)AR transcript in A(1)KO hearts, and the message for A(2A), A(2B), and A(3) adenosine receptors was similar in uninstrumented A(1)KO and WT hearts. Ischemia-reperfusion increased A(2B) mRNA expression 2.5-fold in both WT and A(1)KO hearts without changing A(1) or A(3) expression. In WT hearts, ischemia transiently doubled A(2A) mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A(1)KO hearts. Together, these data affirm the cardioprotective role of A(1)ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.

Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism.

Science.gov (United States)

Green, Torrian L; Burket, Jessica A; Deutsch, Stephen I

2016-07-01

NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice. The data implicate an age-dependent contribution of GluN2A-containing NMDA receptors to the regulation of normal social interaction in mice. Specifically, at a dose of PEAQX devoid of any effect on locomotor activity and mouse rotarod performance, the social interaction of 8-week old mice was disrupted without any effect on the social salience of a stimulus mouse. Moreover, PEAQX attenuated stereotypic behavior emerging during social interaction in 4- and 8-week old mice. However, PEAQX had no effect on spontaneous alternations, a measure of spatial working memory, suggesting that neural circuits mediating sociability and spatial working memory may be discrete and dissociable from each other. Also, the data suggest that the regulation of stereotypic behaviors and sociability may occur independently of each other. Because expression of GluN2A-containing NMDA receptors occurs at a later developmental stage, they may be more involved in mediating the pathogenesis of ASDs in patients with histories of "regression" after a period of normal development than GluN2B receptors. Copyright © 2016 Elsevier Inc. All rights

ERK, Akt, and STAT5 are differentially activated by the two growth hormone receptors subtypes of a teleost fish (Oncorhynchus mykiss

Directory of Open Access Journals (Sweden)

Jeffrey eKittilson

2011-09-01

Full Text Available Previously, we found that the teleost fish, rainbow trout, possesses two growth hormone receptor (GHR subtypes that display distinct ligand binding and agonist-induced regulation features. In this study, we used Chinese hamster ovary-K1 cells stably transfected individually with the two trout GHR subtypes, GHR1 and GHR2, to elucidate receptor-effector pathway linkages. Growth hormone (GH stimulated rapid (5-10 min phosphorylation of ERK, Akt, JAk2, and STAT5 in both GHR1- and GHR2-expressing cells; however; STAT5 was activated to a greater extent through GHR1 than through GHR2, whereas ERK and Akt were activated to a greater through GHR2 than through GHR1. Although blockade of the ERK pathway had no effect on the activation of Akt, inhibition of PI3k-Akt partially prevented activation of ERK, suggesting cross-talk between the ERK and PI3K-Akt pathways. JAK2 inhibition completely blocked activation of ERK, Akt, and STAT5, suggesting that all of these pathways link to GHR1 and GHR2 via JAK2. These findings establish important receptor-effector pathway linkages and suggest that the GHR subtypes of teleost fish may be functionally distinct.

Dose-dependent EEG effects of zolpidem provide evidence for GABA(A) receptor subtype selectivity in vivo.

Science.gov (United States)

Visser, S A G; Wolters, F L C; van der Graaf, P H; Peletier, L A; Danhof, M

2003-03-01

Zolpidem is a nonbenzodiazepine GABA(A) receptor modulator that binds in vitro with high affinity to GABA(A) receptors expressing alpha(1) subunits but with relatively low affinity to receptors expressing alpha(2), alpha(3), and alpha(5) subunits. In the present study, it was investigated whether this subtype selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and 25 mg) of zolpidem were administered to rats in an intravenous infusion over 5 min. The time course of the plasma concentrations was determined in conjunction with the change in the beta-frequency range of the EEG as pharmacodynamic endpoint. The concentration-effect relationship of the three doses showed a dose-dependent maximum effect and a dose-dependent potency. The data were analyzed for one- or two-site binding using two pharmacodynamic models based on 1) the descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for GABA(A) receptor modulators that aims to separates drug- and system-specific properties, thereby allowing the estimation of in vivo affinity and efficacy. The application of two-site models significantly improved the fits compared with one-site models. Furthermore, in contrast to the descriptive model, the mechanism-based PK/PD model yielded dose-independent estimates for affinity (97 +/- 40 and 33,100 +/- 14,800 ng x ml(-1)). In conclusion, the mechanism-based PK/PD model is able to describe and explain the observed dose-dependent EEG effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo.

G protein-coupled receptor transmembrane binding pockets and their applications in GPCR research and drug discovery: a survey.

Science.gov (United States)

Kratochwil, Nicole A; Gatti-McArthur, Silvia; Hoener, Marius C; Lindemann, Lothar; Christ, Andreas D; Green, Luke G; Guba, Wolfgang; Martin, Rainer E; Malherbe, Pari; Porter, Richard H P; Slack, Jay P; Winnig, Marcel; Dehmlow, Henrietta; Grether, Uwe; Hertel, Cornelia; Narquizian, Robert; Panousis, Constantinos G; Kolczewski, Sabine; Steward, Lucinda

2011-01-01

G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor. © 2011 Bentham Science Publishers

Cysteamine induces cholecystokinin release from the duodenum. Evidence for somatostatin as an inhibitory paracrine regulator of cholecystokinin secretion in the rat

International Nuclear Information System (INIS)

Abucham, J.; Reichlin, S.

1990-01-01

To determine whether cholecystokinin secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced in vivo with cysteamine (250 mg/kg body wt, IV) or anti-somatostatin antiserum in anaesthetized rats and in vitro with cysteamine (30 micrograms/mL) in a rat duodenum-incubation system. Cholecystokinin secretion was assessed in vivo by measuring amylase in duodenal perfusates collected at 10-minute intervals for 1 hour and in vitro by a carboxy-terminal radioimmunoassay. Cysteamine induced a marked decrease in duodenal immunoreactive somatostatin both in vivo (50%) and in vitro (60%). The rate of amylase secretion increased from 9.7 +/- 2.1 U (mean +/- SE) to 28.0 +/- 4.8 U at 20 minutes (P less than 0.001). The cholecystokinin-receptor antagonist CR-1392 abolished amylase response for 30 minutes, whereas the more potent antagonists Asperlicin (18.0 mg/kg body wt, IV) and L-364,718 (0.25 mg/kg body wt, IV) caused prolonged blockade. The rate of amylase secretion in gastrectomized animals increased from 7.2 +/- 2.0 U to 15.0 +/- 2.2 U 20 minutes after cysteamine administration (P less than 0.01), indicating that the effect was not due to the presence of gastrin. In vitro, cysteamine caused a nearly fourfold increase in cholecystokinin secretion compared with controls (63.1 +/- 4.9 vs. 15.2 +/- 3.7, respectively; P less than 0.001). In vivo immunoneutralization of circulating somatostatin with a high-affinity and high-capacity antiserum produced no significant change in the rate of amylase secretion. These results suggest that cholecystokinin secretion is tonically inhibited by somatostatin and that this effect is mediated by locally secreted (paracrine) but not by circulating somatostatin

Stereocontrolled dopamine receptor binding and subtype selectivity of clebopride analogues synthesized from aspartic acid.

Science.gov (United States)

Einsiedel, Jürgen; Weber, Klaus; Thomas, Christoph; Lehmann, Thomas; Hübner, Harald; Gmeiner, Peter

2003-10-06

Employing the achiral 4-aminopiperidine derivative clebopride as a lead compound, chiral analogues were developed displaying dopamine receptor binding profiles that proved to be strongly dependent on the stereochemistry. Compared to the D1 receptor, the test compounds showed high selectivity for the D2-like subtypes including D2(long), D2(short), D3 and D4. The highest D4 and D3 affinities were observed for the cis-3-amino-4-methylpyrrolidines 3e and the enantiomer ent3e resulting in K(i) values of 0.23 and 1.8 nM, respectively. The benzamides of type 3 and 5 were synthesized in enantiopure form starting from (S)-aspartic acid and its unnatural optical antipode.

Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties.

Science.gov (United States)

Casale, Amanda E; Foust, Amanda J; Bal, Thierry; McCormick, David A

2015-11-25

The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main

Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

NARCIS (Netherlands)

J. Nonnekens (Julie); M. van Kranenburg (Melissa); C.E.M.T. Beerens (Cecile); M. Suker (Mustafa); M. Doukas (Michael); C.H.J. van Eijck (Casper); M. de Jong (Marcel); D.C. van Gent (Dik)

2016-01-01

textabstractMetastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with

Long-term activation upon brief exposure to xanomleline is unique to M1 and M4 subtypes of muscarinic acetylcholine receptors.

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Eva Šantrůčková

Full Text Available Xanomeline is an agonist endowed with functional preference for M1/M4 muscarinic acetylcholine receptors. It also exhibits both reversible and wash-resistant binding to and activation of these receptors. So far the mechanisms of xanomeline selectivity remain unknown. To address this question we employed microfluorometric measurements of intracellular calcium levels and radioligand binding to investigate differences in the short- and long-term effects of xanomeline among muscarinic receptors expressed individually in Chinese hamster ovary cells. 1/One-min exposure of cells to xanomeline markedly increased intracellular calcium at hM1 and hM4, and to a lesser extent at hM2 and hM3 muscarinic receptors for more than 1 hour. 2/Unlike the classic agonists carbachol, oxotremorine, and pilocarpine 10-min exposure to xanomeline did not cause internalization of any receptor subtype. 3/Wash-resistant xanomeline selectively prevented further increase in intracellular calcium by carbachol at hM1 and hM4 receptors. 4/After transient activation xanomeline behaved as a long-term antagonist at hM5 receptors. 5/The antagonist N-methylscopolamine (NMS reversibly blocked activation of hM1 through hM4 receptors by xanomeline. 6/NMS prevented formation of xanomeline wash-resistant binding and activation at hM2 and hM4 receptors and slowed them at hM1, hM3 and hM5 receptors. Our results show commonalities of xanomeline reversible and wash-resistant binding and short-time activation among the five muscarinic receptor subtypes. However long-term receptor activation takes place in full only at hM1 and hM4 receptors. Moreover xanomeline displays higher efficacy at hM1 and hM4 receptors in primary phasic intracellular calcium release. These findings suggest the existence of particular activation mechanisms specific to these two receptors.

Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: First comparative results using the somatostatin analogues Lu-177 DOTA-NOC and Lu-177 DOTA-TATE

International Nuclear Information System (INIS)

Wehrmann, C.; Senftleben, S.; Baum, R.P.

2005-01-01

Peptide receptor radionuclide therapy (PRRT) is used in our department since 5 years (approx. 400 applications) for the treatment of patients with metastatic neuroendocrine tumors. Of all known peptides, the somatostatin analogue DOTA-NOC shows in vitro the highest affinity to somatostatin receptors (sstr) 3 and 5 and a very high affinity to sstr 2. We studied the in vivo behaviour of the two peptides DOTA-NOC and DOTA-TATE (highest affinity to sstr 2) by the use of different parameters like tumor and organ uptake, effective half-lifes (kinetics) and mean absorbed organ and tumor doses. We studied 27 patients with metastatic neuroendocrine tumors with high somatostatin expression, as verified prior to treatment by Ga-68 DOTA-NOC receptor PET/CT or somatostatin receptor scintigraphy (Tc-99m EDDA-Hynic TOC or In-111 OctreoScan, planar and SPECT). 22 patients (8M and 14F; aged 619 years) were treated with 2500 6790 MBq Lu-177 DOTA-TATE. Another 5 patients (1M and 4F, aged 6310 years) were treated with 4000 7400 MBq Lu-177 DOTA-NOC. Labelling efficiency and radiochemical purity using Lutetium-177 chloride (obtained from PerkinElmer Life Sciences, USA) were constantly over 99.5%. Whole-body scans (anterior/posterior) were performed at 0.5h, 3h, 24h, 48h, 72h and 96h p.i. ROIs were drawn over the whole-body, organs, and different metastases (mainly in the liver). Blood samples were obtained in 12 patients after therapy with Lu-177 DOTA-TATE over 5 days for calculating the kinetics in blood. The ROI results were used to determine the uptake and effective half-life in different organs (kidney, spleen, liver, bone etc.) and the tumor residence times. By means of geometric mean, and after background correction, the ROI results were also used to calculate the estimated absorbed organ and tumor doses using the OLINDA software. Compared to Lu-177 DOTA-TATE (=100%), the uptake of Lu-177 DOTA-NOC was higher for the whole-body (45%) and for normal tissues (28%), and also in the

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide.

Science.gov (United States)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Traub-Weidinger, Tatjana; Uprimny, Christian; von Guggenberg, Elisabeth; Decristoforo, Clemens; Warwitz, Boris; Widmann, Gerlig; Virgolini, Irene Johanna

2013-02-01

The aim of this study was to evaluate the impact of (68)Ga-labelled DOTA(0)-lanreotide ((68)Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or (68)Ga-labelled DOTA(0),Tyr(3)-octreotide ((68)Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or (68)Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent (68)Ga-DOTA-LAN PET to evaluate a treatment option with (90)Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. (68)Ga-DOTA-LAN and (68)Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of (68)Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for (68)Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. (68)Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV(max)) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to (68)Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. (68)Ga-DOTA-TOC revealed more tumour sites than (68)Ga

A new class of pyrazolo[5,1-c][1,2,4]triazines as γ-aminobutyric type A (GABAA) receptor subtype ligand: synthesis and pharmacological evaluation.

Science.gov (United States)

Guerrini, Gabriella; Ciciani, Giovanna; Daniele, Simona; Martini, Claudia; Costagli, Camilla; Guarino, Chiara; Selleri, Silvia

2018-05-15

A comparison between compounds with pyrazolo[1,5-a]pyrimidine structure (series 4-6) and pyrazolo[5,1-c][1,2,4]triazine core (series 9) as ligands at GABA A -receptor subtype, was evaluated. Moreover, for pyrazolotriazine derivatives having binding recognition, the interaction on recombinant rat α(1-3,5) GABA A receptor subtypes, was performed. Among these latter, emerge compounds 9c, 9k, 9l, 9m and 9n as α1-selective and 9h as α2-selective ligands. Copyright © 2018 Elsevier Ltd. All rights reserved.

Structure-Based Prediction of Subtype Selectivity of Histamine H3 Receptor Selective Antagonists in Clinical Trials

DEFF Research Database (Denmark)

Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder

2011-01-01

applications, including treatment of Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity.(1) However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity...... and antagonists. We find that E2065.46 contributes most in binding H3 selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH3HR and hH4HR are involved in H3/ H4 subtype selectivity. In addition, we find that M3786.55 in hH3HR provides...... additional hydrophobic interactions different from hH4HR (the corresponding amino acid of T3236.55 in hH4HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH3HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2...

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue

NARCIS (Netherlands)

Fiebrich, H. -B.; van den Berg, G.; Kema, I. P.; Links, T. P.; Kleibeuker, J. H.; van Beek, A. P.; Walenkamp, A. M. E.; Sluiter, W. J.; de Vries, E. G. E.

2010-01-01

P>Background Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels

Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase

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Julie Simard

2009-01-01

Full Text Available An agonist-occupied β2-adrenergic receptor (β2-AR recruits G protein receptor kinase-2 (GRK2 which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the two β-AR subtypes. Using transiently transfected HEK 293 cells expressing either β1- or β2-AR, we also observed that in presence of an agonist, β2-AR, but not β1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is, β1×β2-AR can activate the PI-3K/Akt pathway whereas β2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K by β2- or β1×β2-AR stimulation. Ligand-mediated internalization of the β2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further that β2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.

Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

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Melis, Marleen; Krenning, Eric P.; Bernard, Bert F.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Barone, Raffaella [UCL, Centre of Nuclear Medicine and Laboratory of PET, Brussels (Belgium); Visser, Theo J. [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)

2005-10-01

Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1-24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [{sup 111}In-DTPA]octreotide, the effects of three inhibitory substances were explored in rats. Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The anti-megalin immunohistochemical staining pattern showed a strong similarity with the renal [{sup 111}In-DTPA]octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged d-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [{sup 111}In-DTPA]octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Renal retention of [{sup 111}In-DTPA]octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part. (orig.)

Association Between Imaging Characteristics and Different Molecular Subtypes of Breast Cancer.

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Wu, Mingxiang; Ma, Jie

2017-04-01

Breast cancer can be divided into four major molecular subtypes based on the expression of hormone receptor (estrogen receptor and progesterone receptor), human epidermal growth factor receptor 2, HER2 status, and molecular proliferation rate (Ki67). In this study, we sought to investigate the association between breast cancer subtype and radiological findings in the Chinese population. Medical records of 300 consecutive invasive breast cancer patients were reviewed from the database: the Breast Imaging Reporting and Data System. The imaging characteristics of the lesions were evaluated. The molecular subtypes of breast cancer were classified into four types: luminal A, luminal B, HER2 overexpressed (HER2), and basal-like breast cancer (BLBC). Univariate and multivariate logistic regression analyses were performed to assess the association between the subtype (dependent variable) and mammography or 15 magnetic resonance imaging (MRI) indicators (independent variables). Luminal A and B subtypes were commonly associated with "clustered calcification distribution," "nipple invasion," or "skin invasion" (P cancers showed association with persistent enhancement in the delayed phase on MRI and "clustered calcification distribution" on mammography (P breast tumor, which are potentially useful tools in the diagnosis and subtyping of breast cancer. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes.

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Olsen, Richard W

2015-01-01

GABAA receptors (GABA(A)Rs) mediate rapid inhibitory transmission in the brain. GABA(A)Rs are ligand-gated chloride ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABA(A)Rs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABA(A)Rs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site and the high-affinity, relevant to intoxication, ethanol site. The benzodiazepine site is specific for certain GABA(A)R subtypes, mainly synaptic, while the ethanol site is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the mammalian GABA(A)R protein, allow homology modeling of GABA(A)R subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation. © 2015 Elsevier Inc. All rights reserved.

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes

DEFF Research Database (Denmark)

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies...

Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in endocrine gastro-entero-pancreatic tumours

International Nuclear Information System (INIS)

Lebtahi, R.; Genin, R.; Rouzet, F.; Bleicner-Perez, S.; Lievre, A.; Scigliano, S.; Vialle, C.; Le Guludec, D.; Cadiot, G.; Sobhani, I.; Mignon, M.

2005-01-01

Somatostatin receptors scintigraphy (SRS) is a sensitive method for the detection of endocrine gastro-entero-pancreatic tumors. The aim of this study was to evaluate the sensitivity of anterior and posterior planar associated to single photon emission computerized tomography (SPECT) compared to anterior and posterior planar associated to additional lateral and oblique views in the detection of abdominal endocrine tumors. One hundred and sixty four patients with endocrine gastro-entero-pancreatic tumors were included in this study. Scintigraphic images were performed after injection of 189 ± 23 MBq of 111 In-Pentetreotide. Abdominal planar images were performed 4 h and 24 hours after injection. Abdominal SPECT was performed at 24 hours. The combination of anterior and posterior abdominal planar images with SPECT using iterative reconstruction detected significantly more tumoral sites compared to multiple planar images (298 versus 280 for the liver, p = 0.01 and 90 versus 88 for coeliac area). In particular liver lesions were better delineated on tomographic slices. The combination of 111 In-Pentetreotide SPECT with anterior and posterior planar images is more sensitive than multiple planar images to detect abdominal endocrine tumors. (author)

Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals

International Nuclear Information System (INIS)

Storch, D.; Schmitt, J.S.; Waldherr, C.; Maecke, H.R.; Waser, B.; Reubi, J.C.

2007-01-01

Radiometallated analogues of the regulatory peptide somatostatin are of interest in the in vivo localization and targeted radiotherapy of somatostatin receptor-overexpressing tumors. An important aspect of their use in vivo is a fast and efficient labeling (complexation) protocol for radiometals along with a high specific activity. We describe in this manuscript synthetic methods for the coupling of two chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid = DOTA) to the bioactive peptide [Tyr 3 ,Thr 8 ]-octreotide (TATE) in order to increase the specific activity (radioactivity in Bq per mole peptide). The full chelator-linker-peptide conjugate was assembled on solid support using standard Fmoc chemistry. Two DOTA-chelators were linked to the peptide using lysine or N,N'-bis(3-aminopropyl)-glycine (Apg); in addition, pentasarcosine (Sar 5 ) was used as a spacer between the chelators and the peptide to probe its influence on biology and pharmacology. Complexation rates with In 3+ and Y 3+ salts and the corresponding radiometals were high, the bis-DOTA-derivatives showed higher complexation rates and gave higher specific activity than DOTA-TATE. Pharmacological and biological data of the complexed molecules did not show significant differences if compared to the parent peptide [ 111/nat In-DOTA]-TATE except for [( 111/nat In-DOTA) 2 -Apg]-TATE which showed a lower binding affinity and rate of internalization into tumor cells. The biodistribution of [( 111/nat In-DOTA)-Lys( 111/nat In-DOTA)]-TATE in the rat tumor model (AR4-2J) showed a high and specific (as shown by a blocking experiment) tracer uptake in somatostatin receptor-positive tissue but a lower tumor uptake compared to [ 111/nat In-DOTA]-TATE. (orig.)

The SOL-2/Neto auxiliary protein modulates the function of AMPA-subtype ionotropic glutamate receptors.

Science.gov (United States)

Wang, Rui; Mellem, Jerry E; Jensen, Michael; Brockie, Penelope J; Walker, Craig S; Hoerndli, Frédéric J; Hauth, Linda; Madsen, David M; Maricq, Andres V

2012-09-06

The neurotransmitter glutamate mediates excitatory synaptic transmission by gating ionotropic glutamate receptors (iGluRs). AMPA receptors (AMPARs), a subtype of iGluR, are strongly implicated in synaptic plasticity, learning, and memory. We previously discovered two classes of AMPAR auxiliary proteins in C. elegans that modify receptor kinetics and thus change synaptic transmission. Here, we have identified another auxiliary protein, SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR. In sol-2 mutants, behaviors dependent on glutamatergic transmission are disrupted, GLR-1-mediated currents are diminished, and GLR-1 desensitization and pharmacology are modified. Remarkably, a secreted variant of SOL-1 delivered in trans can rescue sol-1 mutants, and this rescue depends on in cis expression of SOL-2. Finally, we demonstrate that SOL-1 and SOL-2 have an ongoing role in the adult nervous system to control AMPAR-mediated currents. Copyright © 2012 Elsevier Inc. All rights reserved.

Somatostatin receptor scintigraphy to predict the clinical evolution and therapeutic response of thyroid-associated ophthalmopathy

International Nuclear Information System (INIS)

Nocaudie, M.; Bailliez, A.; Itti, E.; Marchandise, X.

1999-01-01

Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves' disease, four Hashimoto's thyroiditis, two isolated in appearance: Means' syndrome). Each patient underwent hormonal (free T 3 and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and 111 In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. At 4 and 24 h after the intravenous injection of 111 MBq of 111 In-pentetreotide, planar imaging centred on the head and neck (anterior and both lateral views) was carried out. Retrobulbar uptake was assessed by visual semi-quantitative analysis (score given by two independent trained observers) and by quantitative analyses (regions of interest, orbit/brain uptake indices). Patients were ophthalmologically followed up for 6 months and then classified as improved or not. Visual semi-quantitative analysis of 4-h/24-h planar images was correlated with the ophthalmological evolution (χ 2 test, P 111 In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed. (orig.)

Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin sst4 Receptor in the Antinociceptive and Anti-inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide

Directory of Open Access Journals (Sweden)

István Z. Bátai

2018-02-01

Full Text Available Transient receptor potential ankyrin 1 (TRPA1 non-selective ligand-gated cation channels are mostly expressed in primary sensory neurons. Polysulfides (POLYs are Janus-faced substances interacting with numerous target proteins and associated with both protective and detrimental processes. Activation of TRPA1 in sensory neurons, consequent somatostatin (SOM liberation and action on sst4 receptors have recently emerged as mediators of the antinociceptive effect of organic trisulfide dimethyl trisulfide (DMTS. In the frame of the present study, we set out to compare the participation of this mechanism in antinociceptive and anti-inflammatory effects of inorganic sodium POLY and DMTS in carrageenan-evoked hind-paw inflammation. Inflammation of murine hind paws was induced by intraplantar injection of carrageenan (3% in 30 µL saline. Animals were treated intraperitoneally with POLY (17 µmol/kg or DMTS (250 µmol/kg or their respective vehicles 30 min prior paw challenge and six times afterward every 60 min. Mechanical pain threshold and swelling of the paws were measured by dynamic plantar aesthesiometry and plethysmometry at 2, 4, and 6 h after initiation of inflammation. Myeloperoxidase (MPO activity in the hind paws were detected 6 h after challenge by luminescent imaging. Mice genetically lacking TRPA1 ion channels, sst4 receptors and their wild-type counterparts were used to examine the participation of these proteins in POLY and DMTS effects. POLY counteracted carrageenan-evoked mechanical hyperalgesia in a TRPA1 and sst4 receptor-dependent manner. POLY did not influence paw swelling and MPO activity. DMTS ameliorated all examined inflammatory parameters. Mitigation of mechanical hyperalgesia and paw swelling by DMTS were mediated through sst4 receptors. These effects were present in TRPA1 knockout animals, too. DMTS inhibited MPO activity with no participation of the sensory neuron–SOM axis. While antinociceptive effects of

Somatostatin receptor scintigraphy and intraoperative gamma probe detection in the localisation and treatment of pancreatic insulinoma

International Nuclear Information System (INIS)

Loh, Nelson K.; Macdonald, William B.; Dunne, Marina L.; Rao, Sudhakar

2009-01-01

Full text: Aims: We report a case of insulinoma that was successfully enucleated under radio-guidance after an initial unsuccessful laparotomy. This case highlights the utility of Somatostatin Receptor Scintigraphy (SRS) and gamma probe in the localisation and treatment of neuroendocrine tumours. Methods: The patient presented with recurrent hypoglycaemia. An abdominal CT scan identified a lesion in the uncinate process of the pancreas, however, laparotomy with use of intraoperative ultrasound failed to localise the lesion. SRS with SPECTICT was then requested by the surgical team with a view to radio-guided surgery. Results: SRS demonstrated an octreotide-avid tumour in the posterior uncinate process of the pancreas, and confirmed suitability for radio-guided surgery. At re-exploration, the surgeon was again unable to palpate the lesion or localise it with intraoperative ultrasound, however, the lesion was successfully detected and removed with the use of a gamma probe. A postoperative SRS confirmed complete excision and histopathology was diagnostic of insulinoma. Conclusion: This case highlights the utility of SRS in the intraoperative localisation and surgical excision of neuroendocrine tumours. The lesion was unable to be localised clinically or with intraoperative ultrasound but was successfully detected with scintigraphic techniques. The surgical team acknowledge that the use of a gamma probe enabled enucleation of the insulinoma, which obviated the need for an invasive Whipple's procedure.

In vivo somatostatin, vasopressin, and oxytocin synthesis in diabetic rat hypothalamus

International Nuclear Information System (INIS)

Fernstrom, J.D.; Fernstrom, M.H.; Kwok, R.P.

1990-01-01

The in vivo labeling of somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin was studied in rat hypothalamus after third ventricular administration of [35S]cysteine to streptozotocin-diabetic and normal rats. Immunoreactive somatostatin levels in hypothalamus were unaffected by diabetes, as was the incorporation of [35S]cysteine into hypothalamic somatostatin-14 and somatostatin-28. In contrast, immunoreactive vasopressin levels in hypothalamus and posterior pituitary (and oxytocin levels in posterior pituitary) were below normal in diabetic rats. Moreover, [35S]cysteine incorporation into hypothalamic vasopressin and oxytocin (probably mainly in the paraventricular nucleus because of its proximity to the third ventricular site of label injection) was significantly above normal. The increments in vasopressin and oxytocin labeling were reversed by insulin administration. In vivo cysteine specific activity and the labeling of acid-precipitable protein did not differ between normal and diabetic animals; effects of diabetes on vasopressin and oxytocin labeling were therefore not caused by simple differences in cysteine specific activity. These results suggest that diabetes (1) does not influence the production of somatostatin peptides in hypothalamus but (2) stimulates the synthesis of vasopressin and oxytocin. For vasopressin at least, the increase in synthesis may be a compensatory response to the known increase in its secretion that occurs in uncontrolled diabetes

Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER-/PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact?

Science.gov (United States)

Foley, Niamh M; Coll, J M; Lowery, A J; Hynes, S O; Kerin, M J; Sheehan, M; Brodie, C; Sweeney, K J

2017-09-11

Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.

Does somatostatin have a role in the regulation of cortisol secretion in primary pigmented nodular adrenocortical disease (PPNAD)? A clinical and in vitro investigation

NARCIS (Netherlands)

Z. Bram (Zakariae); P. Xekouki (Paraskevi); E. Louiset (Estelle); M. Keil (Mark); D. Avgeropoulos (Dimitrios); C. Giatzakis (Christoforos); M. Nesterova (Maria); N. Sinaii (Ninet); L.J. Hofland (Leo); R. Cherqaoui (Rabia); H. Lefebvre (Hervé); C.A. Stratakis (Constantine)

2014-01-01

textabstractContext: Somatostatin (SST) receptors (SSTRs) are expressed in a number of tissues, including the adrenal cortex, but their role in cortisol secretion has not been well characterized. Objectives: The objective of the study was to investigate the expression of SSTRs in the adrenal cortex

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

DEFF Research Database (Denmark)

Dencker, Ditte; Thomsen, Morgane; Wörtwein, Gitta

2011-01-01

's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based...... site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess...... the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS....

Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig

DEFF Research Database (Denmark)

Schmidt, P T; Hansen, L; Hilsted, L

2004-01-01

BACKGROUND: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin....... METHODS: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. RESULTS: CCK infusion...... at 10(-9) M and 10(-8) M decreased gastrin output to 70.5% +/- 7.6% (n = 8) and 76.3% +/- 3.6% (n = 7) of basal output, respectively. CCK at 10(-10) M had no effect (n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 +/- 38.2% (n = 7) of basal secretion...

(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors

DEFF Research Database (Denmark)

Ahmadian, H; Nielsen, B; Bräuner-Osborne, Hans

1997-01-01

of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3......Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist...... microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM)....

Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

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Kelly, Catriona, E-mail: catriona.kelly@qub.ac.uk [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom); Flatt, Peter R.; McClenaghan, Neville H. [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom)

2010-08-20

Research highlights: {yields} TGP52 cells display enhanced functionality in pseudoislet form. {yields} Somatostatin content was reduced, but secretion increased in high glucose conditions. {yields} Cellular interactions and environment alter the somatostatin status of TGP52 cells. -- Abstract: Introduction: Somatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. Methods: This study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5 mM glucose) or DMEM (25 mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. Results: TGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P < 0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P < 0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. Conclusions: Somatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

International Nuclear Information System (INIS)

Kelly, Catriona; Flatt, Peter R.; McClenaghan, Neville H.

2010-01-01

Research highlights: → TGP52 cells display enhanced functionality in pseudoislet form. → Somatostatin content was reduced, but secretion increased in high glucose conditions. → Cellular interactions and environment alter the somatostatin status of TGP52 cells. -- Abstract: Introduction: Somatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. Methods: This study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5 mM glucose) or DMEM (25 mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. Results: TGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P < 0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P < 0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. Conclusions: Somatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors

NARCIS (Netherlands)

Kasheverov, I.E.; Zhmak, M.N.; Vulfius, C.A.; Corbacheva, E.V.; Mordvintsev, D.Y.; Utkin, Y.N.; van Elk, R.; Smit, A.B.; Tsetlin, V.I.

2006-01-01

α-Conotoxins from Conus snails are indispensable tools for distinguishing various subtypes of nicotinic acetylcholine receptors (nAChRs), and synthesis of α-conotoxin analogs may yield novel antagonists of higher potency and selectivity. We incorporated additional positive charges into α-conotoxins

Molecular subtypes and imaging phenotypes of breast cancer

Directory of Open Access Journals (Sweden)

Nariya Cho

2016-10-01

Full Text Available During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2, and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

Molecular subtypes and imaging phenotypes of breast cancer

Energy Technology Data Exchange (ETDEWEB)

Cho, Nariya [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of)

2016-08-15

During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

Molecular subtypes and imaging phenotypes of breast cancer

International Nuclear Information System (INIS)

Cho, Nariya

2016-01-01

During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics

Current knowledge on the sensitivity of the 68Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours

International Nuclear Information System (INIS)

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; Guggenberg, Elisabeth von; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Ilanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-01-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three 68 Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these 68 Ga-sstr-binding peptides in the imaging setting. On 68 Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUV max ) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUV max -values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUV max -data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with 68 Ga

Current knowledge on the sensitivity of the (68)Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours.

Science.gov (United States)

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; von Guggenberg, Elisabeth; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Llanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-10-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three (68)Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these (68)Ga-sstr-binding peptides in the imaging setting. On (68)Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUVmax) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUVmax-values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUVmax-data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with (68)Ga

The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

DEFF Research Database (Denmark)

Ørgaard, Anne; Holst, Jens J

2017-01-01

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion...... on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn...

Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

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de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

2012-01-01

For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

Evaluation of stereoisomers of 4-fluoroalkyl analogues of 3-quinuclidinyl benzilate in in vivo competition studies for the M1, M2, and M3 muscarinic receptor subtypes in brain

International Nuclear Information System (INIS)

Kiesewetter, Dale O.; Eckelman, William C.; Jaetae, Lee; Paik, Chang H.; Park, Seok G.

1995-01-01

To develop a subtype selective muscarinic acetylcholine receptor (mAChR) antagonist for PET, fluorine-19 labeled alkyl analogues of quinuclidinyl benzilate (QNB) were synthesized by stereoselective reactions. To investigate these analogues for tissue subtype specificity, in vivo competitive binding studies were performed in rat brain using (R)-3-quinuclidinyl (R)-4-[ 125 I]Iodobenzilate (IQNB). Five, fifty, or five-hundred nmol of the non-radioactive ligands were coinjected intravenously with 8 pmol of the radioligand. Cold (R,R)-IQNB blocked (R,R)-[ 125 I]IQNB in a dose-dependent manner, without showing regional specificity. For the (R,S)-fluoromethyl, -fluoroethyl, and -fluoropropyl derivatives, a higher percent blockade was seen at 5 and 50 nmol levels in M2 predominant tissues (medulla, pons, and cerebellum) than in M1 predominant tissues (cortex, striatum and hippocampus). The blockade pattern of the radioligand also correlated qualitatively with the percentage of M2 receptors in the region. The S-quinuclidinyl analogues showed M2 selectivity but less efficient blockade of the radioligand, indicating lower affinities. Radioligand bound to the medulla was inversely correlated to the M2 relative binding affinity of the fluoroalkyl analogues. These results indicate that the nonradioactive ligand blocks the radioligand based on the affinity of the nonradioactive ligand for a particular receptor subtype compared to the affinity of the radioligand for the same receptor subtype. Of the seven compounds evaluated, (R,S)-fluoromethyl-QNB appears to show the most selectivity for the M2 subtypes in competition studies in vivo

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

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Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Subtype classification for prediction of prognosis of breast cancer from a biomarker panel: correlations and indications

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Chen C

2014-02-01

Full Text Available Chuang Chen,1 Jing-Ping Yuan,2,3 Wen Wei,1 Yi Tu,1 Feng Yao,1 Xue-Qin Yang,4 Jin-Zhong Sun,1 Sheng-Rong Sun,1 Yan Li2 1Department of Breast and Thyroid Surgery, Wuhan University, Renmin Hospital, Wuhan, 2Department of Oncology, Zhongnan Hospital of Wuhan University and Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, 3Department of Pathology, The Central Hospital of Wuhan, Wuhan, 4Medical School of Jingchu University of Technology, Jingmen, People’s Republic of China Background: Hormone receptors, including the estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 (HER2, and other biomarkers like Ki67, epidermal growth factor receptor (EGFR, also known as HER1, the androgen receptor, and p53, are key molecules in breast cancer. This study evaluated the relationship between HER2 and hormone receptors and explored the additional prognostic value of Ki67, EGFR, the androgen receptor, and p53. Methods: Quantitative determination of HER2 and EGFR was performed in 240 invasive breast cancer tissue microarray specimens using quantum dot (QD-based nanotechnology. We identified two subtypes of HER2, ie, high total HER2 load (HTH2 and low total HER2 load (LTH2, and three subtypes of hormone receptor, ie, high hormone receptor (HHR, low hormone receptor (LHR, and no hormone receptor (NHR. Therefore, breast cancer patients could be divided into five subtypes according to HER2 and hormone receptor status. Ki67, p53, and the androgen receptor were determined by traditional immunohistochemistry techniques. The relationship between hormone receptors and HER2 was investigated and the additional value of Ki67, EGFR, the androgen receptor, and p53 for prediction of 5-year disease-free survival was assessed. Results: In all patients, quantitative determination showed a statistically significant (P<0.001 negative correlation between HER2 and the hormone receptors and a significant

Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection.

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Yung, Bryan S; Brand, Cameron S; Xiang, Sunny Y; Gray, Charles B B; Means, Christopher K; Rosen, Hugh; Chun, Jerold; Purcell, Nicole H; Brown, Joan Heller; Miyamoto, Shigeki

2017-02-01

Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P 1 , S1P 2 , and S1P 3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to G q . We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα 13 but not Gα 12 , Gα q , or Gα i . Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P 3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P 3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P 3 KO mouse heart. CYM-51736, an S1P 3 -specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P 3 receptor- and Gα 13 -mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P 3 receptors could provide therapeutic benefits in ischemic heart disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Somatostatin-like peptide and regeneration capacities in planarians.

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Bautz, A; Schilt, J

1986-11-01

The presence of a neuropeptide immunologically related to somatostatin (SRIF) has been investigated in the neurosecretory cells of two regenerating planarian species (Dugesia lugubris and Dendrocoelum lacteum). A correlation has been shown between the discharge of the SRIF-like-immunoreactive cells during the first hours after amputation and the capacity to regenerate, and between the persistence of numerous positive cells and the lack of regeneration. These results suggest that somatostatin might play a regulatory (inhibitory) role on the cellular proliferation which leads to the blastema edification.

SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

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Dalm, Simone U; Haeck, Joost; Doeswijk, Gabriela N; de Blois, Erik; de Jong, Marion; van Deurzen, Carolien H M

2017-10-01

Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111 In-DOTA-Tyr 3 -octreotate (SSTR agonist) and 111 In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177 Lu-DOTA-Tyr 3 -octreotate or 177 Lu-DOTA-JR11. Results: 111 In-DOTA-JR11 binding to human BC tissue was significantly higher than 111 In-DOTA-Tyr 3 -octreotate binding ( P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer

Function of brain α2B-adrenergic receptor characterized with subtype-selective α2B antagonist and KO mice.

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Luhrs, Lauren; Manlapaz, Cynthia; Kedzie, Karen; Rao, Sandhya; Cabrera-Ghayouri, Sara; Donello, John; Gil, Daniel

2016-12-17

Noradrenergic signaling, through the α 2A and α 2C adrenergic receptors modulates the cognitive and behavioral symptoms of disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction. However, it is unknown whether the α 2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α 2B receptor in CNS function via the discovery and use of the first subtype-selective α 2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α 2B receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of α 2 subtypes in the brain, we compared α 2B KO, α 2A KO and α 2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α 2B KO mice exhibited increased marble burying and α 2C KO mice exhibited an increased startle response to a pulse stimulus, but otherwise intact prepulse inhibition. To further explore compulsive behavior, we evaluated novelty-induced locomotor hyperactivity and found that α 2B KO and α 2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α 2C KO mice increased activity at lower doses relative to either α 2A KO or WT mice. However, α 2B KO mice exhibited stereotypy at doses of amphetamine that were only locomotor stimulatory to all other genotypes. Following co-administration of AGN-209419 with low-dose amphetamine in WT mice, stereotypy was observed, mimicking the α 2B KO phenotype. These findings suggest that the α 2B receptor is involved in CNS behaviors associated with sensorimotor gating and compulsivity, and may be therapeutically relevant for disorders such as schizophrenia, ADHD, post-traumatic stress disorder, addiction, and

Excessive grooming induced by somatostatin or its analog SMS 201-995

NARCIS (Netherlands)

Wimersma Greidanus, T.B. van; Maigret, C.; Krechting, B.

1987-01-01

Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS

Depletion of somatostatin-like immunoreactivity in the rat central nervous system by cysteamine

International Nuclear Information System (INIS)

Sagar, S.M.; Landry, D.; Millard, W.J.; Badger, T.M.; Arnold, M.A.; Martin, J.B.

1982-01-01

Selective neurotoxins have been of value in providing a means for specifically interfering with the actions of endogenous neurotransmitter candidates. Others have shown cysteamine (CSH) to deplete the gastrointestinal tract and hypothalamus of rats of immunoreactive somatostatin, suggesting a toxic action of that compound directed against somatostatin-containing cells. The present study further defines the actions of cysteamine on somatostatin in the central nervous system. (CNS). Cysteamine hydrochloride administered subcutaneously results in a depletion of somatostatin-like immunoreactivity (SLI) in the retina, brain, and cervical spinal cord of rats. The effect is demonstrable at doses of 30 mg/kg of body weight and above, occurs within 2 to 4 hr of a single injection of the drug, and is largely reversible within 1 week. The mean depletion of SLI observed within the CNS varies from 38% in cerebral cortex to 65% in cervical spinal cord 24 hr following administration of CSH, 300 mg/kg of body weight, s.c. By gel permeation chromatography, all molecular weight forms of SLI are affected, with the largest reductions in those forms that co-chromatograph with synthetic somatostatin-14 and somatostatin-28. These results indicate that CSH has a generalized, rapid, and largely reversible effect in depleting SLI from the rat CNS

Opioid receptor subtypes mediating the noise-induced decreases in high-affinity choline uptake in the rat brain.

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Lai, H; Carino, M A

1992-07-01

Acute (20 min) exposure to 100-dB white noise elicits a naltrexone-sensitive decrease in sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. In the present study, the subtypes of opioid receptors involved were investigated by pretreating rats with microinjection of specific opioid-receptor antagonists into the lateral cerebroventricle before noise exposure. We found that the noise-induced decrease in high-affinity choline uptake in the hippocampus was blocked by pretreatment with either mu-, delta-, or kappa-opioid-receptor antagonists, whereas the effect of noise on frontal cortical high-affinity choline uptake was blocked by a mu- and delta- but not by a kappa-antagonist. These data further confirm the role of endogenous opioids in mediating the effects of noise on central cholinergic activity and indicate that different neural mechanisms are involved in the effects of noise on the frontal cortical and hippocampal cholinergic systems.

Clinical applications of Gallium-68

International Nuclear Information System (INIS)

Banerjee, Sangeeta Ray; Pomper, Martin G.

2013-01-01

Gallium-68 is a positron-emitting radioisotope that is produced from a 68 Ge/ 68 Ga generator. As such it is conveniently used, decoupling radiopharmacies from the need for a cyclotron on site. Gallium-68-labeled peptides have been recognized as a new class of radiopharmaceuticals showing fast target localization and blood clearance. 68 Ga-DOTATOC, 8 Ga-DOTATATE, 68 Ga-DOTANOC, are the most prominent radiopharmaceuticals currently in use for imaging and differentiating lesions of various somatostatin receptor subtypes, overexpressed in many neuroendocrine tumors. There has been a tremendous increase in the number of clinical studies with 68 Ga over the past few years around the world, including within the United States. An estimated ∼10,000 scans are being performed yearly in Europe at about 100 centers utilizing 68 Ga-labeled somatostatin analogs within clinical trials. Two academic sites within the US have also begun to undertake human studies. This review will focus on the clinical experience of selected, well-established and recently applied 68 Ga-labeled imaging agents used in nuclear medicine. - Highlights: ► A summary of the emerging clinical uses of 68 Ga-based radiopharmaceuticals is provided. ► 68 Ga-PET may prove as or more clinically robust than the corresponding 18 F-labeled agents. ► 68 Ga-radiopeptides were studied for targeting of somatostatin receptors subtypes. ► 68 Ga-DOTATOC, 68 Ga-DOTATATE, 68 Ga-DOTANOC, are currently in clinical trials

Contribution of scintigraphy for somatostatin receptors in case of non-iodine-fixating metastases of thyroid epithelioma

International Nuclear Information System (INIS)

Couty, H.; Andrieu, J.M.; Baudet, L.; Faurous, P.; Artus, J.C.; Jaffiol, C.

1997-01-01

The objective of this work was to evaluate the sensitivity and importance of scintigraphy of somatostatin receptors (SSR) in the detection of non iodine-fixating metastases of thyroid epithelioma. We have studied retrospectively 7 patients with a detectable thyroglobulin under hormonal hindrance, amounting after cessation of treatment up to 72 - 1500 μ g/l and a normal post-irradiation therapy (3.7 GBq of 131 I) scintigraphy. These patients (4 F / 3 M), aged from 27 to 74 years (average age, 54 years), were treated by total and ganglionic curettage for papillary cancer of thyroid. Their evolutive surveillance extended from 1 to 24 years (on average, 8.4 years) and they received curative cumulated 131 I activities of 13 to 26 GBq. Each of them benefited by an osseous scintigraphy, of a cervico-thoraco-abdominal TDM and of a 111 In Pentetreotide SSR. The SSR was positive for 4/7 patients showing cervico-mediastinal fixations, the localizations being not detected by TDM. The osseous scintigraphy revealed once to be positive showing a costal lesion already detected by SSR. Cervical non-palpable adenopathies were detected by TDM for one patient. The anatomical-pathological analysis confirmed their thyroid origin. For other two patients the TDM showed suspect pulmonary nodules. These cervical and pulmonary localization were not detected by SSR. The SSR + TDM couple was positive for 6/7 patients. In conclusion, in this series the sensitivity of SSR was estimated to be 57%. Besides, the results obtained showed a net complementarity between the detection performances of SSR and TDM

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

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Heiko Löhr

2018-05-01

Full Text Available Summary: Anorexigenic pro-opiomelanocortin (Pomc/alpha-melanocyte stimulating hormone (αMSH neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin (Sst-neurons that express the melanocortin receptor Mc4r, elevated growth hormone (GH expression in the pituitary, and enhanced somatic growth. Mc4r expression and αMSH responsiveness are conserved in Sst-expressing hypothalamic neurons of mice. Thus, acquired leptin resistance and attenuation of pomca transcription in response to excessive caloric intake may represent an ancient mechanism to promote somatic growth when food resources are plentiful. : The melanocortin system controls energy homeostasis and somatic growth, but the underlying mechanisms are elusive. Löhr et al. identify a functional neural circuit in which Pomc neurons stimulate hypothalamic somatostatin neurons, thereby inhibiting hypophyseal growth hormone production. Excessive feeding and acquired leptin resistance attenuate this pathway, allowing faster somatic growth when food resources are rich. Keywords: Pomc neuron, somatostatin neuron, somatic growth, growth hormone, melanocortin system, high-fat diet, obesity, leptin resistance, zebrafish, mouse

Technetium-99m somatostatin analogues: effect of labelling methods and peptide sequence

International Nuclear Information System (INIS)

Decristoforo, C.; Mather, S.J.

1999-01-01

In this paper the preclinical evaluation of the somatostatin analogue RC160 labelled with technetium-99m using bifunctional chelators (BFCs) based on the hydrazinonicotinamide (HYNIC) and N 3 S system is described and a comparison made with [Tyr 3 ]-octreotide (TOC). Conjugates of both peptides with HYNIC, and of RC160 with benzoyl-MAG 3 and an N 3 S-adipate derivative were prepared and radiolabelling performed at high specific activities using tricine, tricine/nicotinic acid and ethylenediamine-N,N'-diacetic adic (EDDA) as co-ligands for HYNIC conjugates. All conjugates and 99m Tc-labelled peptides showed preserved binding affinity for the somatostatin receptor (IC50, Kd 99m Tc-RC160 derivatives compared with 99m Tc-EDDA/HYNIC-[Tyr 3 ]-octreotide (0.2%-3.5%ID/g vs 9.7%ID/g) and correlated well with the reduced internalisation rate for RC160 derivatives. Our results show that the selection of the labelling approach as well as the right choice of the peptide structure are crucial for labelling peptides with 99m Tc to achieve complexes with favourable biodistribution. Despite the relatively low tumour uptake compared with 99m Tc-EDDA/HYNIC-[Tyr 3 ]-octreotide, 99m Tc-RC160 could play a role in imaging tumours that do not bind octreotide derivatives. (orig.)

Effect of somatostatin on glucose homeostasis in conscious long-fasted dogs

International Nuclear Information System (INIS)

Stevenson, R.W.; Steiner, K.E.; Hendrick, G.K.; Cherrington, A.D.

1987-01-01

The effects of somatostatin plus intraportal insulin and glucagon replacement (pancreatic clamp) on carbohydrate metabolism were studied in conscious dogs fasted for 7 days so that gluconeogenesis was a major contributor to total glucose production. By use of [3- 3 H]glucose, glucose production (R a ) and utilization (R d ) and glucose clearance were assessed before and after implementation of the pancreatic clamp. After an initial control period, somatostatin (0.8 μg·kg -1 ·min -1 ) was infused with intraportal replacement amounts of glucagon and insulin. The insulin infusion rate was varied to maintain euglycemia and then kept constant for 250 min. Plasma glucagon was similar before and during somatostatin infusion, while plasma insulin was lower. Plasma glucose levels remained similar while R a and R d and the ratio of glucose clearance to plasma insulin were significantly increased. Net hepatic lactate uptake and [ 14 C]alanine plus [ 14 C]lactate conversion to [ 14 C]glucose increased. In conclusion, somatostatin alters glucose clearance in 7-day fasted dogs, resulting in changes in several indices of carbohydrate metabolism

Co-expression of two subtypes of melatonin receptor on rat M1-type intrinsically photosensitive retinal ganglion cells.

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Wen-Long Sheng

Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGCs are involved in circadian and other non-image forming visual responses. An open question is whether the activity of these neurons may also be under the regulation mediated by the neurohormone melatonin. In the present work, by double-staining immunohistochemical technique, we studied the expression of MT1 and MT2, two known subtypes of mammalian melatonin receptors, in rat ipRGCs. A single subset of retinal ganglion cells labeled by the specific antibody against melanopsin exhibited the morphology typical of M1-type ipRGCs. Immunoreactivity for both MT1 and MT2 receptors was clearly seen in the cytoplasm of all labeled ipRGCs, indicating that these two receptors were co-expressed in each of these neurons. Furthermore, labeling for both the receptors were found in neonatal M1 cells as early as the day of birth. It is therefore highly plausible that retinal melatonin may directly modulate the activity of ipRGCs, thus regulating non-image forming visual functions.

Peculiarities of diagnostics and clinical course of different immunohistochemical subtypes of breast cancer

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El Khazhzh M.Kh.

2014-09-01

Full Text Available Modern global guidelines in oncology consider treatment of various forms of breast cancer according to molecular tumor subtype. Steroid receptors, epidermal growth factor receptors, p53, Ki67 proliferative activity index and others are the key indicators of aggressiveness of malignant breast tumors. The material for this study was the retrospective study of the standard set of breast cancer immuno¬histochemical markers (estrogen receptors, progesterone, epidermal growth factor type 2 in 8171 patients. 4 groups of patients - luminal A, luminal B, triple negative and HER2-neu positive subtypes of tumors were identified according to immunohistochemical status. We analyzed overall survival without relapse in 491 patients with breast cancer, clinical data and data of immunohistochemical studies were matched. Based on the investigation it was determined that in the early stages of the disease (1-2 luminal A subtype of cancer is often diagnosed. In the late stages the most common subtype is HER2-neu positive breast cancer. Herewith, patients with luminal A subtype of cancer have the best performance of the overall survival (OS (32,91±2,33 months, and the worst results were found in patients with HER2 - neu positive breast cancer (22,58±1,28 months. The data obtained determine HER2 - neu positive subtype as the most aggressive type of breast cancer, and the luminal A subtype – as the least aggressive one.

99mTc labelled peptides for imaging of peripheral receptors

International Nuclear Information System (INIS)

Mustanser, J.; Anjum, A.

2001-01-01

Several peptides are being used as radiopharmaceuticals for receptor imaging scintigraphy. The peptide receptors are found in the tumours of various sites in the human body. Somatostatin is one of those, which is expressed by a variety of tumours say in brain cortex, medullary carcinoma of thyroid, adrenal glands, pancreas and gut. Therefore neuropeptides based on somatostatin analogues are labelled with different radionuclide, 123 I and 111 In. Efforts are underway to label RC-160 (an analogue of somatostatin) with 99m Tc because of its favourable radiation dosimetry, short half-life, low price, high count rate and better diagnostic efficacy. In this project various methods of labelling RC-160 with different radionuclides 125 I and 99m Tc have been studied in detail. Radioiodination of RC-160 was tried with 125 I using the iodogen method as directed and then with Chloramine T method. Labelling of RC-160 peptide with 99m Tc was done using two different aspects. Direct labelling with 99m Tc and indirect labelling with 99m Tc using double chelating agents. Radiochemical quality control was carried out applying instant thin layer chromatography using ITLC-SG strips in 85% of methanol. Later the HPLC analysis was used for its evaluation. To label RC-160 with 99m Tc the approach of direct labelling was attempted first. 46% labelling could be achieved with 95% of radiochemical purity. The biodistribution of 99m Tc-RC-160 complex in rats has also been studied to determine uptake in various sites of somatostatin receptors. Eventually, attempt was made to synthesize biomolecule by conjugating Boc protected RC-160 with benzoyl MAG-3. As a result 80% of Boc-RC-160 went under conjugation with benzoyl MAG-3. (author)

Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

Science.gov (United States)

Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

2016-06-01

In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms

DEFF Research Database (Denmark)

Engelund Luna, Iben; Monrad, Nina; Binderup, Tina

2016-01-01

, and biochemical features as well as treatment and prognosis. DESIGN: Twenty-three patients with p-dSOM (9 duodenal, 12 pancreatic, 2 unknown primary tumour) were identified from our prospective neuroendocrine tumour (NET) database, and data according to the study aims were recorded. RESULTS: Of the 9 patients...... with duodenal SOM the m/f ratio was 4/5. All males and one female had NF-1. Seven patients had stage 1A-B and 2 had stage 2B disease. The Ki-67 index was 1-5% (median 2%). Plasma somatostatin was elevated in patients with 2B disease. Of the 14 patients with pancreatic SOM or unknown primary tumour the m/f ratio...... was 2/12. One male had MEN-1. Five had stage 1A-2B and nine had stage 4. The Ki-67 index was 1-40% (median 7%). Plasma somatostatin was elevated in seven patients. Patients reported symptoms related to the somatostatinoma syndrome, but none fulfilled the criteria for a full syndrome. Primary tumour...

Current knowledge on the sensitivity of the {sup 68}Ga-somatostatin receptor positron emission tomography and the SUV{sub max} reference range for management of pancreatic neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; Guggenberg, Elisabeth von; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Ilanos Geraldo; Rodrigues, Margarida; Uprimny, Christian [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

2016-10-15

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three {sup 68}Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these {sup 68}Ga-sstr-binding peptides in the imaging setting. On {sup 68}Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUV{sub max}) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUV{sub max}-values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUV{sub max}-data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients

Somatostatin receptor scintigraphy to predict the clinical evolution and therapeutic response of thyroid-associated ophthalmopathy

Energy Technology Data Exchange (ETDEWEB)

Nocaudie, M.; Bailliez, A.; Itti, E. [Centre Hospitalier Regional et Universitaire, Lille (France). Service Central de Medecine Nucleaire et Imagerie Fonctionnelle; Bauters, C.; Wemeau, J.L. [Clinique d`Endocrinologie, Centre Hospitalier Regional et Universitaire de Lille (France); Marchandise, X.

1999-05-01

Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves` disease, four Hashimoto`s thyroiditis, two isolated in appearance: Means` syndrome). Each patient underwent hormonal (free T{sub 3} and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and {sup 111}In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. At 4 and 24 h after the intravenous injection of 111 MBq of {sup 111}In-pentetreotide, planar imaging centred on the head and neck (anterior and both lateral views) was carried out. Retrobulbar uptake was assessed by visual semi-quantitative analysis (score given by two independent trained observers) and by quantitative analyses (regions of interest, orbit/brain uptake indices). Patients were ophthalmologically followed up for 6 months and then classified as improved or not. Visual semi-quantitative analysis of 4-h/24-h planar images was correlated with the ophthalmological evolution ({chi}{sup 2} test, P<0.01). All ten patients in whom scintigraphy was considered positive were clinically improved at 6 months, and of the seven patients in whom scintigraphy was negative, six were not improved. Nevertheless, objective quantitative analysis did not succeed in confirming these results. We conclude that {sup 111}In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed

99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives.

Science.gov (United States)

Decristoforo, C; Mather, S J; Cholewinski, W; Donnemiller, E; Riccabona, G; Moncayo, R

2000-09-01

[111In-diethylene triamine penta-acetic acid-D-Phe1]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99mTc-EDDA/HYNIC-TOC were compared with those of 111In-DTPA-octreotide in six cases, and with those of 111In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111In-DTPA-octreotide but faster than that of 111In-DOTA-TOC, while urinary excretion was lower compared with the 111In derivatives. Semi-quantitative region of interest analysis showed that 99mTc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99mTc images. We conclude that 99mTcEDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111In-labelled octreotide derivatives.

99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours: first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives

International Nuclear Information System (INIS)

Decristoforo, C.; Cholewinski, W.; Donnemiller, E.; Riccabona, G.; Moncayo, R.

2000-01-01

[ 111 In-diethylene triamine penta-acetic acid-d-Phe 1 ]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99m Tc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99m Tc-EDDA/HYNIC-TOC were compared with those of 111 In-DTPA-octreotide in six cases, and with those of 111 In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111 In-DTPA-octreotide but faster than that of 111 In-DOTA-TOC, while urinary excretion was lower compared with the 111 In derivatives. Semi-quantitative region of interest analysis showed that 99m Tc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111 In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99m Tc images. We conclude that 99m Tc-EDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111 In-labelled octreotide derivatives. (orig.)

Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa.

Science.gov (United States)

Hadgu, Endale; Seifu, Daniel; Tigneh, Wondemagegnhu; Bokretsion, Yonas; Bekele, Abebe; Abebe, Markos; Sollie, Thomas; Merajver, Sofia D; Karlsson, Christina; Karlsson, Mats G

2018-02-14

Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa. In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases. The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer. The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and

Patient-specific dosimetry in peptide receptor radionuclide therapy: a clinical review

International Nuclear Information System (INIS)

Chalkia, M.T.; Stefanoyiannis, A.P.; Chatziioannou, S.N.; Efstathopoulos, E.P.; Round, W.H.; Nikiforidis, G.C.

2015-01-01

Neuroendocrine tumours (NETs) belong to a relatively rare class of neoplasms. Nonetheless, their prevalence has increased significantly during the last decades. Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment approach for inoperable or metastasised NETs. The therapeutic effect is based on the binding of radiolabelled somatostatin analogue peptides with NETs’ somatostatin receptors, resulting in internal irradiation of tumours. Pre-therapeutic patient-specific dosimetry is essential to ensure that a treatment course has high levels of safety and efficacy. This paper reviews the methods applied for PRRT dosimetry, as well as the dosimetric results presented in the literature. Focus is given on data concerning the therapeutic somatostatin analogue radiopeptides 111 In-[DTPA o , D -Phe 1 ]-octreotide ( 111 In-DTPA-octreotide), 90 Y-[DOTA o ,Tyr 3 ]-octreotide ( 90 Y-DOTATOC) and 177 Lu-[DOTA o ,Tyr 3 ,Thr 8 ]-octreotide ( 177 Lu-DOTATATE). Following the Medical Internal Radiation Dose (MIRD) Committee formalism, dosimetric analysis demonstrates large interpatient variability in tumour and organ uptake, with kidneys and bone marrow being the critical organs. The results are dependent on the image acquisition and processing protocol, as well as the dosimetric imaging radiopharmaceutical.

The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study.

Science.gov (United States)

Mendez, Maria Andreina; Horder, Jamie; Myers, Jim; Coghlan, Suzanne; Stokes, Paul; Erritzoe, David; Howes, Oliver; Lingford-Hughes, Anne; Murphy, Declan; Nutt, David

2013-05-01

GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [(11)C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA α5 subtype. These results provide initial evidence of a GABAA α5 deficit in ASD and support further investigations of the GABA system in this disorder. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Reproductive profiles and risk of breast cancer subtypes

DEFF Research Database (Denmark)

Brouckaert, Olivier; Rudolph, Anja; Laenen, Annouschka

2017-01-01

Background: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. Methods: We used...... pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer...... the risk for TNBC (OR = 0.78, CI 0.70-0.88, p diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC....

Somatostatin receptor PET in neuroendocrine tumours: {sup 68}Ga-DOTA{sup 0},Tyr{sup 3}-octreotide versus {sup 68}Ga-DOTA{sup 0}-lanreotide

Energy Technology Data Exchange (ETDEWEB)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [Vienna Medical University, Department of Nuclear Medicine, Vienna (Austria); Widmann, Gerlig [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria)

2013-03-15

The aim of this study was to evaluate the impact of {sup 68}Ga-labelled DOTA{sup 0}-lanreotide ({sup 68}Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or {sup 68}Ga-labelled DOTA{sup 0},Tyr{sup 3}-octreotide ({sup 68}Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or {sup 68}Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent {sup 68}Ga-DOTA-LAN PET to evaluate a treatment option with {sup 90}Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 {+-} 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. {sup 68}Ga-DOTA-LAN and {sup 68}Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of {sup 68}Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for {sup 68}Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. {sup 68}Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV{sub max}) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to {sup 68}Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. {sup 68}Ga

The radioimmunoassay and physiology of somatostatin in the pancreas and gastrointestinal tract.

Science.gov (United States)

McIntosh, C; Arnold, R

1978-05-01

Radioimmunoassays for somatostain have demonstrated that high concentrations of the polypeptide are present in the pancreas and gastrointestinal tract of a number of species. Although measurement in tissue extracts is relatively unproblematic, detection and characterization of somatostatin-like material in plasma has proved technically difficult. Studies of pancreatic somatostatin release in vitro suggest a possible function in the regulation of islet hormone secretion, but the mode of action remains to be elucidated. Although, at present, no clinical relevance can be attributed to the somatostain radioimmunoassay reports of somatostatin secreting tumors and changes in stomach tissue content in patients with ulcer disease indicate a contributory role in the pathophysiology of certain disease states.

Peptide receptor chemoradionuclide therapy in small cell carcinoma: from bench to bedside

International Nuclear Information System (INIS)

Lewin, Jeremy; Rao, Aparna; Mileshkin, Linda; Cullinane, Carleen; Akhurst, Tim; Eu, Peter; Waldeck, Kelly; Watkins, D.N.; Hicks, Rodney J.

2015-01-01

Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary, have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chemoradionuclide therapy (PRCRT). In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT. Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by 68 Ga-DOTA-octreotate (GaTate) (tumour to background uptake ratio = 35). The combination of PRRT using 177 Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value < 0.05). PRCRT was associated with significantly prolonged survival versus PRRT (p value = 0.0001) or chemotherapy alone (p value = 0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months. Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC. (orig.)

Peptide receptor chemoradionuclide therapy in small cell carcinoma: from bench to bedside

Energy Technology Data Exchange (ETDEWEB)

Lewin, Jeremy; Rao, Aparna; Mileshkin, Linda [Division of Hematology and Medical Oncology, East Melbourne, VIC (Australia); Cullinane, Carleen [Division of Cancer Research, East Melbourne, VIC (Australia); The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC (Australia); Akhurst, Tim; Eu, Peter [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Waldeck, Kelly [Division of Cancer Research, East Melbourne, VIC (Australia); Watkins, D.N. [Monash University, Monash Institute of Medical Research, Clayton, VIC (Australia); Hicks, Rodney J. [Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC (Australia)

2015-01-15

Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary, have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chemoradionuclide therapy (PRCRT). In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT. Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by {sup 68}Ga-DOTA-octreotate (GaTate) (tumour to background uptake ratio = 35). The combination of PRRT using {sup 177}Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value < 0.05). PRCRT was associated with significantly prolonged survival versus PRRT (p value = 0.0001) or chemotherapy alone (p value = 0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months. Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC. (orig.)

In vitro structure-activity relationship of Re-cyclized octreotide analogues

Energy Technology Data Exchange (ETDEWEB)

Dannoon, Shorouk F. [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Bigott-Hennkens, Heather M. [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Ma Lixin [Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); International Institute of Nano and Molecular Medicine, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Gallazzi, Fabio [Structural Biology Core, University of Missouri, Columbia, MO 65211 (United States); Lewis, Michael R., E-mail: lewismic@missouri.ed [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Jurisson, Silvia S., E-mail: jurissons@missouri.ed [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States)

2010-07-15

Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods: Various octreotide analogue sequences and coordination systems (e.g., S{sub 2}N{sub 2} and S{sub 3}N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with {sup 111}In-DOTA-Tyr{sup 3}-octreotide in AR42J rat pancreatic tumor cells yielded IC{sub 50} values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr{sup 3}-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr{sup 3}-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS{sub 3} and N{sub 2}S{sub 2} coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of {sup 99m}Tc-cyclized analogue 4.

Dopamine receptors - physiological understanding to therapeutic intervention potential

NARCIS (Netherlands)

Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

1999-01-01

There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a

Dopamine receptors - physiological understanding to therapeutic intervention potential

NARCIS (Netherlands)

Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a

Chemokine receptors and cortical interneuron dysfunction in schizophrenia.

Science.gov (United States)

Volk, David W; Chitrapu, Anjani; Edelson, Jessica R; Lewis, David A

2015-09-01

Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; pschizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

Tachykinin receptors in the equine pelvic flexure

International Nuclear Information System (INIS)

Sonea, I.M.; Wilson, D.V.; Bowker, R.M.; Robinson, N.E.

1997-01-01

Tachykinins, of which substance P (SP) is the prototype, are neuropeptides which are widely distributed in the nervous systems. In the equine gut, SP is present in enteric nerves and is a powerful constrictor of enteric muscle; in other species, SP is also known to have potent vasodilatory and pro-inflammatory effects. The specific effects of SP are determined by the subtype of receptor present in the target tissue. There are 3 known subtypes of tachykinin receptors, distinguished by their relative affinities for SP and other tachykinins. The distribution of SP binding sites in the equine pelvic flexure was determined using 125I-Bolton Hunter SP (I-BHSP) autoradiography. Most I-BHSP binding sites were determined to be saturable and specific, therefore presumably representing tachykinin receptors. The greatest degree of I-BHSP binding occurred over very small vessels, and over the muscularis mucosae; I-BHSP binding was also intense over the circular muscle of the muscularis externa and mucosa, and present, although less intense, over the longitudinal muscle of the muscularis externa. Competition of I-BHSP with specific receptor agonists for binding sites in the equine pelvic flexure were used to determine the subtypes of tachykinin receptors present. The neurokinin-1 receptor subtype predominated in the equine pelvic flexure, followed by the neurokinin-3 receptor subtype

Pertussis toxin inhibits somatostatin-induced K+ conductance in human pituitary tumor cells

International Nuclear Information System (INIS)

Yamashita, N.; Kojima, I.; Shibuya, N.; Ogata, E.

1987-01-01

The effect of pertussis toxin on somatostatin-induced K + current was examined in dissociated human pituitary tumor cells obtained from two acromegalic patients. Somatostatin-induced hyperpolarization or K + current was observed in 20 of 23 cells in adenoma 1 and 10 of 11 cells in adenoma 2. After treatment with pertussis toxin for 24 h, these responses were completely suppressed (0/14 in adenoma, 1, 0/10 in adenoma 2). Spontaneous action potentials, K + , Na + , and Ca 2+ currents were well preserved after pertussis toxin treatment. When crude membrane fraction was incubated with [ 32 P]NAD, a 41K protein was ADP-ribosylated by pertussis toxin. Hormone release was inhibited by somatostatin and this inhibition was blocked by pertussis toxin treatment

Greater absolute risk for all subtypes of breast cancer in the US than Malaysia.

Science.gov (United States)

Horne, Hisani N; Beena Devi, C R; Sung, Hyuna; Tang, Tieng Swee; Rosenberg, Philip S; Hewitt, Stephen M; Sherman, Mark E; Anderson, William F; Yang, Xiaohong R

2015-01-01

Hormone receptor (HR) negative breast cancers are relatively more common in low-risk than high-risk countries and/or populations. However, the absolute variations between these different populations are not well established given the limited number of cancer registries with incidence rate data by breast cancer subtype. We, therefore, used two unique population-based resources with molecular data to compare incidence rates for the 'intrinsic' breast cancer subtypes between a low-risk Asian population in Malaysia and high-risk non-Hispanic white population in the National Cancer Institute's surveillance, epidemiology, and end results 18 registries database (SEER 18). The intrinsic breast cancer subtypes were recapitulated with the joint expression of the HRs (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor-2 (HER2). Invasive breast cancer incidence rates overall were fivefold greater in SEER 18 than in Malaysia. The majority of breast cancers were HR-positive in SEER 18 and HR-negative in Malaysia. Notwithstanding the greater relative distribution for HR-negative cancers in Malaysia, there was a greater absolute risk for all subtypes in SEER 18; incidence rates were nearly 7-fold higher for HR-positive and 2-fold higher for HR-negative cancers in SEER 18. Despite the well-established relative breast cancer differences between low-risk and high-risk countries and/or populations, there was a greater absolute risk for HR-positive and HR-negative subtypes in the US than Malaysia. Additional analytical studies are sorely needed to determine the factors responsible for the elevated risk of all subtypes of breast cancer in high-risk countries like the United States.

Hormone-receptor expression and ovarian cancer survival

DEFF Research Database (Denmark)

Sieh, Weiva; Köbel, Martin; Longacre, Teri A

2013-01-01

Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated ...

Memory Effects of Benzodiazepines: Memory Stages and Types Versus Binding-Site Subtypes

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Miroslav M. Savic

2005-01-01

Full Text Available Benzodiazepines are well established as inhibitory modulators of memory processing. This effect is especially prominent when applied before the acquisition phase of a memory task. This minireview concentrates on the putative subtype selectivity of the acquisition-impairing action of benzodiazepines. Namely, recent genetic studies and standard behavioral tests employing subtype-selective ligands pointed to the predominant involvement of two subtypes of benzodiazepine binding sites in memory modulation. Explicit memory learning seems to be affected through the GABAA receptors containing the α1 and α5 subunits, whereas the effects on procedural memory can be mainly mediated by the α1 subunit. The pervading involvement of the α1 subunit in memory modulation is not at all unexpected because this subunit is the major subtype, present in 60% of all GABAA receptors. On the other hand, the role of α5 subunits, mainly expressed in the hippocampus, in modulating distinct forms of memory gives promise of selective pharmacological coping with certain memory deficit states.

Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

Energy Technology Data Exchange (ETDEWEB)

Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

1986-06-01

The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

Expression changes of serotonin receptor gene subtype 5HT3a in peripheral blood mononuclear cells from schizophrenic patients treated with haloperidol and Olanzapin.

Science.gov (United States)

Shariati, Gholam Reza; Ahangari, Ghasem; Hossein-nezhad, Arash; Asadi, Seyed Mohammad; Pooyafard, Farzaneh; Ahmadkhaniha, Hamid Reza

2009-09-01

Serotonin receptors are involved in pathophysiology of schizophrenia and may mediate other neurotransmitter effects. We investigated serotonin receptors gene expression in peripheral blood mononuclear cells (PBMC) of naïve schizophrenic patients, before and after treatment. Also serotonin receptor gene expression was compared in two treatment groups including Haloperidol and Olanzapine. The PBMC was separated from whole blood by Ficoll-hypaque. The total cellular RNA was extracted and the cDNA was synthesized. This process was followed by real-time PCR using primer pairs specific for 5HT(3a) serotonin receptor mRNA and beta-actin as internal control. The results showed the presence of subtype of serotonin receptor in lymphocytes. Serotonin gene expression showed significant changes in Olanzapine treatment group which correlated with Clinical Global Impression (CGI) score improvement. In conclusion, the present study has shown that human PBMC express serotonin receptors 5HT(3a). Moreover, clinical symptom improvement of Olanzapin may be demonstrated by a change in serotonin receptor gene expression.

Identification of the receptors for somatostatin (SST) and cortistatin (CST) in chickens and investigation of the roles of cSST28, cSST14, and cCST14 in inhibiting cGHRH1-27NH2-induced growth hormone secretion in cultured chicken pituitary cells.

Science.gov (United States)

Meng, Fengyan; Huang, Guian; Gao, Shunyu; Li, Juan; Yan, Zhenxin; Wang, Yajun

2014-03-25

Somatostatin receptors (SSTRs) are proposed to mediate the actions of somatostatin (SST) and its related peptide, cortistatin (CST), in vertebrates. However, the identity, functionality, and tissue expression of these receptors remain largely unknown in most non-mammalian vertebrates including birds. In this study, five SSTRs (named cSSTR1, cSSTR2, cSSTR3, cSSTR4, cSSTR5) were cloned from chicken brain by RT-PCR. Using a pGL3-CRE-luciferase reporter system, we demonstrated that activation of each cSSTR expressed in CHO cells by cSST28, cSST14 and cCST14 treatment could inhibit forskolin-induced luciferase activity of CHO cells, indicating the functional coupling of all cSSTRs to Gi protein(s). Interestingly, cSSTR1-4 expressed in CHO cells could be activated by cSST28, cSST14 and cCST14 with high potencies, suggesting that they may function as the receptors common for these peptides. In contrast, cSSTR5 could be potently activated by cSST28 only, indicating that it is a cSST28-specific receptor. Using RT-PCR, wide expression of cSSTRs was detected in chicken tissues including pituitary. In accordance with their expression in pituitary, cSST28, cSST14, and cCST14 were demonstrated to inhibit basal and novel cGHRH1-27NH2-induced GH secretion in cultured chicken pituitary cells dose-dependently (0-10nM) by Western blot analysis, suggesting the involvement of cSSTR(s) common for these peptides in mediating their inhibitory actions. Collectively, our study establishes a molecular basis to elucidate the roles of SST/CST in birds and provide insights into the roles of SST/CST in vertebrates, such as their conserved actions on pituitary. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression.

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Thomas P Stricker

2017-03-01

Full Text Available Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+ subtype and fourteen triple negative (TN subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3'UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors.

Somatostatin and serum gastrin in normal subjects and in patients with pernicious anaemia, chronic liver and renal disease

Energy Technology Data Exchange (ETDEWEB)

Le Roith, D; Vinik, A I; Epstein, S; Baron, P; Olkenitzky, M N; Pimstone, B L

1975-09-13

The effects of somatostatin (growth hormone release inhibiting hormone) on basal gastrin were studied in patients suffering from pernicious anaemia and chronic renal and liver disease, and during sequential arginine/insulin-stimulated gastrin release in normal subjects. When basal gastrin concentrations were normal (10-50 pg/ml) in controls and in patients who were in renal and liver failure, somatostatin had no effect on gastrin levels. Raised basal gastrin levels in pernicious anaemia and in 2 cases of chronic renal disease, were significantly inhibited by somatostatin with a half-life (T-half) of 3 to 4 minutes. Arginine infusion caused an insignificant rise in serum gastrin which was unaffected by somatostatin, whereas insulin hypoglycaemia significantly stimulated gastrin release, which was inhibited by somatostatin.

The clinical impact of a combined gamma camera/CT imaging system on somatostatin receptor imaging of neuroendocrine tumours

International Nuclear Information System (INIS)

Hillel, P.G.; Beek, E.J.R. van; Taylor, C.; Lorenz, E.; Bax, N.D.S.; Prakash, V.; Tindale, W.B.

2006-01-01

AIM: With a combined gamma camera/CT imaging system, CT images are obtained which are inherently registered to the emission images and can be used for the attenuation correction of SPECT and for mapping the functional information from these nuclear medicine tomograms onto anatomy. The aim of this study was to evaluate the clinical impact of SPECT/CT using such a system for somatostatin receptor imaging (SRI) of neuroendocrine tumours. MATERIALS AND METHODS: SPECT/CT imaging with 111 In-Pentetreotide was performed on 29 consecutive patients, the majority of whom had carcinoid disease. All SPECT images were first reported in isolation and then re-reported with the addition of the CT images for functional anatomical mapping (FAM). RESULTS: Fifteen of the 29 SPECT images were reported as abnormal, and in 11 of these abnormal images (73%) FAM was found to either establish a previously unknown location (7/11) or change the location (4/11) of at least one lesion. The revised location could be independently confirmed in 64% of these cases. Confirmation of location was not possible in the other patients due to either a lack of other relevant investigations, or the fact that lesions seen in the SPECT images were not apparent in the other investigations. FAM affected patient management in 64% of the cases where the additional anatomical information caused a change in the reported location of lesions. CONCLUSION: These results imply that FAM can improve the reporting accuracy for SPECT SRI with significant impact on patient management

Evidence for Alpha Receptors in the Human Ureter

Science.gov (United States)

Madeb, Ralph; Knopf, Joy; Golijanin, Dragan; Bourne, Patricia; Erturk, Erdal

2007-04-01

An immunohistochemical and western blot expression analysis of human ureters was performed in order to characterize the alpha-1-adrenergic receptor distribution along the length of the human ureteral wall. Mapping the distribution will assist in understanding the potential role alpha -1-adrenergic receptors and their subtype density might have in the pathophysiology of ureteral colic and stone passage. Patients diagnosed with renal cancer or bladder cancer undergoing nephrectomy, nephroureterectomy, or cystectomy had ureteral specimens taken from the proximal, mid, distal and tunneled ureter. Tissues were processed for fresh frozen examination and fixed in formalin. None of the ureteral specimens were involved with cancer. Serial histologic sections and immunohistochemical studies were performed using antibodies specific for alpha-1-adrenergic receptor subtypes (alpha 1a, alpha 1b, alpha 1d). The sections were examined under a light microscope and scored as positive or negative. In order to validate and quantify the alpha receptor subtypes along the human ureter. Western blotting techniques were applied. Human ureter stained positively for alpha -1-adrenergic receptors. Immunostaining appeared red, with intense reaction in the smooth muscle of the ureter and endothelium of the neighboring blood vessels. There was differential expression between all the receptors with the highest staining for alpha-1D subtype. The highest protein expression for all three subtypes was in the renal pelvis and decreased with advancement along the ureter to the distal ureter. At the distal ureter, there was marked increase in expression as one progressed towards the ureteral orifice. The same pattern of protein expression was exhibited for all three alpha -1-adrenergic receptor subtypes. We provide preliminary evidence for the ability to detect and quantify the alpha-1-receptor subtypes along the human ureter which to the best of our knowledge has never been done with

Adenosine receptor desensitization and trafficking.

Science.gov (United States)

Mundell, Stuart; Kelly, Eamonn

2011-05-01

As with the majority of G-protein-coupled receptors, all four of the adenosine receptor subtypes are known to undergo agonist-induced regulation in the form of desensitization and trafficking. These processes can limit the ability of adenosine receptors to couple to intracellular signalling pathways and thus reduce the ability of adenosine receptor agonists as well as endogenous adenosine to produce cellular responses. In addition, since adenosine receptors couple to multiple signalling pathways, these pathways may desensitize differentially, while the desensitization of one pathway could even trigger signalling via another. Thus, the overall picture of adenosine receptor regulation can be complex. For all adenosine receptor subtypes, there is evidence to implicate arrestins in agonist-induced desensitization and trafficking, but there is also evidence for other possible forms of regulation, including second messenger-dependent kinase regulation, heterologous effects involving G proteins, and the involvement of non-clathrin trafficking pathways such as caveolae. In this review, the evidence implicating these mechanisms is summarized for each adenosine receptor subtype, and we also discuss those issues of adenosine receptor regulation that remain to be resolved as well as likely directions for future research in this field. Copyright © 2010 Elsevier B.V. All rights reserved.

Study of pharmacokinetics and biodistribution of radiolabelled receptor specific peptides in laboratory animals

International Nuclear Information System (INIS)

Laznickova, A.; Laznicek, M.; Trejtnar, F.; Maecke, H.R.; Mather, S.J.

2001-01-01

Somatostatin analogues labelled with different radionuclides could be employed for visualization or treatment of somatostatin receptor-positive tumours. An octapeptide 111 In [DTPA] octreotide is a synthetic radiolabelled somatostatin analogue which is currently in clinical use for detecting small neuroendocrine tumours and metastases not detectable by conventional means. However, several other somatostatin analogues have been under development and testing. The aim of this study was to radiolabel selected somatostatin receptor-binding octapeptides by different radionuclides and to report the results of their biodistribution in rats. The study was focused on the direct labelling of vapreotide (RC-160) with 99m Tc, on the conjugates of octreotide with DFO (desferrioxamine) for labelling with 67 Ga, and on the conjugates of octreotide and TOC with DOTA (tetraazacyclo-dodecane tetraacetic acid) for labelling with 88 Y. In the present study, 88 Y isotope instead of 90 Y was used as a label as 88 Y exhibits a longer half life of decay and emits gamma radiation which can be much more easily detected in biological samples than beta emission. The labelling of octreotide analogues with metal radionuclides using derived bifunctional chelates was simple, straightforward and consistently resulted in high radiochemical purity of the product. On the other hand, the application of the direct labelling method for labelling of RC-160 with 99m Tc was difficult because all procedures had to be made under nitrogen atmosphere and an attainment of high yield proved to be highly dependent on the accurate observation of reaction conditions. The labelling efficiency makes an immediate use of the radiolabelled RC-160 for biological studies impossible and it is necessary to involve the purification step into the labelling procedure. All radiolabelled receptor specific peptides under study exhibited rapid radioactivity clearance from the blood and most organs and tissues. On the other hand

Diabetes and Breast Cancer Subtypes.

Directory of Open Access Journals (Sweden)

Heleen K Bronsveld

Full Text Available Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes.This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years, women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR, HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211 and women without diabetes (n = 101, irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55, HER2-negative (OR = 2.84(95%CI:1.11-7.22, and basal-like (OR = 3.14(95%CI:1.03-9.60 tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45 and triple negative (OR = 2.60(95%CI:0.88-7.67 tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general.We found no compelling evidence that women with diabetes

Diabetes and Breast Cancer Subtypes.

Science.gov (United States)

Bronsveld, Heleen K; Jensen, Vibeke; Vahl, Pernille; De Bruin, Marie L; Cornelissen, Sten; Sanders, Joyce; Auvinen, Anssi; Haukka, Jari; Andersen, Morten; Vestergaard, Peter; Schmidt, Marjanka K

2017-01-01

Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes. This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55)), HER2-negative (OR = 2.84(95%CI:1.11-7.22)), and basal-like (OR = 3.14(95%CI:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general. We found no compelling evidence that women with diabetes, treated

High molecular somatostatin, an interfering factor in radioimmunoassay

International Nuclear Information System (INIS)

Diel, F.; Schneider, E.; Baumann, H.

1977-01-01

Cyclic Tyr 1 -somatostatin (Tyr 1 -SRIF) is radioiodinated by the lactoperoxidase method. Purification is achieved by Sephadex G-25 adsorption chromatography. Specific anti-SRIF serum (FA1) has been raised in rabbits. A dose response curve is obtained in the range of 5 - 5,000 pg per tube using an antiserum dilution of 1:2,000. There is little cross-reaction with linear somatostatin and none with ocytocin, (lys-, arg-) vasopressin, valinomycin, polymyxin, insulin, glucagon, human growth hormone (hGH), and thyrotropin-releasing hormone (TRH). For recovery tests, extraction procedures are necessary. Thin-layer chromatography (TLC) and polyacrylamide-disc-electrophoresis (Disc-PAGE) are performed to identify the presumed high molecular 125 I-Tyr 1 -SRIF associate. This high molecular associate may represent an interfering factor in the radioimmunoassay for cyclic SRIF. (orig./AJ) [de

Interferon α subtypes in HIV infection.

Science.gov (United States)

Sutter, Kathrin; Dickow, Julia; Dittmer, Ulf

2018-02-13

Type I interferons (IFN), which are immediately induced after most virus infections, are central for direct antiviral immunity and link innate and adaptive immune responses. However, several viruses have evolved strategies to evade the IFN response by preventing IFN induction or blocking IFN signaling pathways. Thus, therapeutic application of exogenous type I IFN or agonists inducing type I IFN responses are a considerable option for future immunotherapies against chronic viral infections. An important part of the type I IFN family are 12 IFNα subtypes, which all bind the same receptor, but significantly differ in their biological activities. Up to date only one IFNα subtype (IFNα2) is being used in clinical treatment against chronic virus infections, however its therapeutic success rate is rather limited, especially during Human Immunodeficiency Virus (HIV) infection. Recent studies addressed the important question if other IFNα subtypes would be more potent against retroviral infections in in vitro and in vivo experiments. Indeed, very potent IFNα subtypes were defined and their antiviral and immunomodulatory properties were characterized. In this review we summarize the recent findings on the role of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus infection. This includes their induction during HIV/SIV infection, their antiretroviral activity and the regulation of immune response against HIV by different IFNα subtypes. The findings might facilitate novel strategies for HIV cure or functional cure studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

The influence of somatostatin receptor scintigraphy during preoperative staging of non-functioning pancreatic neuroendocrine tumours

International Nuclear Information System (INIS)

Jilesen, A.P.J.; Hoefnagel, S.J.M.; Busch, O.R.C.; Bennink, R.J.; Gouma, D.J.; Nieveen van Dijkum, E.J.M.

2016-01-01

Aim: To determine whether somatostatin receptor scintigraphy (SRS) influences the preoperative staging and clinical management of non-functioning pancreatic neuroendocrine tumours (NF-pNETs). Materials and methods: All SRS examinations performed between 2002–2013 were selected. Patients with NF-pNET were included if both computed tomography (CT) and SRS was performed during preoperative staging. The diagnostic accuracy of CT and SRS for detecting NF-pNET metastases was analysed. Altered TNM classification and changed clinical management were calculated. Changed management was defined as a change from surgical resection into systemic treatment or vice versa. NF-pNETs were defined as tumours without clinical symptoms of hormonal hypersecretion. Results: Overall, 62 patients with NF-pNET were included with a mean age of 57 years (SD: 12.4) 2 . In 28 patients (45%), CT and SRS were correct and in agreement in the detection of primary tumour/metastases. In 34 patients (55%), one of the techniques was incorrect and therefore, there was no agreement. SRS altered the TNM classification in 14 patients (23%) and clinical management in nine patients (15%). In patients without metastases on CT, SRS detected lymph node metastases in one patient. The sensitivity to detect the primary tumour with CT was 95% and with SRS was 73%. In detecting metastases, the sensitivity and specificity were both 85% for CT versus 80% and 90% for SRS. Conclusion: Overall, CT and SRS were in agreement in the detection of NF-pNET. In NF-pNET without suspicious metastatic lesions on CT, SRS has limited value. SRS may be indicated to confirm lesions suspicious for neuroendocrine tumours metastases. - Highlights: • In 28 patients (45%), CT and SRS were correct and in agreement in the detection of primary tumor/metastases. • In 34 patients (55%) one of the modalities was incorrect and therefore, there was no agreement. • Sensitivity to detect the primary tumor with CT and SRS were 95% versus 73

Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

International Nuclear Information System (INIS)

Reubi, Jean Claude; Waser, Beatrice

2003-01-01

Peptide receptors have been found to represent excellent targets for in vivo cancer diagnosis and therapy. Recent in vitro studies have shown that many cancers can overexpress not only one but several peptide receptors concomitantly. One of the challenges for nuclear medicine in this field in the coming decade will be to take advantage of the co-expression of peptide receptors for multireceptor tumour targeting. In vitro receptor studies can reveal which peptide receptor is overexpressed in which tumour and which receptors are co-expressed in an individual tumour; such knowledge is a prerequisite for successful in vivo development. One group of tumours of particular interest in this respect is the neuroendocrine tumours, which have previously been shown often to express peptide receptors. This review summarises our investigations of the concomitant expression of 13 different peptide receptors, in more than 100 neuroendocrine tumours of the human intestine, pancreas and lung, using in vitro receptor autoradiography with subtype-selective ligands. The incidence and density of the somatostatin receptors sst 1 -sst 5 , the VIP receptors VPAC 1 and VPAC 2 , the CCK 1 and CCK 2 receptors, the three bombesin receptor subtypes BB 1 (NMB receptor), BB 2 (GRP receptor) and BB 3 , and GLP-1 receptors were evaluated. While the presence of VPAC 1 and sst 2 was detected in the majority of these neuroendocrine tumours, the other receptors, more differentially expressed, revealed a characteristic receptor pattern in several tumour types. Ileal carcinoids expressed sst 2 and VPAC 1 receptors in virtually all cases and had CCK 1 , CCK 2 , sst 1 or sst 5 in approximately half of the cases; they were the only tumours of this series to express NMB receptors. Insulinomas were characterised by a very high incidence of GLP-1, CCK 2 and VPAC 1 receptors, with the GLP-1 receptors expressed in a particularly high density; they expressed sst 2 in two-thirds and sst 1 in approximately half of

Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

OpenAIRE

Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

1992-01-01

Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and ...

GH and IGF-I induction by passive immunization of rainbow trout Oncorhynchus mykiss Walbaum using a somatostatin 14 antibody

Science.gov (United States)

Inhibition of the growth axis by somatostatin was studied in juvenile rainbow trout using passive immunization with a previously isolated somatostatin antibody (antiSS-14). Upon subcutaneously injection of laying hens (Gallus domesticus) with conjugated somatostatin-14 (SS-14), the antiSS-14 was iso...

AMPA receptor ligands

DEFF Research Database (Denmark)

Strømgaard, Kristian; Mellor, Ian

2004-01-01

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

Somatostatin analogue scintigraphy and tuberculosis: case report

International Nuclear Information System (INIS)

Biancheri, I.; Rudenko, B.; Vautrin, P.; Raddoul, J.; Lamfichek, N.; Kantelip, B.; Mantion, G.

2005-01-01

Scintigraphy using a radiolabelled somatostatin analogue (111 In-pentetreotide) is useful in the detection of neuroendocrine tumors. But this radiopharmaceutical accumulates also in solid tumours or in inflammatory diseases such as granulomatosis. We present a case of 111 In-pentetreotide uptake in a tuberculous adenopathy. (author)

[3H]WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity

International Nuclear Information System (INIS)

Norman, A.B.; Battaglia, G.; Creese, I.

1985-01-01

In the presence of a 30 nM prazosin mask, [ 3 H]-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ([ 3 H]WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [ 3 H] WB4101 binding in cerebral cortex. We have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at [ 3 H]WB4101-binding sites in the presence of 30 nM prazosin and [ 3 H] lysergic acid diethylamide ([ 3 H]LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of [ 3 H]WB4101 is significantly lower than the Bmax of [ 3 H]LSD in various brain regions. WB4101 competition for [ 3 H] LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of [ 3 H]WB4101 binding derived from saturation experiments. This suggests that [ 3 H]WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by [ 3 H]LSD. The selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for [ 3 H]WB4101 but compete for multiple [ 3 H]LSD 5-HT1 binding sites. These data indicate that [ 3 H]WB4101 selectively labels the 5-HT1A serotonin receptor, whereas [ 3 H] LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of [ 3 H]WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of [ 3 H]WB4101 binding

Somatostatin-IRES-Cre Mice: Between Knockout and Wild-Type?

Science.gov (United States)

Viollet, Cécile; Simon, Axelle; Tolle, Virginie; Labarthe, Alexandra; Grouselle, Dominique; Loe-Mie, Yann; Simonneau, Michel; Martel, Guillaume; Epelbaum, Jacques

2017-01-01

The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre (SOM-cre) mouse strains are increasingly used to unravel the physiology of SOM-containing neurons. However, while knock-in targeting strategy greatly improves Cre-Lox system accuracy, recent reports have shown that genomic insertion of Cre construct per se can markedly affect physiological function. We show that Cre transgene insertion into the 3'UTR of the somatostatin gene leads to the selective and massive depletion of endogenous SOM in all tested brain regions. It also strongly impacts SOM-related neuroendocrine responses in a similar manner to what has been reported for SST KO mice: increased corticosterone levels after 30-min restraint stress, decreased amplitude and regularity of ultradian growth hormone secretory patterns accompanied by changes in sexually dimorphic liver gene expression ( serpina1, Cyp2b9, Cyp2a4, Cyp2d9, and Cyp7b1 ). In addition to demonstrating the need for examination of the consequences of Cre transgenesis, these results also reveal how this SOM-cre strain may be a useful tool in studying the functional consequences of moderate to low SOM levels as reported in neurological and psychiatric disorders.

Receptor scintigraphy using the Tc-99M-labelled somatostatin analogue EDDA-TRYCINE-HYNIC-TOC: clinical results in different tumor types and comparison with In-111 DOTATOC during Y-90 DOTATOC radioreceptor therapy

International Nuclear Information System (INIS)

Baum, R.P.; Schmuecking, M.; Fischer, S.; Przetak, C.; Niesen, A.; Maecke, H.R.

2002-01-01

Aim: To evaluate Tc-99m EDDA-TRYCINE-HYNIC-TOC in patients with somatostatin receptor positive tumours (staging, pre-therapeutic dosimetry for radioreceptor therapy and restaging after therapy) in comparison with In-111 DOTATOC. Material and Methods: The Tc-99m labelled somatostatin analogue was synthesized by an optimized procedure in our pharmaceutical laboratory using lyophilized kits (radiochemical purity by HPLC, TLC > 95%, product stability in vitro 4 to 6h). So far, 58 patients (60 examinations) were studied after injection of 580-890 MBq (median 673 MBq) EDDA-TRYCINE-HYNIC-TOC. The histologically proven tumours were neuroendocrine neoplasias, renal carcinomas, bronchial carcinoma, mesothelioma and malignant fibrous histiocytoma. The imaging protocol consisted of whole-body scans and planar images of the tumor region (15 min, 1 h, 2 h, 4 h, 8 h, 24 h p.i.) and additionally SPECT-images (1 h und 4 h p.i.). For semi-quantitative assessment, individual regions of interest (ROI) were drawn in order to generate time-activity curves and to calculate tumour-to-tissue/background ratios which were compared by visual grading (scala 0 to 3+). Furthermore, pharmacokinetic analyses were carried out (radioactivity kinetics in plasma and urine). In some selected patients, image fusion of whole-body scans was performed with CT and/or MRT and/or PET using a NUD software and a HERMES computer. Results: 10 out of 58 patients showed an intense tracer accumulation in the SSTR-positive tumours (visual 3+, tumour/background ratio >2,5). In these patients, radioreceptor therapy was carried out using Y-90 DOTATOC (simultaneous injection von 150 MBq In-111 DOTATOC). All pretherapeutic scans with the Tc-99m labelled ligand (4 h p.i.) showed a similar overall pattern of biodistribution and tumour uptake in comparison to the therapy scans with In-111 / Y-90 DOTATOC (24 h p.i.). The Tc-99m EDDA-TRYCINE-HYNIC-TOC scans (incl. SPECT) offered superior imaging properties with earlier tumour

Effect of somatostatin on nonesterified fatty acid levels modifies glucose homeostasis during fasting

International Nuclear Information System (INIS)

Hendrick, G.K.; Frizzell, R.T.; Cherrington, A.D.

1987-01-01

In the 7-days fasted conscious dog, unlike the postabsorptive conscious dog, somatostatin infusion results in decreased levels of nonesterified fatty acids (NEFA) and increased glucose utilization (R d ) even when insulin and glucagon levels are held constant. The aim of this study was to determine whether NEFA replacement in such animals would prevent the increase in R d . In each of three protocols there was an 80-min tracer equilibration period, a 40-min basal period, and a 3-h test period. During the test period in the first protocol saline was infused, in the second protocol somatostatin was infused along with intraportal replacement amounts of insulin and glucagon (hormone replacement), while in the third protocol somatostatin plus the pancreatic hormones were infused with concurrent heparin plus Intralipid infusion. Glucose turnover was assessed using [3- 3 H]glucose. The peripheral levels of insulin, glucagon, and glucose were similar and constant in all three protocols; however, during somatostatin infusion, exogenous glucose infusion was necessary to maintain euglycemia. The NEFA level was constant during saline infusion and decreased in the hormone replacement protocol. In the hormone replacement plus NEFA protocol, the NEFA level did not change during the first 90-min period and then increased during the second 90-min period. After a prolonged fast in the dog, (1) somatostatin directly or indirectly inhibits adipose tissue NEFA release and causes a decrease in the plasma NEFA level, and (2) this decrease in the NEFA level causes an increase in R d

Pharmacological interference with metabotropic glutamate receptor subtype 7 but not subtype 5 differentially affects within- and between-session extinction of Pavlovian conditioned fear.

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Toth, Iulia; Dietz, Monika; Peterlik, Daniel; Huber, Sabine E; Fendt, Markus; Neumann, Inga D; Flor, Peter J; Slattery, David A

2012-03-01

Fear extinction is defined as the attenuation of a conditioned-fear memory by re-exposing animals to the conditioned stimulus without the aversive stimulus. This process is known to be effectively enhanced via administration of D-cycloserine (DCS), a partial NMDA-receptor agonist. However, other glutamatergic mechanisms, such as interference with metabotropic glutamate receptor (mGluR) subtypes 5 and 7 in the extinction of aversive memories are insufficiently understood. Using the allosteric mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), and DCS for comparison, we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influenced within- and between-session conditioned-fear extinction training and extinction retention in rats. We show that when injected before extinction training, mGluR7 activation with AMN082 enhanced freezing and thereby attenuated within-session fear extinction, whereas both DCS and the mGluR5 receptor antagonist MPEP had no effect on this process. However, these differential drug effects were not long lasting, as no difference in extinction retention were observed 24 h later. Therefore, we assessed whether the compounds affect 24 h consolidation of extinction training following incomplete extinction training (between-session extinction). Similar to DCS, AMN082- but not MPEP-treated rats showed facilitated extinction retention, as exhibited by decreased freezing. Finally, using fluoxetine, we provide evidence that the effect of AMN082 on between-session extinction retention is most likely not via increasing 5-HT transmission. These findings demonstrate that mGluR7 activation differentially modulates conditioned-fear extinction, in dependence on the protocol employed, and suggests drugs with AMN082-like mechanisms as potential add-on drugs following exposure-based psychotherapy for fear-related human

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

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Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

2017-10-06

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Seventh Symposium on Subtypes of Musccarinic Receptors.

Science.gov (United States)

1997-01-01

nociceptive pain, are less than ideal. For mild to moderate pain, the first line of therapy includes aspirin, acetaminophen/ paracetamol , and nonsteroidal...due to receptor degradation triggered by prolonged carbachol occupancy. This down-regulation was accompanied by uncoupling of the M2-receptors after 24...be under control by the m3 mAChR, suggesting a complex receptor regulation of phosphoinositide metabolism, including degradation and synthesis. Future

Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.

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Hillman, Kristin L; Doze, Van A; Porter, James E

2005-08-01

Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective beta-AR antagonists. ICI-118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [alpha-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the beta2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (K(b)) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective beta1-AR antagonists CGP 20712A [(+/-)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2'-hydroxy-3'-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists

Pattern of distant recurrence according to the molecular subtypes in Korean women with breast cancer

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Park Hyung Seok

2012-01-01

Full Text Available Abstract Background Distant recurrence is one of the most important risk factors in overall survival, and distant recurrence is related to a complex biologic interaction of seed and soil factors. The aim of the study was to investigate the association between the molecular subtypes and patterns of distant recurrence in patients with breast cancer. Methods In an investigation of 313 women with breast cancer who underwent surgery from 1994 and 2000, the expressions of estrogen and progestrone receptor (ER/PR, and human epithelial receptor-2 (HER2 were evaluated. The subtypes were defined as luminal-A, luminal-HER2, HER2-enriched, and triple negative breast cancer (TNBC according to ER, PR, and HER2 status. Results Bone was the most common site of distant recurrence. The incidence of first distant recurrence site was significantly different among the subtypes. Brain metastasis was more frequent in the luminal-HER2 and TNBC subtypes. In subgroup analysis, overall survival in patients with distant recurrence after 24 months after surgery was significantly different among the subtypes. Conclusions Organ-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer may be considered.

Somatostatin-immunoreactive senile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques.

Science.gov (United States)

Yamashita, Akiko; Fuchs, Eberhard; Taira, Masato; Yamamoto, Takamitsu; Hayashi, Motoharu

2012-06-01

Previously, we demonstrated decreased expression of somatostatin mRNA in aged macaque brain, particularly in the prefrontal cortex. To investigate whether or not this age-dependent decrease in mRNA is related to morphological changes, we analyzed somatostatin cells in the cerebra of aged Japanese macaques and compared them with those in rats and tree shrews, the latter of which are closely related to primates. Brains of aged macaques, tree shrews, and rats were investigated by immunohistochemistry with special emphasis on somatostatin. We observed degenerating somatostatin-immunoreactive cells in the cortices of aged macaques and tree shrews. Somatostatin-immunoreactive senile plaque-like structures were found in areas 6 and 8 and in the nucleus accumbens of macaques, as well as in the nucleus accumbens and the cortex of aged tree shrews, where amyloid accumulations were observed. Somatostatin degenerations may be related to amyloid accumulations and may play roles in impairments of cognitive functions during aging. © 2012 John Wiley & Sons A/S.

Uneventful octreotide LAR therapy throughout three pregnancies, with favorable delivery and anthropometric measures for each newborn: a case report

Directory of Open Access Journals (Sweden)

Naccache Deeb

2011-08-01

Full Text Available Abstract Introduction The safety of octreotide use, in its short-acting preparation, in pregnancy is still unclear. This report provides the first documentation of uneventful octreotide LAR use during three pregnancies in a woman with bronchial carcinoid-associated adrenocorticotropic hormone-dependent Cushing's syndrome. Case presentation A 25-year-old Arabic woman presented to our emergency department with rapid onset of headache, flaring acne and hirsutism, facial puffiness, weight gain and paroxysmal myopathy, and paranoiac thoughts of rape and sexual intimidation. After undergoing surgical removal of a mass by left lower lung lobectomy, her residual lung disease medical therapy failed. Chronic octreotide LAR injections were initiated as indicated by a positive octreoscan. Follow-up revealed a long-lasting positive response to octreotide. Avidity of octreotide to somatostatin receptor sub-type 2 was later confirmed by a positive somatostatin receptor sub-type 2 in the resected tumor specimen. Against our instructions, the patient had three spontaneous pregnancies leading to delivery of three full-term healthy children while her octreotide LAR therapy continued. Conclusion This case adds more data supporting the potential for the safe use of octreotide and the feasibility of octreotide LAR use during pregnancy, making compliance with the patient's preference not to withdraw octreotide therapy as soon as her pregnancy is confirmed a thoughtful option.

Reducing the n-gram feature space of class C GPCRs to subtype-discriminating patterns

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König Caroline

2014-12-01

Full Text Available G protein-coupled receptors (GPCRs are a large and heterogeneous superfamily of receptors that are key cell players for their role as extracellular signal transmitters. Class C GPCRs, in particular, are of great interest in pharmacology. The lack of knowledge about their full 3-D structure prompts the use of their primary amino acid sequences for the construction of robust classifiers, capable of discriminating their different subtypes. In this paper, we investigate the use of feature selection techniques to build Support Vector Machine (SVM-based classification models from selected receptor subsequences described as n-grams. We show that this approach to classification is useful for finding class C GPCR subtype-specific motifs.

Radiogenomic correlation in lung adenocarcinoma with epidermal growth factor receptor mutations: Imaging features and histological subtypes

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Hong, Su Jin [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Hanyang University, Department of Radiology, School of Medicine, Seoul (Korea, Republic of); Kim, Tae Jung [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Samsung Medical Center, Department of Radiology, Seoul (Korea, Republic of); Choi, Yo Won [Hanyang University, Department of Radiology, School of Medicine, Seoul (Korea, Republic of); Park, Jeong-Soo [Dankook Universicity, Department of Biochemistry, College of Medicine, Cheonan (Korea, Republic of); Chung, Jin-Haeng [Seoul National University Bundang Hospital, Department of Pathology, Seongnam-si, Gyeonggi-do (Korea, Republic of); Lee, Kyung Won [Seoul National University Bundang Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of)

2016-10-15

To correlate imaging features of resected lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and the IASLC/ATS/ERS classification histological subtypes. In 250 consecutive patients with resected lung adenocarcinoma, EGFR mutation status was correlated with demographics, imaging features including ground-glass opacity (GGO) proportion and the IASLC/ATS/ERS classification histological subtypes. EGFR mutations were significantly more frequent in women (54.5 % vs. 38.1 %, p = 0.011) and in never-smokers (54.7 % vs. 35.3 %, p = 0.003). GGO proportion was significantly higher in tumours with EGFR mutation than in those without (30.3 ± 33.8 % vs. 19.0 ± 29.3 %, p = 0.005). EGFR mutation was significantly more frequent in tumours with GGO ≥ 50 % and tumours with any GGO (p = 0.026 and 0.008, respectively). Adenocarcinomas with exon 19 or 21 mutation showed significantly higher GGO proportion than that in EGFR wild-type tumours (p = 0.009 and 0.029, respectively). Absence of GGO was an independent predictor of negative EGFR mutation (odds ratio, 1.81; 95 % confidence interval, 1.16-3.04; p = 0.018). GGO proportion in adenocarcinomas with EGFR mutation was significantly higher than that in EGFR wild-type tumours, and the absence of GGO on CT was an independent predictor of negative EGFR mutation. (orig.)

Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation

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Susan M Farabaugh

2015-04-01

Full Text Available Insulin-like growth factor (IGF signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the IGF1 receptor (IGF1R. Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.

The analgesic effect of clonixine is not mediated by 5-HT3 subtype receptors.

Science.gov (United States)

Paeile, C; Bustamante, S E; Sierralta, F; Bustamante, D; Miranda, H F

1995-10-01

1. The analgesic effect of clonixinate of L-lysine (Clx) in the nociceptive C-fiber reflex in rat and in the writhing test in mice is reported. 2. Clx was administered by three routes, i.v., i.t. and i.c.v., inducing a dose-dependent antinociception. 3. The antinociceptive effect of Clx was 40-45% with respect to the control integration values in the nociceptive C-fiber reflex method. 4. The writhing test yielded ED50 values (mg/kg) of 12.0 +/- 1.3 (i.p.), 1.8 +/- 0.2 (i.t.) and 0.9 +/- 0.1 (i.c.v.) for Clx administration. 5. Ondansetron was not able to antagonize the antinociception response of Clx in the algesiometric tests used. 6. Chlorophenilbiguanide did not produce any significative change in the analgesic effect of Clx in the nociceptive C-fiber reflex method. 7. It is suggested that the mechanism of action of the central analgesia of Clx is not mediated by 5-HT3 subtype receptors.

Proteomic maps of breast cancer subtypes

DEFF Research Database (Denmark)

Tyanova, Stefka; Albrechtsen, Reidar; Kronqvist, Pauliina

2016-01-01

Systems-wide profiling of breast cancer has almost always entailed RNA and DNA analysis by microarray and sequencing techniques. Marked developments in proteomic technologies now enable very deep profiling of clinical samples, with high identification and quantification accuracy. We analysed 40...... oestrogen receptor positive (luminal), Her2 positive and triple negative breast tumours and reached a quantitative depth of >10,000 proteins. These proteomic profiles identified functional differences between breast cancer subtypes, related to energy metabolism, cell growth, mRNA translation and cell......-cell communication. Furthermore, we derived a signature of 19 proteins, which differ between the breast cancer subtypes, through support vector machine (SVM)-based classification and feature selection. Remarkably, only three proteins of the signature were associated with gene copy number variations and eleven were...

Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry.

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Hörsch, Dieter; Ezziddin, Samer; Haug, Alexander; Gratz, Klaus Friedrich; Dunkelmann, Simone; Krause, Bernd Joachim; Schümichen, Carl; Bengel, Frank M; Knapp, Wolfram H; Bartenstein, Peter; Biersack, Hans-Jürgen; Plöckinger, Ursula; Schwartz-Fuchs, Sabine; Baum, R P

2013-01-01

Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.

Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors

DEFF Research Database (Denmark)

Madsen, U; Brehm, L; Schaumburg, Kjeld

1990-01-01

The relationship between conformational flexibility and agonist or antagonist actions at the N-Methyl-D-aspartic acid (NMDA) subtype of central L-glutamic acid (GLU) receptors of a series of racemic piperidinedicarboxylic acids (PDAs) was studied. The conformational analyses were based on 1H NMR...... receptors. Each of the three cyclic acidic amino acids showing NMDA agonist activities was found to exist as an equilibrium mixture of two conformers in aqueous solution. In contrast, the NMDA antagonists cis-2,3-PDA and cis-2,4-PDA as well as the inactive compounds trans-2,5-PDA and cis-2,6-PDA were shown...

Subtypes of attention deficit-hyperactivity disorder (ADHD) and cannabis use.

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Loflin, Mallory; Earleywine, Mitch; De Leo, Joseph; Hobkirk, Andrea

2014-03-01

The current study examined the association between subtypes of attention-deficit/hyperactivity disorder (ADHD) and cannabis use within a sample of 2811 current users. Data were collected in 2012 from a national U.S. survey of cannabis users. A series of logistic regression equations and chi-squares were assessed for proportional differences between users. When asked about the ADHD symptoms they have experienced when not using cannabis, a higher proportion of daily users met symptom criteria for an ADHD diagnoses of the subtypes that include hyperactive-impulsive symptoms than the inattentive subtype. For nondaily users, the proportions of users meeting symptom criteria did not differ by subtype. These results have implications for identifying which individuals with ADHD might be more likely to self-medicate using cannabis. Furthermore, these findings indirectly support research linking relevant cannabinoid receptors to regulatory control.

Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine

DEFF Research Database (Denmark)

Krogsgaard-Larsen, Niels; Delgar, Claudia; Koch, Karina

2017-01-01

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b...... to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C,O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents......), for cloned homomeric kainic acid receptor subtype 1 (GluK1) was attained (Ki = 4 µM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 µM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared...

Establishment of Radiolabelling Method for the Development of Neurodegenerative Disease Imaging Agent Using 5-HT1A Subtype of Receptor Anatagonist

International Nuclear Information System (INIS)

Choi, Sun Ju; Choi, Sang Mu; Kim, On Hee; Hong, Young Don; Park, Kyung Bae

2005-01-01

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain. And it is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy and diagnosis of diseases. Serotonin is synthesized from the amino acid L-tryptophan by sequential hydroxylation and decarboxylation. It is stored in presynaptic vesicles and released from nerve terminals during neuronal firing. One of the best-characterised binding sites for serotonin is the 5-HT1A receptor. This is mainly due to the relatively early discovery of a selective ligand, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for this subpopulation. Thus, many researchers have tried to develop a radioligand capable of assessing in vivo changes in 5-HT1A receptors in depressed subjects, people with anxiety disorders, patients with Alzheimer's disease and schizophrenics. In present study, we studied the radioligands which would play a role in visualization and quantification of this important neuroreceptor for single-photon emission tomography (SPET)

Receptor imaging with a new Tc-99m labelled somatostatin analogue (Tc-99m EDDA-TRYCINE-HYNIC-TOC): first clinical results and comparison with In-111 Dotatoc during radioreceptor therapy with Y-90 Dotatoc

International Nuclear Information System (INIS)

Baum, R.P.; Schmuecking, M.; Fischer, S.; Przetak, C.; Niesen, A.; Maecke, H.R.

2002-01-01

Full text: To evaluate Tc-99m EDDA-TRYCINE-HYNIC-TOC (TET-H-TOC) in patients with somatostatin receptor (SSTR)-positive tumors (staging, pretherapeutic indication for radioreceptor therapy and restaging after therapy) in comparison with In-111 DOTATOC. The Tc-99m labelled somatostatin analogue was synthesized by an optimized procedure in our pharmaceutical lab using lyophilized kits (radiochemical purity by HPLC, TLC > 95 %, product stability in vitro 4 to 6 h). So far, 46 patients (53 examinations) were studied after injection of 580-890 MBq (median 673 MBq) TET-H-TOC. The histologically proven tumors were endocrine neoplasias, renal carcinomas, bronchial carcinoma, mesothelioma and malignant fibrous histiocytoma. The imaging protocol consisted of whole-body scans and planar images of the tumor region (15 min, 1 h, 2 h, 4 h, 8 h, 24 h p.i.) and additionally SPECT-images (1 h and 4 h p.i.). For semi-quantitative assessment, individual regions of interest (ROI) were drawn in order to generate time-activity curves and to calculate tumor-to-tissue/background ratios which were compared by visual grading (scale 0 to 3+). Furthermore, pharmacokinetic analyses were carried out (radioactivity kinetics in plasma and urine). In some selected patients, image fusion of the whole-body scans was performed with CT and/or MRT and/or PET using a HERMES computer. 7 out of 46 patients showed an intense tracer accumulation in the SSTR-positive tumors (visual 3+, tumor / background ratio >2,5). In these patients, radioreceptor therapy was carried out using Y-90 DOTATOC (simultaneous injection of 150 MBq In-111 DOTATOC). All pretherapeutic scans with the Tc-99m labelled ligand (4 h p.i.) showed a similar overall pattern of biodistribution and tumor uptake in comparison to the therapy scans with In-111 / Y-90 DOTATOC 24 h p.i. The Tc-99m EDDA-HYNIC-TOC scans (incl. SPECT) offered superior imaging properties with earlier tumor visualization (all lesions were detected 1 h p.i.) as compared

Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands

DEFF Research Database (Denmark)

Poulsen, Steen Seier

1984-01-01

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output......, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited...... growth factor and bicarbonate from Brunner's glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner's gland secretion is suggested....

Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

Energy Technology Data Exchange (ETDEWEB)

Reubi, Jean Claude; Waser, Beatrice [Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box 62, 3010, Berne (Switzerland)

2003-05-01

Peptide receptors have been found to represent excellent targets for in vivo cancer diagnosis and therapy. Recent in vitro studies have shown that many cancers can overexpress not only one but several peptide receptors concomitantly. One of the challenges for nuclear medicine in this field in the coming decade will be to take advantage of the co-expression of peptide receptors for multireceptor tumour targeting. In vitro receptor studies can reveal which peptide receptor is overexpressed in which tumour and which receptors are co-expressed in an individual tumour; such knowledge is a prerequisite for successful in vivo development. One group of tumours of particular interest in this respect is the neuroendocrine tumours, which have previously been shown often to express peptide receptors. This review summarises our investigations of the concomitant expression of 13 different peptide receptors, in more than 100 neuroendocrine tumours of the human intestine, pancreas and lung, using in vitro receptor autoradiography with subtype-selective ligands. The incidence and density of the somatostatin receptors sst{sub 1}-sst{sub 5}, the VIP receptors VPAC{sub 1} and VPAC{sub 2}, the CCK{sub 1} and CCK{sub 2} receptors, the three bombesin receptor subtypes BB{sub 1} (NMB receptor), BB{sub 2} (GRP receptor) and BB{sub 3}, and GLP-1 receptors were evaluated. While the presence of VPAC{sub 1} and sst{sub 2} was detected in the majority of these neuroendocrine tumours, the other receptors, more differentially expressed, revealed a characteristic receptor pattern in several tumour types. Ileal carcinoids expressed sst{sub 2} and VPAC{sub 1} receptors in virtually all cases and had CCK{sub 1}, CCK{sub 2}, sst{sub 1} or sst{sub 5} in approximately half of the cases; they were the only tumours of this series to express NMB receptors. Insulinomas were characterised by a very high incidence of GLP-1, CCK{sub 2} and VPAC{sub 1} receptors, with the GLP-1 receptors expressed in a

Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor α7 subtype

International Nuclear Information System (INIS)

Ogawa, Mikako; Nishiyama, Shingo; Tsukada, Hideo; Hatano, Kentaro; Fuchigami, Takeshi; Yamaguchi, Hiroshi; Matsushima, Yoshitaka; Ito, Kengo; Magata, Yasuhiro

2010-01-01

Introduction: The nicotinic acetylcholine receptor (nAChR) α7 subtype (α 7 nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled α 7 nAChR ligands, (R)-2-[ 11 C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([ 11 C](R)-MeQAA) and its isomer (S)-[ 11 C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[ 11 C]MeQAA for in vivo imaging of α 7 nAChR in the brain was evaluated in mice and monkeys. Methods: The binding affinity for α 7 nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. Results: The affinity for α 7 nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([ 11 C](R)-MeQAA: 7.68 and [ 11 C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [ 11 C](R)-MeQAA was slow in the hippocampus (α 7 nAChR-rich region) but was rapid in the cerebellum (α 7 nAChR-poor region). On the other hand, the clearance was fast for [ 11 C](S)-MeQAA in all regions. The brain uptake of [ 11 C](R)-MeQAA was decreased by methyllycaconitine (α 7 nAChR antagonist) treatment. In monkeys, α 7 nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [ 11 C](R)-MeQAA, while the uptake was rather homogeneous for [ 11 C](S)-MeQAA. Conclusions: [ 11 C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for α 7 nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain α 7 nAChRs in vivo.

Characterization of the 1H-cyclopentapyrimidine-2,4(1H,3H)-dione derivative (S)-CPW399 as a novel, potent, and subtype-selective AMPA receptor full agonist with partial desensitization properties

DEFF Research Database (Denmark)

Campiani, G; Morelli, E; Nacci, V

2001-01-01

(S)-CPW399 (2b) is a novel, potent, and subtype-selective AMPA receptor full agonist that, unlike (S)-willardiine and related compounds, in mouse cerebellar granule cells, stimulated an increase in [Ca(2+)](i), and induced neuronal cell death in a time- and concentration-dependent manner. Compound...... 2b appears to be a weakly desensitizing, full agonist at AMPA receptors and therefore represents a new pharmacological tool to investigate the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitization....

Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study.

Science.gov (United States)

Troester, Melissa A; Sun, Xuezheng; Allott, Emma H; Geradts, Joseph; Cohen, Stephanie M; Tse, Chiu-Kit; Kirk, Erin L; Thorne, Leigh B; Mathews, Michelle; Li, Yan; Hu, Zhiyuan; Robinson, Whitney R; Hoadley, Katherine A; Olopade, Olufunmilayo I; Reeder-Hayes, Katherine E; Earp, H Shelton; Olshan, Andrew F; Carey, Lisa A; Perou, Charles M

2018-02-01

African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood. Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (≤50 years vs > 50 years) using chi-square tests and analysis of variance tests. Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR = 1.45, 95% CI = 1.02 to 2.06, for Luminal B; OR = 2.04, 95% CI = 1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women. Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Childhood adversities are not a predictors of SSTR4met in alcoholics

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Berent Dominika

2017-10-01

Full Text Available Genome methylation may modulate synaptic plasticity, being a potential background for mental disorder. Adverse childhood experiences (ACEs, known to be frequently reported by patients with alcohol dependence (AD, have been proposed as one of environmental inequities influencing DNA methylation. The study is aiming 1.To assess a promoter region methylation in gene for somatostatin receptor subtype-4 (SSTR4, a receptor for somatostatin, a neurotransmitter engaged in neuroplasticity and memory formation, in patients with AD; 2. To verify if SSTR4 promoter methylation is associated with ACEs and other selected environmental factors. Methodology: 176 patients with AD and 127 healthy controls were interviewed regarding 13 categories of ACEs; a structured self-reported questionnaire - to measure the sociodemographic and clinical characteristics; a module of Catalogue of Healthy Behavior – to assess nutritional health habits; the Alcohol Use Disorders Identification Test – to assess drinking severity. The SSTR4 promoter region methylation status was performed via methylation-specific PCR, and the genotyping for the SSTR4 rs2567608 functional polymorphism - according to the manufacturer’s standard PCR protocol.

Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat

NARCIS (Netherlands)

Gispen, W.H.; Adan, R.A.H.; Szklarczyk, A.W.; Oosterom, J.; Brakkee, J.H.; Nijenhuis, W.A.; Schaaper, W.M.; Meloen, R.H.

1999-01-01

Since the melanocortin MC3 and melanocortin MC4 receptors are the main melanocortin receptor subtypes expressed in rat brain, we characterized the activity and affinity of nine melanocortin receptor ligands using these receptors in vitro, as well as their activity in a well-defined

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors.

Science.gov (United States)

Linares, Andrea; Couling, Leena E; Carrera, Eduardo J; Speth, Robert C

2016-06-07

This protocol describes receptor binding patterns for Angiotensin II (Ang II) in the rat brain using a radioligand specific for Ang II receptors to perform receptor autoradiographic mapping. Tissue specimens are harvested and stored at -80 °C. A cryostat is used to coronally section the tissue (brain) and thaw-mount the sections onto charged slides. The slide-mounted tissue sections are incubated in (125)I-SI-Ang II to radiolabel Ang II receptors. Adjacent slides are separated into two sets: 'non-specific binding' (NSP) in the presence of a receptor saturating concentration of non-radiolabeled Ang II, or an AT1 Ang II receptor subtype (AT1R) selective Ang II receptor antagonist, and 'total binding' with no AT1R antagonist. A saturating concentration of AT2 Ang II receptor subtype (AT2R) antagonist (PD123319, 10 µM) is also present in the incubation buffer to limit (125)I-SI-Ang II binding to the AT1R subtype. During a 30 min pre-incubation at ~22 °C, NSP slides are exposed to 10 µM PD123319 and losartan, while 'total binding' slides are exposed to 10 µM PD123319. Slides are then incubated with (125)I-SI-Ang II in the presence of PD123319 for 'total binding', and PD123319 and losartan for NSP in assay buffer, followed by several 'washes' in buffer, and water to remove salt and non-specifically bound radioligand. The slides are dried using blow-dryers, then exposed to autoradiography film using a specialized film and cassette. The film is developed and the images are scanned into a computer for visual and quantitative densitometry using a proprietary imaging system and a spreadsheet. An additional set of slides are thionin-stained for histological comparisons. The advantage of using receptor autoradiography is the ability to visualize Ang II receptors in situ, within a section of a tissue specimen, and anatomically identify the region of the tissue by comparing it to an adjacent histological reference section.

Regulation of ATP-sensitive K+ channels in insulinoma cells: Activation by somatostatin and protein kinase C and the role of cAMP

International Nuclear Information System (INIS)

De Weille, J.R.; Schmid-Antomarchi, H.; Fosset, M.; Lazdunski, M.

1989-01-01

The actions of somatostatin and of the phorbol ester 4β-phorbol 12-myristate 13-acetate (PMA) were studied in rat insulinoma (RINm5F) cells by electrophysiological and 86 Rb + flux techniques. Both PMA and somatostatin hyperpolarize insulinoma cells by activating ATP-sensitive K + channels. The presence of intracellular GTP is required for the somatostatin effects. PMA- and somatostatin-induced hyperpolarization and channel activity are inhibited by the sulfonylurea glibenclamide. Glibenclamide-sensitive 86 Rb + efflux from insulinoma cells is stimulated by somatostatin in a dose-dependent manner (half maximal effect at 0.7 nM) and abolished by pertussis toxin pretreatment. Mutual roles of a GTP-binding protein, of protein kinase C, and of cAMP in the regulation of ATP-sensitive K + channels are discussed

Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes.

Science.gov (United States)

Newman-Tancredi, Adrian; Cussac, Didier; Quentric, Yann; Touzard, Manuelle; Verrièle, Laurence; Carpentier, Nathalie; Millan, Mark J

2002-11-01

Although certain antiparkinson agents interact with serotonin (5-HT) receptors, little information is available concerning functional actions. Herein, we characterized efficacies of apomorphine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, roxindole, and terguride at human (h)5-HT(1A), h5-HT(1B), and h5-HT(1D) receptors [guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding], and at h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors (depletion of membrane-bound [(3)H]phosphatydilinositol). All drugs stimulated h5-HT(1A) receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT(1B) receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC(50) values of 5.8-7.6): h5-HT(1D) sites were activated with a similar range of efficacies and greater potency (7.1-8.5). Piribedil and apomorphine were inactive at h5-HT(1B) and h5-HT(1D) receptors. At h5-HT(2A) receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6-8.8) agonist properties (49-103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT(2B) receptors. At 5-HT(2C) receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75-96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT(2A) and 5-HT(2C) receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT(1A) sites, their contrasting actions at 5-HT(2A) and 5-HT(2C) sites may be of particular significance to their

Neuromedin B receptor in esophagus: evidence for subtypes of bombesin receptors

International Nuclear Information System (INIS)

Von Schrenck, T.; Heinz-Erian, P.; Moran, T.; Mantey, S.A.; Gardner, J.D.; Jensen, R.T.

1989-01-01

To identify receptors for bombesin-related peptides in the rat esophagus, we measured binding of 125I-Bolton-Hunter neuromedin B (125I-BH-neuromedin B) and 125I-[Tyr4]bombesin to tissue sections from the rat esophagus and compared the results with those for rat pancreas. Esophagus bound both tracers, whereas pancreas bound only 125I-[Tyr4]bombesin. In each tissue binding was saturable, dependent on pH, on time, and on temperature, reversible, and specific. Autoradiography demonstrated binding of both tracers only to the muscularis mucosae of the esophagus and binding of 125I-[Tyr4]bombesin diffusely over pancreatic acini. In the esophagus, the relative potencies for inhibition of binding of both tracers were as follows: neuromedin B greater than bombesin greater than GRP = neuromedin C; similar relative potencies were found for causing contraction of muscle strips from whole esophagus and from the isolated muscularis mucosae. In pancreas tissue sections and dispersed acini, the relative potencies for inhibition of binding of 125I-[Tyr4]bombesin were as follows: bombesin greater than GRP = neuromedin C much greater than neuromedin B. Similar relative potencies were found for stimulation of enzyme secretion from dispersed pancreatic acini. Computer analysis in both tissues demonstrated only a single binding site. The present study demonstrates that rat esophagus muscle possesses specific receptors for bombesin-related peptides. Furthermore, this study shows that the esophageal bombesin receptors represent a previously unidentified class of bombesin receptors in that they have a higher affinity for neuromedin B than for bombesin. In contrast, the pancreatic bombesin receptors have, like all other bombesin receptors described to date, a high affinity for bombesin, but low affinity for neuromedin B

Establishment of Radiolabelling Method for the Development of Neurodegenerative Disease Imaging Agent Using 5-HT{sub 1A} Subtype of Receptor Anatagonist

Energy Technology Data Exchange (ETDEWEB)

Choi, Sun Ju; Choi, Sang Mu; Kim, On Hee; Hong, Young Don; Park, Kyung Bae [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2005-07-01

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain. And it is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy and diagnosis of diseases. Serotonin is synthesized from the amino acid L-tryptophan by sequential hydroxylation and decarboxylation. It is stored in presynaptic vesicles and released from nerve terminals during neuronal firing. One of the best-characterised binding sites for serotonin is the 5-HT1A receptor. This is mainly due to the relatively early discovery of a selective ligand, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) for this subpopulation. Thus, many researchers have tried to develop a radioligand capable of assessing in vivo changes in 5-HT1A receptors in depressed subjects, people with anxiety disorders, patients with Alzheimer's disease and schizophrenics. In present study, we studied the radioligands which would play a role in visualization and quantification of this important neuroreceptor for single-photon emission tomography (SPET)

Cloning and expression of a rat brain α2B-adrenergic receptor

International Nuclear Information System (INIS)

Flordellis, C.S.; Handy, D.E.; Bresnahan, M.R.; Zannis, V.I.; Gavras, H.

1991-01-01

The authors isolated a cDNA clone (RBα 2B ) and its homologous gene (GRα 2B ) encoding an α 2B -adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor (α 2 -C4) and divergent from the rat kidney nonglycosylated α 2B subtype (RNGα 2 ). Transient expression of RBα 2B in COS-7 cells resulted in high-affinity saturable binding for [ 3 H]rauwolscine and a high receptor number in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine > yohimbine > prazosin > oxymetazoline, with a prazosin-to-oxymetazoline K i ratio of 0.34. This profile is characteristic of the α 2B -adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major and two minor mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GRα 2B may be transcriptionally active. These findings show that rat brain expresses an α 2B -adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated α 2B subtype. Thus the rat expresses at least two divergent α 2B -adrenergic receptors

Structure-activity studies of RFamide peptides reveal subtype-selective activation of neuropeptide FF1 and FF2 receptors.

Science.gov (United States)

Findeisen, Maria; Rathmann, Daniel; Beck-Sickinger, Annette G

2011-06-06

Selectivity is a major issue in closely related multiligand/multireceptor systems. In this study we investigated the RFamide systems of hNPFF₁R and hNPFF₂R that bind the endogenous peptide hormones NPFF, NPAF, NPVF, and NPSF. By use of a systematic approach, we characterized the role of the C-terminal dipeptide with respect to agonistic properties using synthesized [Xaa 7]NPFF and [Xaa 8]NPFF analogues. We were able to identify only slight differences in potency upon changing the position of Arg 7, as all modifications resulted in identical behavior at the NPFF₁R and NPFF₂R. However, the C-terminal Phe 8 was able to be replaced by Trp or His with only a minor loss in potency at the NPFF₂R relative to the NPFF₁R. Analogues with shorter side chains, such as α-amino-4-guanidino butyric acid ([Agb 7]NPFF) or phenylglycine ([Phg 8]NPFF), decreased efficacy for the NPFF₁ R to 25-31 % of the maximal response, suggesting that these agonist-receptor complexes are more susceptible to structural modifications. In contrast, mutations to the conserved Asp 6.59 residue in the third extracellular loop of both receptors revealed a higher sensitivity toward the hNPFF₂R receptor than toward hNPFF₁R. These data provide new insight into the subtype-specific agonistic activation of the NPFF₁ and NPFF(2) receptors that are necessary for the development of selective agonists. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁ and hypertension (S1P₃ in rat.

Directory of Open Access Journals (Sweden)

Ryan M Fryer

Full Text Available Sphingosine-1-phospate (S1P and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X receptor agonist produces modest hypertension in patients (2-3 mmHg in 1-yr trial as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension, and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls, BAF312 (0.3, 3.0, 30.0 mg/kg/d had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.

In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours - impact of peptide mass

International Nuclear Information System (INIS)

Velikyan, Irina; Sundin, Anders; Eriksson, Barbro; Lundqvist, Hans; Soerensen, Jens; Bergstroem, Mats; Langstroem, Bengt

2010-01-01

Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [ 68 Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [ 68 Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 μg of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [ 68 Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. Results: [ 68 Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 μg of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Discussion: Three sequential PET-CT examinations using 68 Ga-based tracer was carried out in 1 day. The use of high SRA [ 68 Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [ 68 Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management.

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

DEFF Research Database (Denmark)

Engelstoft, Maja S; Park, Won-Mee; Sakata, Ichiro

2013-01-01

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro......, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi....../o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi...

Subtype-selective regulation of IP(3) receptors by thimerosal via cysteine residues within the IP(3)-binding core and suppressor domain.

Science.gov (United States)

Khan, Samir A; Rossi, Ana M; Riley, Andrew M; Potter, Barry V L; Taylor, Colin W

2013-04-15

IP(3)R (IP(3) [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca(2+) channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP(3)R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP(3)-evoked Ca(2+) release via IP(3)R1 and IP(3)R2, but inhibited IP(3)R3. Activation of IP(3)R is initiated by IP(3) binding to the IBC (IP(3)-binding core; residues 224-604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1-223). Thimerosal (100 μM) stimulated IP(3) binding to the isolated NT (N-terminal; residues 1-604) of IP(3)R1 and IP(3)R2, but not to that of IP(3)R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP(3)) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP(3)R activation. IP(3) binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP(3)R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP(3) binding to the chimaeric NT and IP(3)-evoked Ca(2+) release from the chimaeric IP(3)R. This is the first systematic analysis of the effects of a thiol reagent on each IP(3)R subtype. We conclude that thimerosal selectively sensitizes IP(3)R1 and IP(3)R2 to IP(3) by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor.

Subtype-selective regulation of IP3 receptors by thimerosal via cysteine residues within the IP3-binding core and suppressor domain

Science.gov (United States)

Khan, Samir A.; Rossi, Ana M.; Riley, Andrew M.; Potter, Barry V. L.; Taylor, Colin W.

2013-01-01

IP3R (IP3 [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca2+ channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP3R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP3-evoked Ca2+ release via IP3R1 and IP3R2, but inhibited IP3R3. Activation of IP3R is initiated by IP3 binding to the IBC (IP3-binding core; residues 224–604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1–223). Thimerosal (100 μM) stimulated IP3 binding to the isolated NT (N-terminal; residues 1–604) of IP3R1 and IP3R2, but not to that of IP3R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP3) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP3R activation. IP3 binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP3R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP3 binding to the chimaeric NT and IP3-evoked Ca2+ release from the chimaeric IP3R. This is the first systematic analysis of the effects of a thiol reagent on each IP3R subtype. We conclude that thimerosal selectively sensitizes IP3R1 and IP3R2 to IP3 by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor. PMID:23282150

An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors.

Science.gov (United States)

Gabriel, Michael; Decristoforo, Clemens; Donnemiller, Eveline; Ulmer, Hanno; Watfah Rychlinski, Christine; Mather, Stephen J; Moncayo, Roy

2003-05-01

The aim of this study was to compare the imaging abilities of the recently developed somatostatin analog, (99m)Tc-hydrazinonicotinyl-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC [(99m)Tc-TOC]), with (111)In-diethylenediaminepentaacetic acid-D-Phe(1)-octreotide ((111)In-OCT [Octreoscan]) in patients undergoing routine somatostatin receptor (SSTR) scintigraphy. Forty-one patients (20 men, 21 women; age range, 29-75 y; mean age, 56.7 y) with either histologically proven or biologically and clinically suspected endocrine tumors were enrolled in the study. Four groups were distinguished: (a) patients being evaluated for the detection and localization of neuroendocrine tumors (n = 6), (b) tumor staging (n = 19), (c) patients being investigated to determine the SSTR status of tumor lesions (n = 11), and (d) patient follow-up studies (n = 5). Each patient received a mean activity of 150 MBq (111)In-OCT and 350-400 MBq (99m)Tc-TOC. Scintigraphy with (99m)Tc-TOC was performed 4 h after injection and scintigraphy with (111)In-OCT was performed 4 and 24 h after injection. SPECT studies of areas of interest were performed 4 h after injection for both tracers as well as at 24 h after injection for (111)In-OCT. The time interval between the studies using each tracer ranged from 2 to 22 d (mean interval, 9.3 d). (111)In-OCT and (99m)Tc-TOC showed an equivalent scan result in 32 patients (78%), 9 cases showed discrepancies (22%), false-negative results with (111)In-OCT were seen in 6 cases (14.6%), whereas (99m)Tc-TOC was false-positive in 2 cases (4.9%). (111)In-OCT was true-negative in both cases. The false-positive findings of the (99m)Tc-TOC studies were caused by nonspecific uptake in the bowel. In 1 case, (99m)Tc-TOC correctly identified a metastasis in the lumbar spine but both scan results were false-positive because of an inflammatory process. In 21 patients with SSTR-expressing tumors, the semiquantitative region-of-interest analysis showed that (99m)Tc-TOC achieved higher tumor

Receptor PET/CT for determining the somatostatin receptor status of neuroendocrine tumors before and after peptide receptor radionuclide therapy (PRRT): Clinical experience after 1,500 studies

International Nuclear Information System (INIS)

Baum, R.P.; Prasad, V.; Leonhardi, J.; Kroeger, R.; Wortmann, R.; Mueller, D.

2007-01-01

Full text: The octapeptide [DOTA]-1-Nal3-octreotide (DOTA-NOC) has 3 to 4 times higher binding affinity to sstr2 than DOTATOC (Wild 2003). We labeled this peptide with the Ga-68 (t1/2 68 min) and used it in pts with metastatic NET before/after PRRT for evaluating the sstr status by semiquantitative PET/CT imaging. Methods: Ga-68 was eluted from a Ge-68/Ga-68 generator using 0.1 M HCl. Following purifications, Ga-68 was eluted into a labeling vial containing 0.05 mg DOTA-NOC. Radiolabeling yields of >80% were achieved within 15 min at >95C. After purification (C18 cartridge) and a final elution, 370-700 MBq of Ga-68 DOTA-NOC were obtained with 100% radiochemical purity within 20 min (about 70% yield). Results: 1,500 PET/CT studies were performed in pts with histologically proven NET and progressive metastases before and after PRRT. Acquisition was started 20-270 min after injection of a mean of 100 MBq (46-260 MBq) Ga-68 DOTA-NOC using an LSO-based PET/CT (biograph DUO, Siemens). SUV were determined for all tumor lesions and normal tissues. SUV in metastases was as high as 152 whereas normal tissue was in the range of 0.4 (lung) to 33 (spleen). Outstanding PET/CT images of all known tumor lesions and in addition very small lymph node and bone metastases (<5 mm) were easily visualized as early as 20 min p.i. Clearly more lesions were detected as compared to Tc-99m EDDA-HYNIC-TOC or In-111 DOTA-NOC SPECT or as seen on CT or MRI images (especially regarding lymph node metastases, bone lesions and unknown primaries). Conclusions: Molecular receptor PET/CT imaging using the Ga-68-labeled somatostatin analogue DOTA-NOC detects neuroendocrine tumor metastases with very high diagnostic sensitivity and specificity. Semiquantitative uptake measurements (SUV) allow predicting the tumor uptake of Y-90 or Lu-177- labeled peptides before PRRT and are highly useful for therapy control to determine the 'molecular tumor response' which can precede the morphologic responses by months

Characterization of rat cerebral cortical beta adrenoceptor subtypes using (-)-[125I]-iodocyanopindolol

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Tiong, A.H.; Richardson, J.S.

1990-01-01

(-)-[125I]-Iodocyanopindolol [-(ICYP)], used to characterize beta adrenoceptors on membrane preparations from rat cerebral cortex, was shown to have affinity for both beta adrenoceptors and serotonin receptors. Therefore, 10 microM serotonin was added to the assays to prevent (-)ICYP binding to serotonin receptors. Under these conditions, (-)ICYP binding to the cortical membrane preparation was reversible and saturable, and the association reaction was very slow. The dissociation reaction was also very slow, and revealed two affinity states corresponding to a high and a low affinity state. Scatchard analysis showed a single class of binding sites with an equilibrium dissociation constant (KD) of 20.7 pM, and a maximal density of binding sites (Bmax) of 95.1 fmol/mg membrane protein. Displacement binding analyses revealed a potency series of (-) isoproterenol greater than (-) epinephrine equal to (-) norepinephrine, suggesting a predominance of the beta 1 adrenoceptor subtype. Detailed competition ligand binding studies with the selective beta 1 adrenoceptor antagonist ICI-89406 and the selective beta 2 adrenoceptor antagonist ICI-118551, showed that about 70% of the beta adrenoceptor population in the rat cortex is of the beta 1 subtype with the remainder being of the beta 2 subtype. We conclude that since (-)ICYP binds to both beta adrenoceptors and serotonin receptors, it is important to prevent the binding of (-)ICYP to serotonin receptors by adding a suppressing ligand like excess cold serotonin when assaying beta adrenoceptors. We have presented the first such characterization of rat cerebral cortical beta adrenoceptors with (-)ICYP in this study

Union of {sup 99m} Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer; Union del {sup 99m} Tc-HYNIC-TOC a los receptores de somatostatina en celulas de cancer de pancreas

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Rodriguez C, J. [Facultad de Medicina, UAEM, 50000 Toluca, Estado de Mexico (Mexico); Ramirez I, M.T. [INCMNSZ, Vasco de Quiroga Num. 15, Tlalpan, 14000 Mexico D.F. (Mexico); Ferro F, G.; Pedraza L, M. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

2005-07-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide {sup 99m}Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with {sup 99m}Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The {sup 99m}Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide {sup 99m}Tc-UBI and the {sup 99m}TcO{sub 4}. The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the {sup 99m}Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the {sup 99m

Union of {sup 99m} Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer; Union del {sup 99m} Tc-HYNIC-TOC a los receptores de somatostatina en celulas de cancer de pancreas

Energy Technology Data Exchange (ETDEWEB)

Rodriguez C, J [Facultad de Medicina, UAEM, 50000 Toluca, Estado de Mexico (Mexico); Ramirez I, M T [INCMNSZ, Vasco de Quiroga Num. 15, Tlalpan, 14000 Mexico D.F. (Mexico); Ferro F, G; Pedraza L, M [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

2005-07-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide {sup 99m}Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with {sup 99m}Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The {sup 99m}Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide {sup 99m}Tc-UBI and the {sup 99m}TcO{sub 4}. The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the {sup 99m}Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the {sup 99m

99mTc labelled peptide for imaging of peripheral receptors

International Nuclear Information System (INIS)

Mishra, A.K.; Mishra, P.; Chuttani, K.; Sharma, R.K.; Lazar Mathew, T.

2001-01-01

Conjugates of somatostatin analogues, RC-160 with different bifunctional chelators to label with 99m Tc, were synthesized. Conjugates with hydrazinonicotinamide (HYNIC) and compounds (benzoyl MAG-3 and CITC-DTPA) were prepared on a small scale with high purity and evaluated as different types of chelators on RC-160. Stability studies performed under physiological conditions showed high stability. Peptide conjugates could be labelled at high specific activities (307inCi/umol) with 99m Tc and different transchelator were used for the HYNIC conjugates. The resulting radiolabelled with ( 99m Tc and 1251) complexes were highly stable and showed binding affinity to somatostatin receptors in the nanomolar range. The radioconjugates were administered to rabbits and mice in order to study their in vivo stability, biokinetics and biodistribution. (author)

Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β--emitting 177Lu in human pancreatic adenocarcinoma cells

International Nuclear Information System (INIS)

Nayak, Tapan K.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Prossnitz, Eric R.; Stabin, Michael G.; Atcher, Robert W.

2007-01-01

Introduction: Advance clinical cancer therapy studies of patients treated with somatostatin receptor (sstr)-targeted [DOTA 0 -Tyr 3 ]octreotide (DOTATOC) labeled with low-linear-energy-transfer (LET) β - -emitters have shown overall response rates in the range of 15-33%. In order to improve outcomes, we sought to compare the therapeutic effectiveness of sstr-targeted high-LET α-emitting 213 Bi to that of low-LET β - -emitting 177 Lu by determining relative biological effectiveness (RBE) using the external γ-beam of 137 Cs as reference radiation. Methods: Sstr-expressing human pancreatic adenocarcinoma Capan-2 cells and A549 control cells were used for this study. The effects of different radiation doses of 213 Bi and 177 Lu labeled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and sstr-targeted DOTATOC were investigated with a clonogenic cell survival assay. Apoptosis was measured using the Cell Death Detection ELISA PLUS 10x kit. Results: Using equimolar DOTATOC treatment with concurrent irradiation with a 137 Cs source as reference radiation, the calculated RBE of [ 213 Bi]DOTATOC was 3.4, as compared to 1.0 for [ 177 Lu]DOTATOC. As measured in terms of absorbance units, [ 213 Bi]DOTATOC caused a 2.3-fold-greater release of apoptosis-specific mononucleosomes and oligonucleosomes than [ 177 Lu]DOTATOC at the final treatment time of 96 h (P 213 Bi]DOTATOC is therapeutically more effective in decreasing survival than is [ 177 Lu]DOTATOC in human pancreatic adenocarcinoma cells due to its comparatively higher RBE

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

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Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi; Sanders, Melinda E.; Chakravarthy, A. Bapsi; Shyr, Yu; Pietenpol, Jennifer A.

2011-01-01

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies. PMID:21633166

Predicting Subtype Selectivity for Adenosine Receptor Ligands with Three-Dimensional Biologically Relevant Spectrum (BRS-3D)

Science.gov (United States)

He, Song-Bing; Ben Hu; Kuang, Zheng-Kun; Wang, Dong; Kong, De-Xin

2016-11-01

Adenosine receptors (ARs) are potential therapeutic targets for Parkinson’s disease, diabetes, pain, stroke and cancers. Prediction of subtype selectivity is therefore important from both therapeutic and mechanistic perspectives. In this paper, we introduced a shape similarity profile as molecular descriptor, namely three-dimensional biologically relevant spectrum (BRS-3D), for AR selectivity prediction. Pairwise regression and discrimination models were built with the support vector machine methods. The average determination coefficient (r2) of the regression models was 0.664 (for test sets). The 2B-3 (A2B vs A3) model performed best with q2 = 0.769 for training sets (10-fold cross-validation), and r2 = 0.766, RMSE = 0.828 for test sets. The models’ robustness and stability were validated with 100 times resampling and 500 times Y-randomization. We compared the performance of BRS-3D with 3D descriptors calculated by MOE. BRS-3D performed as good as, or better than, MOE 3D descriptors. The performances of the discrimination models were also encouraging, with average accuracy (ACC) 0.912 and MCC 0.792 (test set). The 2A-3 (A2A vs A3) selectivity discrimination model (ACC = 0.882 and MCC = 0.715 for test set) outperformed an earlier reported one (ACC = 0.784). These results demonstrated that, through multiple conformation encoding, BRS-3D can be used as an effective molecular descriptor for AR subtype selectivity prediction.

Role of estrogen receptor-α on food demand elasticity.

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Minervini, Vanessa; Rowland, Neil E; Robertson, Kimberly L; Foster, Thomas C

2015-05-01

Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions. © Society for the Experimental Analysis of Behavior.

PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

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Bastien Roy RL

2012-10-01

Full Text Available Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER, progesterone receptor (PR, and Her2/neu (HER2 protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH. Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC ≥ 0.9. Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B subtypes (92%, but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74% and Luminal A tumors were less likely to have high proliferation (11% vs 77%. Seventy-seven percent (30/39 of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57% and HER2-E (30% subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as

Preoperative core needle biopsy is accurate in determining molecular subtypes in invasive breast cancer

International Nuclear Information System (INIS)

Chen, Xiaosong; Yuan, Ying; Fei, Xiaochun; Jin, Xiaolong; Shen, Kunwei; Sun, Long; Mao, Yan; Zhu, Siji; Wu, Jiayi; Huang, Ou; Li, Yafen; Chen, Weiguo; Wang, Jianhua

2013-01-01

Estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 have been increasingly evaluated by core needle biopsy (CNB) and are recommended for classifying breast cancer into molecular subtypes. However, the concordance rate between CNB and open excision biopsy (OEB) has not been well documented. Patients with paired CNB and OEB samples from Oct. 2009 to Feb. 2012 in Ruijin Hospital were included. ER, PgR, HER2, and Ki67 were determined by immunohistochemistry (IHC). Patients with HER2 IHC 2+ were further examined by FISH. Cutoff value for Ki67 high expression was 14%. Molecular subtypes were constructed as follows: Luminal A, Luminal B, Triple Negative, and HER2 positive. There were 298 invasive breast cancer patients analyzed. Concordance rates for ER, PgR, and HER2 were 93.6%, 85.9%, and 96.3%, respectively. Ki67 expression was slightly higher in OEB than in CNB samples (29.3% vs. 26.8%, P = 0.046). Good agreement (κ = 0.658) was demonstrated in evaluating molecular subtypes between CNB and OEB, with a concordance rate of 77.2%. We also used a different Ki67 cutoff value (20%) for determining Luminal A and B subtypes in HR (hormone receptor) +/HER2- diseases and the overall concordance rate was 79.2%. However, using a cut-point of Ki67 either 14% or 20% for both specimens, there will be about 14% of HR+/HER2- specimens that are called Luminal A on CNB and Luminal B on OEB. CNB was accurate in determining ER, PgR, and HER2 status as well as non-Luminal molecular subtypes in invasive breast cancer. Ki67 should be retested on OEB samples in HR+/HER2- patients to accurately distinguish Luminal A from B tumors

Preliminary study on the inhibition of nuclear internalization of Tat peptides by conjugation with a receptor-specific peptide and fluorescent dyes

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Shen, Duanwen; Liang, Kexiang; Ye, Yunpeng; Tetteh, Elizabeth; Achilefu, Samuel

2006-02-01

Numerous studies have shown that basic Tat peptide (48-57) internalized non-specifically in cells and localized in the nucleus. However, localization of imaging agents in cellular nucleus is not desirable because of the potential mutagenesis. When conjugated to the peptides that undergo receptor-mediated endocytosis, Tat peptide could target specific cells or pathologic tissue. We tested this hypothesis by incorporating a somatostatin receptor-avid peptide (octreotate, Oct) and two different fluorescent dyes, Cypate 2 (Cy2) and fluorescein 5'-carboxlic acid (5-FAM), into the Tat-peptide sequence. In addition to the Cy2 or 5-FAM-labeled Oct conjugated to Tat peptide (Tat) to produce Tat-Oct-Cypate2 or Tat-Oct-5-FAM, we also labeled the Tat the Tat peptide with these dyes (Tat-Cy2 and Tat-5-FAM) to serve as positive control. A somatostatin receptor-positive pancreatic tumor cell line, AR42J, was used to assess cell internalization. The results show that Tat-5-FAM and Tat-Cypate2 localized in both nucleus and cytoplasm of the cells. In contrast to Tat-Oct-Cypate2, which localized in both the cytoplasm and nucleus, Tat-Oct-5-FAM internalized in the cytoplasm but not in the nucleus of AR42J cells. The internalizations were inhibited by adding non-labeled corresponding peptides, suggesting that the endocytoses of each group of labeled and the corresponding unlabeled compounds occurred through a common pathway. Thus, fluorescent probes and endocytosis complex between octreotate and somatostatin receptors in cytoplasm could control nuclear internalization of Tat peptides.

Somatostatin ontogenesis in the gastrointestinal and pancreatic tract: study in normal rats and during a induced diabetes in neonates rats

International Nuclear Information System (INIS)

Cunha, M.C.

1980-01-01

The ontogenic studies of somatostatin of pancreas, ileum and duodenum of Wistar rats and the rats with induced diabetes were done. The radioimmunologic method to dose the somatostatin was used. (L.M.J.)

Repeated stressful experiences differently affect brain dopamine receptor subtypes

International Nuclear Information System (INIS)

Puglisi-Allegra, S.; Cabib, S.; Kempf, E.; Schleef, C.

1991-01-01

The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them

Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers.

Science.gov (United States)

Imhof, Anna; Brunner, Philippe; Marincek, Nicolas; Briel, Matthias; Schindler, Christian; Rasch, Helmut; Mäcke, Helmut R; Rochlitz, Christoph; Müller-Brand, Jan; Walter, Martin A

2011-06-10

To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers. In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [(90)Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface [(90)Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. Overall, 1,109 patients received 2,472 cycles of [(90)Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P TOC treatment in a large cohort. Response to [(90)Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [(90)Y-DOTA]-TOC treatment and occurrence of renal toxicity.

Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

Science.gov (United States)

Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

2009-01-01

Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

The vasopressin receptor of the blood-brain barrier in the rat hippocampus is linked to calcium signalling

DEFF Research Database (Denmark)

Hess, J.; Jensen, Claus V.; Diemer, Nils Henrik

1991-01-01

Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2......Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2...

RRHGE: A Novel Approach to Classify the Estrogen Receptor Based Breast Cancer Subtypes

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Ashish Saini

2014-01-01

Full Text Available Background. Breast cancer is the most common type of cancer among females with a high mortality rate. It is essential to classify the estrogen receptor based breast cancer subtypes into correct subclasses, so that the right treatments can be applied to lower the mortality rate. Using gene signatures derived from gene interaction networks to classify breast cancers has proven to be more reproducible and can achieve higher classification performance. However, the interactions in the gene interaction network usually contain many false-positive interactions that do not have any biological meanings. Therefore, it is a challenge to incorporate the reliability assessment of interactions when deriving gene signatures from gene interaction networks. How to effectively extract gene signatures from available resources is critical to the success of cancer classification. Methods. We propose a novel method to measure and extract the reliable (biologically true or valid interactions from gene interaction networks and incorporate the extracted reliable gene interactions into our proposed RRHGE algorithm to identify significant gene signatures from microarray gene expression data for classifying ER+ and ER− breast cancer samples. Results. The evaluation on real breast cancer samples showed that our RRHGE algorithm achieved higher classification accuracy than the existing approaches.

The role of tumor molecular subtypes in formation of personalized approach to the theatment of the breast cancer

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Bondarenko I.N.

2016-05-01

Full Text Available Extreme heterogeneity of breast cancer (BC is considered to be one of the reasons that affects the success of treatment. According to current classifications, there are 4 molecular subtypes (MS. The basis for subtypes division is immunohistochemical testing of tumor cell receptors - estrogen (ER, progesterone (PR, HER2-neu and Ki-67. The doctrine of the tumor MS was the basis for the individualization of therapeutic tactics in patients with breast cancer. It was studied that luminal A subtype is the most common and the most favorable, with hormone therapy being a highly effective treatment method. Luminal B subtype, HER2 - positive and triple negative MS is characterized by a high ag­gressiveness, worse survival rate of patients and better prognostic effect of chemotherapy. The importance of determining the level of Ki-67 for assessment of tumor aggressiveness was revealed. Significant differences in receptor status of the primary tumor and metastases were proven. Data on the impact of changes in receptor status of the tumor prognosis are ambiguous and need further study. The use of targeted agents in the treatment of HER2 + patients can significantly improve treatment outcomes, turning this MS from historically aggressive subgroup to quite favorable.

Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

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Eva Ludvigsen

2011-01-01

Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

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Hwang, Ki-Tae; Kim, Eun-Kyu; Jung, Sung Hoo; Lee, Eun Sook; Kim, Seung Il; Lee, Seokwon; Park, Heung Kyu; Kim, Jongjin; Oh, Sohee; Kim, Young A

2018-06-01

To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.

In vivo binding of [{sup 68}Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours - impact of peptide mass

Energy Technology Data Exchange (ETDEWEB)

Velikyan, Irina [Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala (Sweden); Uppsala Applied Science Lab, GEMS PET Systems, GE Healthcare, SE-752 28 Uppsala (Sweden); Sundin, Anders [Department of Radiology, Karolinska University Hospital, SE-171 76 Stockholm (Sweden); Eriksson, Barbro [Department of Endocrine Oncology, Uppsala University Hospital, SE-751 85 Uppsala (Sweden); Lundqvist, Hans [Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala (Sweden); Soerensen, Jens [Department of Medicinal Sciences, Clinical Physiology and Nuclear Medicine, Uppsala University Hospital, SE-751 85 Uppsala (Sweden); Bergstroem, Mats [Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala (Sweden); Langstroem, Bengt [Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala (Sweden)], E-mail: langstrom@biorg.uu.se

2010-04-15

Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [{sup 68}Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [{sup 68}Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 {mu}g of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [{sup 68}Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. Results: [{sup 68}Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 {mu}g of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Discussion: Three sequential PET-CT examinations using {sup 68}Ga-based tracer was carried out in 1 day. The use of high SRA [{sup 68}Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [{sup 68}Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management.

Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization?

Science.gov (United States)

Storch, Daniel; Béhé, Martin; Walter, Martin A; Chen, Jianhua; Powell, Pia; Mikolajczak, Renata; Mäcke, Helmut R

2005-09-01

Radiolabeled somatostatin analogs are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin receptor-positive tumors. The aim of this study was to compare 3 somatostatin analogs designed for the labeling with (99m)Tc (where HYNIC is 6-hydrazinopyridine-3-carboxylic acid): 6-hydrazinopyridine-3-carboxylic acid(0)-octreotide (HYNIC-OC/(99m)Tc-(1)), [HYNIC(0),Tyr(3)]octreotide (HYNIC-TOC/(99m)Tc-(2)), and [HYNIC(0),Tyr(3),Thr(8)]octreotide (HYNIC-TATE/(99m)Tc-(3)), using ethylenediamine-N,N'-diacetic acid (EDDA) as a coligand. In addition, we compared the (99m)Tc-labeled peptides [(111)In-diethylenetriaminepentaacetic acid(0)]octreotide ([(111)In-DTPA]-OC) and [(111)In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(0),Tyr(3),Thr(8)]octreotide ([(111)In-DOTA]-TATE) with regard to the rate of internalization and the biodistribution in AR4-2J (expressing the somatostatin receptor subtype 2) tumor-bearing rats. The main attention was directed toward a potential correlation between the rate of internalization and the tumor or pancreas uptake. Synthesis was performed on solid phase using a standard Fmoc strategy. Internalization was studied in cell culture (AR4-2J) and biodistribution was studied using a Lewis rat tumor model (AR4-2J). The 5 radiopeptides showed a specific internalization into AR4-2J cells in culture (as shown by blocking experiments). The rate of internalization of the 5 radiopeptides differed significantly according to the following order: (99m)Tc-(1) approximately = [(111)In-DTPA]-OC EDDA/HYNIC]-TATE are suitable candidates for clinical studies.

Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice.

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Joseph, Lauren; Thomsen, Morgane

2017-06-30

Muscarinic M 1 /M 4 receptor stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S D ) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M 1 , M 2 , or M 4 receptors (M 1 -/- , M 2 -/- , M 4 -/- ), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M 1 , M 2 , or M 4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M 1 /M 4 receptors partially substituted for cocaine and increased the S D effect of cocaine, while M 2 -preferring antagonists did not substitute, and reduced the S D effect of cocaine. The cocaine-like effects of scopolamine were absent in M 1 -/- mice. The cocaine S D attenuating effects of methoctramine were absent in M 2 -/- mice and almost absent in M 1 -/- mice. The findings indicate that the cocaine-like S D effects of muscarinic antagonists are primarily mediated through M 1 receptors, with a minor contribution of M 4 receptors. The data also support our previous findings that stimulation of M 1 receptors and M 4 receptors can each attenuate the S D effect of cocaine, and show that this can also be achieved by blocking M 2 autoreceptors, likely via increased acetylcholine release. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis and evaluation in vitro in cancer cells AR42J of the radiopharmaceutical 99mTc-Tyr3-Octreotide-dendrimer similar of somatostatin

International Nuclear Information System (INIS)

Orocio R, E.

2013-01-01

The objective of this project was preparing a multimeric system through the conjugation of several molecules of the peptide Tyr 3 -Octreotide to a dendrimer molecule based on Poly-amidoamine (PAMAM), as well as radiolabeled with 99m Tc and evaluating its behavior like new radiopharmaceutical similar of somatostatin. The dendrimer PAMAM generation 3.5 that possesses terminal groups of sodium carboxylate, was functionalized to peptide Tyr 3 -Octreotide through a reaction of peptide coupling with HATU (hexafluorophosphate (V) of 1-oxide-3-(bis(dimethylamino)methylene)-3H-[1,2,3]triazole[4,5-b]pyridine) as activating agent of carboxylate groups using the Size Exclusion Chromatography (Sec) as purification method. The product was characterized by Ultraviolet visible spectrophotometry, Mid-infrared and Far-infrared, Elemental analysis, Energy dispersive X-ray spectroscopy, Scanning electron microscopy, Thermogravimetry and Differential scanning calorimetry. The radiolabeled with 99m Tc was carried out using a direct method that involves the reduction of the anion TcO 4 - with stannous chloride, so that the dendrimer is capable of coordinating to the technetium forming a chelate compound. The radiochemical purity of the radiolabeled compound was determined by thin layer chromatography using a sodium chloride solution to 20% (m/v) as mobile phase and was verified by molecular exclusion chromatography. The radiolabeled compound was possible to obtain it with a radiochemical purity superior to 90%. Also, the specific and not specific union was evaluated of the synthesized compound in mouse pancreas cancer cells AR42J, positive to somatostatin receptors, showing specific recognition for this receptors type with high cellular internalization. The biodistribution studies were carried out in BALB/c mice at different post injection times and in nude mice with induced tumors AR42J. The results showed that the 99m Tc-PAMAM-Tyr 3 -Octreotide is excreted by via renal as hepatobiliary

Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats.

Science.gov (United States)

Baladi, Michelle G; Newman, Amy H; France, Charles P

2014-02-01

The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. Apomorphine, quinpirole, and lisuride occasioned >90 % responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90 % responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.

Genotoxic evaluation of [DOTA,Tyr3]octreotate labeled with 131I and 177Lu in human peripheral lymphocytes in vitro by micronucleus assay

International Nuclear Information System (INIS)

Suzauki, Miriam Fussae; Silva, Marcia Augusta da; Caldeira Filho, Jose de Souza; Colturato, Maria Tereza; Araujo, Elaine Bortoleti de; Bartolini, Paolo; Okazaki, Kayo

2005-01-01

The radiolabeled receptor-binding peptides have being used for cancer diagnosis and therapy. The octreotate, a somatostatin analogue peptide, bound to various tumors expressing sst receptors (thyroid, pancreas, prostrate, melanoma and lymphomas). The amount and the type of receptors for somatostatin influence the tissue uptake. The [DOTA, Tyr 3 ]octreotate has been used because of its high affinity to somatostatin subtype receptors sstr 2 and sstr 5 . The pharmacokinetic study showed that the blood clearance is rapid and only 9% of the intravenous injected activity remains in human blood after one hour. The aim of this study was to evaluate the cytogenetic effect of radiolabeled [DOTA, Tyr 3 ]octreotate in blood cells in vitro, using the cytokinesis-block micronucleus (MN) assay. This technique allows evaluating the mutagenic effects of both endogenous and exogenous agents at chromosome level. Blood samples of healthy donors were collected in heparinized syringes and exposed to different activities of [DOTA, Tyr 3 ]octreotate labeled with with 131 I (n=3) and 177 Lu (n=3), where radioactive concentration ranged from 600 to 5600 kBq/mL, corresponding to an injected activity of 3.1 to 28.9 GBq in a reference man of 70 kg weight. 131 I and 177 Lu are beta- and gamma-emitters. After one-hour exposition to radiopharmaceuticals at 37 deg C, the cells were washed with culture medium for removing the non internalised octreotate and cultivated for 72 hours, according to criteria adopted by the IAEA. The results showed a positive correlation between radioactive concentrations (X) and the frequency of binucleated cells with micronuclei (Y) (P 131 I-DOTA, Tyr 3 ]octreotate was Y = (1.634 ± 0.236) + (0.912 ± 0.137) 10 -3 X and for [ 177 Lu-DOTA, Tyr 3 ]octreotate was Y = (1.715 ± 0.342) + (0.743 ± 0.135) 10 -3 X. The non labeled molecule, [DOTA, Tyr 3 ]octreotate, has no influence in the induction of cytogenetic damage. The micronucleus assay with rat pancreatic tumor cells

Gastroenteropancreatic Neuroendocrine Tumors: Standardizing Therapy Monitoring with 68Ga-DOTATOC PET/CT Using the Example of Somatostatin Receptor Radionuclide Therapy

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Wolfgang Luboldt

2010-11-01

Full Text Available The purpose of this study was to standardize therapy monitoring of hepatic metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs during the course of somatostatin receptor radionuclide therapy (SRRT. In 21 consecutive patients with nonresectable hepatic metastases of GEP-NETs, chromogranin A (CgA and 68Ga-DOTATOC PET/CT were compared before and after the last SRRT. On 68Ga-DOTATOC PET/CT, the maximum standard uptake values (SUVmax of normal liver and hepatic metastases were calculated. In addition, the volumes of hepatic metastases (volume of interest [VOI] were measured using four cut-offs to separate normal liver tissue from metastases (SUVmax of the normal liver plus 10% [VOIliver+10%], 20% [VOIliver+20%], 30% [VOIliver+30%] and SUV = 10 [VOI10SUV]. The SUVmaxof the normal liver was below 10 (7.2 ± 1.3 in all patients and without significant changes. Overall therapy changes (Δ per patient (mean [95% CI] were statistically significant with p < .01 for ΔCgA = −43 (−69 to −17, ΔSUVmax = −22 (−29 to −14, and ΔVOI10SUV = −53 (−68 to −38% and significant with p < .05 for ΔVOIliver+10% = −29 (−55 to −3%, ΔVOIliver+20% = −32 (−62 to −2 and ΔVOIliver+30% = −37 (−66 to −8. Correlations were found only between ΔCgA and ΔVOI10SUV (r = .595; p < .01, ΔSUVmax and ΔVOI10SUV (0.629, p < .01, and SUVmax and ΔSUVmax (r = .446; p < .05. 68Ga-DOTATOC PET/CT allows volumetric therapy monitoring via an SUV-based cut-off separating hepatic metastases from normal liver tissue (10 SUV recommended.

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-dPhe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

International Nuclear Information System (INIS)

Roesch, F.; Brockmann, J.; Koehle, M.

1999-01-01

[ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide ([ 90 Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was administered at two different peptide concentrations, namely 2 and 100 μg peptide per m 2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide injected. For the 100 μg/m 2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide, respectively. The average effective dose equivalent amounted to 0.23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide in patients with somatostatin receptor-expressing tumours. (orig.)

In vitro effect of Δ9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2

International Nuclear Information System (INIS)

Rettori, V.; Aguila, M.C.; McCann, S.M.; Gimeno, M.F.; Franchi, A.M.

1990-01-01

Previous in vivo studies have shown that Δ 9 -tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E 2 (PGE 2 ) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE 2 suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE 2 synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release

Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor {alpha}{sub 7} subtype

Energy Technology Data Exchange (ETDEWEB)

Ogawa, Mikako [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Nishiyama, Shingo; Tsukada, Hideo [PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu (Japan); Hatano, Kentaro [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Fuchigami, Takeshi [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Yamaguchi, Hiroshi [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Matsushima, Yoshitaka [Department of Chemistry, Hamamatsu University School of Medicine, Hamamatsu (Japan); Ito, Kengo [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan)], E-mail: magata@hama-med.ac.jp

2010-04-15

Introduction: The nicotinic acetylcholine receptor (nAChR) {alpha}7 subtype ({alpha}{sub 7} nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled {alpha}{sub 7} nAChR ligands, (R)-2-[{sup 11}C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([{sup 11}C](R)-MeQAA) and its isomer (S)-[{sup 11}C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[{sup 11}C]MeQAA for in vivo imaging of {alpha}{sub 7} nAChR in the brain was evaluated in mice and monkeys. Methods: The binding affinity for {alpha}{sub 7} nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. Results: The affinity for {alpha}{sub 7} nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([{sup 11}C](R)-MeQAA: 7.68 and [{sup 11}C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [{sup 11}C](R)-MeQAA was slow in the hippocampus ({alpha}{sub 7} nAChR-rich region) but was rapid in the cerebellum ({alpha}{sub 7} nAChR-poor region). On the other hand, the clearance was fast for [{sup 11}C](S)-MeQAA in all regions. The brain uptake of [{sup 11}C](R)-MeQAA was decreased by methyllycaconitine ({alpha}{sub 7} nAChR antagonist) treatment. In monkeys, {alpha}{sub 7} nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [{sup 11}C](R)-MeQAA, while the uptake was rather homogeneous for [{sup 11}C](S)-MeQAA. Conclusions: [{sup 11}C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for {alpha}{sub 7} nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain {alpha}{sub 7} nAChRs in vivo.

Important roles of P2Y receptors in the inflammation and cancer of digestive system.

Science.gov (United States)

Wan, Han-Xing; Hu, Jian-Hong; Xie, Rei; Yang, Shi-Ming; Dong, Hui

2016-05-10

Purinergic signaling is important for many biological processes in humans. Purinoceptors P2Y are widely distributed in human digestive system and different subtypes of P2Y receptors mediate different physiological functions from metabolism, proliferation, differentiation to apoptosis etc. The P2Y receptors are essential in many gastrointestinal functions and also involve in the occurrence of some digestive diseases. Since different subtypes of P2Y receptors are present on the same cell of digestive organs, varying subtypes of P2Y receptors may have opposite or synergetic functions on the same cell. Recently, growing lines of evidence strongly suggest the involvement of P2Y receptors in the pathogenesis of several digestive diseases. In this review, we will focus on their important roles in the development of digestive inflammation and cancer. We anticipate that as the special subtypes of P2Y receptors are studied in depth, specific modulators for them will have good potentials to become promising new drugs to treat human digestive diseases in the near future.

Molecular-based tumour subtypes of canine mammary carcinomas assessed by immunohistochemistry

Directory of Open Access Journals (Sweden)

Sarli Giuseppe

2010-01-01

Full Text Available Abstract Background Human breast cancer is classified by gene expression profile into subtypes consisting of two hormone (oestrogen and/or progesterone receptor-positive types (luminal-like A and luminal-like B and three hormone receptor-negative types [human epidermal growth factor receptor 2-expressing, basal-like, and unclassified ("normal-like"]. Immunohistochemical surrogate panels are also proposed to potentially identify the molecular-based groups. The present study aimed to apply an immunohistochemical panel (anti-ER, -PR, -ERB-B2, -CK 5/6 and -CK14 in a series of canine malignant mammary tumours to verify the molecular-based classification, its correlation with invasion and grade, and its use as a prognostic aid in veterinary practice. Results Thirty-five tumours with luminal pattern (ER+ and PR+ were subgrouped into 13 A type and 22 B type, if ERB-B2 positive or negative. Most luminal-like A and basal-like tumours were grade 1 carcinomas, while the percentage of luminal B tumours was higher in grades 2 and 3 (Pearson Chi-square P = 0.009. No difference in the percentage of molecular subtypes was found between simple and complex/mixed carcinomas (Pearson Chi-square P = 0.47. No significant results were obtained by survival analysis, even if basal-like tumours had a more favourable prognosis than luminal-like lesions. Conclusion The panel of antibodies identified only three tumour groups (luminal-like A and B, and basal-like in the dog. Even though canine mammary tumours may be a model of human breast cancer, the existence of the same carcinoma molecular subtypes in women awaits confirmation. Canine mammary carcinomas show high molecular heterogeneity, which would benefit from a classification based on molecular differences. Stage and grade showed independent associations with survival in the multivariate regression, while molecular subtype grouping and histological type did not show associations. This suggests that caution should be

Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors

DEFF Research Database (Denmark)

Harpsøe, Kasper; Ahring, Philip K; Christensen, Jeppe K

2011-01-01

The neuronal a4ß2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)(ß2)(3) and (a4)(3)(ß2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation...

Functional characterization of estrogen receptor subtypes, ERα and ERβ, mediating vitellogenin production in the liver of rainbow trout

International Nuclear Information System (INIS)

Leanos-Castaneda, Olga; Kraak, Glen van der

2007-01-01

The estrogen-dependent process of vitellogenesis is a key function on oviparous fish reproduction and it has been widely used as an indicator of xenoestrogen exposure. The two estrogen receptor (ER) subtypes, ERα and ERβ, are often co-expressed in the liver of fish. The relative contribution of each ER subtype to modulate vitellogenin production by hepatocytes was studied using selected compounds known to preferentially interact with specific ER subtypes: propyl-pyrazole-triol (PPT) an ERα selective agonist, methyl-piperidino-pyrazole (MPP) an ERα selective antagonist, and diarylpropionitrile (DPN) an ERβ selective agonist. First, the relative binding affinity of the test compounds to estradiol for rainbow trout hepatic nuclear ER was determined using a competitive ligand binding assay. All the test ligands achieved complete displacement of specific [ 3 H]-estradiol binding from the nuclear ER extract. This indicates that the test ligands have the potential to modify the ER function in the rainbow trout liver. Secondly, the ability of the test compounds to induce or inhibit vitellogenin production by primary cultures of rainbow trout hepatocytes was studied. Estradiol and DPN were the only compounds that induced a dose-dependent increase on vitellogenin synthesis. The lack of vitellogenin induction by PPT indicates that ERα could not have a role on this reproductive process whereas the ability of DPN to induce vitellogenin production supports the participation of ERβ. In addition, this hypothesis is reinforced by the results obtained from MPP plus estradiol. On one hand, the absence of suppressive activity of MPP in the estradiol-induced vitellogenin production does not support the participation of ERα. On the other hand, once blocked ERα with MPP, the only manifestation of agonist activity of estradiol would be achieved via ERβ. In conclusion, the present results indicate that vitellogenin production is mainly mediated through ERβ, implying, furthermore

Labeling Lanreotide with 125I and 188Re

International Nuclear Information System (INIS)

Bai Hongsheng

2000-01-01

Lanreotide is a new somatostatin analogue. It can bind to human somatostatin receptor (hSSTR) subtype 2 through 5 with high affinity and to hSSTR subtype I with low affinity. We investigate labeling condition, quality control and stability in vitro of 125 I-Lanreotide and 188 Re-lanreotide respectively. (A) Lanreotide is labeled with 125 I using Chloramine T. The effect of reaction condition (such as reaction time, pH value, Lanreotide amount, quantity of Chloramine T and reaction volume) on labeling yield is investigated in detail. (B) The labeling yield and radiochemical purity (RP) is measured with paper chromatography (PC) and Sep-Pak C 18 Cartridge. (C) The stability of 125 I-Lanreotide in vitro is investigated by labeling compound incubating for 48 hours at 37 deg C in the 0.9% sodium chloride solution and RP is tested by PC at specific time intervals. (D) Lanreotide is labeled directly with 188 Re via the mixture of citrate and tartate using stannous chloride as reduced agent. The influence of reaction conditions such as pH, temperature, amount of stannous chloride, amount of Lanreotide and reaction time on labeling yield is investigated in detail. At the time, the stability in vitro quality control and animal test are evaluated

Night work and breast cancer risk defined by human epidermal growth factor receptor-2 (HER2) and hormone receptor status: A population-based case-control study in France.

Science.gov (United States)

Cordina-Duverger, Emilie; Koudou, Yves; Truong, Thérèse; Arveux, Patrick; Kerbrat, Pierre; Menegaux, Florence; Guénel, Pascal

Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

Melatonin Receptor Genes in Vertebrates

Directory of Open Access Journals (Sweden)

Hua Dong Yin

2013-05-01

Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

Somatostatin analogues labelled with 99mTc

International Nuclear Information System (INIS)

Obenaus, E.; Crudo, J.; Edreira, M.; Viaggi, M.; De Castiglia, S.G.

2001-01-01

The aim of the present work was to study the biological and radiochemical behaviour of two somatostatin analogues, the RC-160 and Tyr3Octreotide(TOC) peptides when labelling with 99m Tc by two methods: direct and indirect using S-benzoyl- mercaptoacetyl triglycine (MAG-3) and hydrazinonicotinamide (HYNIC) as chelating agents. RC-160 was labelled with 125I (30% labelling yield) in order to examine its receptor specificity and to study the biodistribution in normal animals. A total binding of 30% and a non specific binding lower than 10% was obtained. On the other hand, the RC-160 was labelled with 99m Tc by a direct method (70% labelling yield), using sodium ascorbate and dithionite in order to reduce the peptide and 99m Tc, respectively. The synthesis of RC-160 with S-benzoyl MAG-3 and TOC with HYNIC, for labelling with 99m Tc are also described. The conjugates were prepared on a small scale and labelled with the radionuclide using tricine as co-ligands for HYNIC conjugates. Chromatographic studies were performed using HPLC system and radiochemical purities higher than 75% and 95% were obtained respectively. Biodistributions studies in normal Wistar rats were performed and results were correlated with chromatographic and protein binding properties. Lower lipophilicity of the labelled conjugates resulted in a higher renal excretion. HYNIC-TOC complex showed promising results when labelling with 99m Tc using tricine as co-ligand although higher stability should be found for ternary co-ligands compared to tricine. (author)

Localization of P2X receptor subtypes 2, 3 and 7 in human urinary bladder.

Science.gov (United States)

Svennersten, Karl; Hallén-Grufman, Katarina; de Verdier, Petra J; Wiklund, N Peter; Poljakovic, Mirjana

2015-08-08

Voiding dysfunctions are a common problem that has a severe negative impact on the quality of life. Today there is a need for new drug targets for these conditions. The role of ATP receptors in bladder physiology has been studied for some time, primarily in animal models. The aim of this work is to investigate the localization of the ATP receptors P2X2, P2X3 and P2X7 and their colocalization with vimentin and actin in the human urinary bladder. Immunohistochemical analysis was conducted on full-thickness bladder tissues from fundus and trigonum collected from 15 patients undergoing open radical cystectomy due to chronic cystitis, bladder cancer or locally advanced prostate cancer. Colocalization analyses were performed between the three different P2X subtypes and the structural proteins vimentin and actin. Specimens were examined using epifluorescence microscopy and correlation coefficients were calculated for each costaining as well as the mean distance from the laminin positive basal side of the urothelium to the vimentin positive cells located in the suburothelium. P2X2 was expressed in vimentin positive cells located in the suburothelium. Less distinct labelling of P2X2 was also observed in actin positive smooth muscle cells and in the urothelium. P2X3 was expressed in vimentin positive cells surrounding the smooth muscle, and in vimentin positive cells located in the suburothelium. Weaker P2X3 labelling was seen in the urothelium. P2X7 was expressed in the smooth muscle cells and the urothelium. In the suburothelium, cells double positive for P2X2 and vimentin where located closer to the urothelium while cells double positive for P2X3 and vimentin where located further from the urothelium. The results from this study demonstrate that there is a significant difference in the expression of the purinergic P2X2, P2X3 and P2X7 receptors in the different histological layers of the human urinary bladder.

Breast cancer molecular subtypes and survival in a hospital-based sample in Puerto Rico

International Nuclear Information System (INIS)

Ortiz, Ana Patricia; Frías, Orquidea; Pérez, Javier; Cabanillas, Fernando; Martínez, Lisa; Sánchez, Carola; Capó-Ramos, David E; González-Keelan, Carmen; Mora, Edna; Suárez, Erick

2013-01-01

Information on the impact of hormone receptor status subtypes in breast cancer (BC) prognosis is still limited for Hispanics. We aimed to evaluate the association of BC molecular subtypes and other clinical factors with survival in a hospital-based female population of BC cases in Puerto Rico. We analyzed 663 cases of invasive BC diagnosed between 2002 and 2005. Information on HER-2/neu (HER-2) overexpression, estrogen (ER), and progesterone (PR) receptor status and clinical characteristics were retrieved from hospitals cancer registries and record review. Survival probabilities by covariates of interest were described using the Kaplan–Meier estimators. Cox proportional hazards models were employed to assess factors associated with risk of BC death. Overall, 17.3% of BC cases were triple-negative (TN), 61.8% were Luminal-A, 13.3% were Luminal-B, and 7.5% were HER-2 overexpressed. In the multivariate Cox model, among patients with localized stage, women with TN BC had higher risk of death (adjusted hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.29–5.12) as compared to those with Luminal-A status, after adjusting for age at diagnosis. In addition, among women with regional/distant stage at diagnosis, those with TN BC (HR: 5.48, 95% CI: 2.63–11.47) and those HER-2+, including HER-2 overexpressed and Luminal-B, (HR: 2.73, 95% CI:1.30–5.75) had a higher mortality. This is the most comprehensive epidemiological study to date on the impact of hormone receptor expression subtypes in BC survival in Puerto Rico. Consistent to results in other populations, the TN subtype and HER-2+ tumors were associated with decreased survival

High prevalence of luminal B breast cancer intrinsic subtype in Colombian women.

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Serrano-Gomez, Silvia Juliana; Sanabria-Salas, Maria Carolina; Hernández-Suarez, Gustavo; García, Oscar; Silva, Camilo; Romero, Alejandro; Mejía, Juan Carlos; Miele, Lucio; Fejerman, Laura; Zabaleta, Jovanny

2016-07-01

Breast cancer is the most frequent malignancy in women worldwide. Distinct intrinsic subtypes of breast cancer have different prognoses, and their relative prevalence varies significantly among ethnic groups. Little is known about the prevalence of breast cancer intrinsic subtypes and their association with clinicopathological data and genetic ancestry in Latin Americans. Immunohistochemistry surrogates from the 2013 St. Gallen International Expert Consensus were used to classify breast cancers in 301 patients from Colombia into intrinsic subtypes. We analyzed the distribution of subtypes by clinicopathological variables. Genetic ancestry was estimated from a panel of 80 ancestry informative markers. Luminal B breast cancer subtype was the most prevalent in our population (37.2%) followed by luminal A (26.3%), non-basal triple negative (NBTN) (11.6%), basal like (9%), human epidermal growth factor receptor 2 (HER2) enriched (8.6%) and unknown (7.3%). We found statistical significant differences in distribution between Colombian region (P = 0.007), age at diagnosis (P = 0.0139), grade (P studies analyzing the molecular profiles of breast cancer in Colombian women will help us understand the molecular basis of this subtype distribution and compare the molecular characteristics of the different intrinsic subtypes in Colombian patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly

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Shen, Ming; Zhang, Qilin [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Liu, Wenjuan; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yang, Yeping [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Wang, Meng [Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Soochow University, Division of Endocrinology, the Second Affiliated Hospital, Suzhou (China); Zhu, Jingjing [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Neuropathology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Zhao, Yao; Wang, Yongfei [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Yao, Zhenwei [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Radiology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Lu, Yun [Fudan University, Department of Nuclear Medicine, Huashan Hospital, Shanghai Medical College, Shanghai (China)

2016-11-15

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly. (orig.)

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly

International Nuclear Information System (INIS)

Shen, Ming; Zhang, Qilin; Liu, Wenjuan; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yang, Yeping; Wang, Meng; Zhu, Jingjing; Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Zhao, Yao; Wang, Yongfei; Yao, Zhenwei; Lu, Yun

2016-01-01

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly. (orig.)

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly.

Science.gov (United States)

Shen, Ming; Zhang, Qilin; Liu, Wenjuan; Wang, Meng; Zhu, Jingjing; Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yao, Zhenwei; Lu, Yun; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Yang, Yeping; Zhao, Yao; Wang, Yongfei

2016-11-01

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly.

Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese, Malay and natives of Sarawak, Malaysia.

Science.gov (United States)

Devi, C R Beena; Tang, Tieng Swee; Corbex, Marilys

2012-12-15

We determined the incidences of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) subtypes among breast cancer cases in Sarawak, Malaysia and their correlation with various risk factors in the three ethnic groups: Chinese, Malay and native. Subtype status was ascertained for 1,034 cases of female breast cancer (93% of all cases diagnosed since 2003), and the age-standardized incidence rates (ASRs) of each subtype were inferred. Case-case comparisons across subtypes were performed for reproductive risk factors. We found 48% luminal A (ER+/PR+/HER2-), 29% triple-negative (ER-/PR-/HER2-), 12% triple-positive (ER+/PR+/HER2+) and 11% HER2-overexpressing (ER-/PR-/HER2+) subtypes, with ASRs of 10.6, 6.0, 2.8 and 2.8 per 100,000, respectively. The proportions of subtypes and ASRs differed significantly by ethnic groups: HER2-positive cases were more frequent in Malays (29%; 95% CI [23;35]) than Chinese (22%; [19;26] and natives (21%; [16;26]); triple-negative cases were less frequent among Chinese (23%; [20;27]) than Malays (33%; [27;39]) and natives (37%; [31;43]). The results of the case-case comparison were in accordance with those observed in western case series. Some uncommon associations, such as between triple-negative subtype and older age at menopause (OR, 1.59; p < 0.05), were found. The triple-negative and HER2+ subtypes predominate in our region, with significant differences among ethnic groups. Our results support the idea that the risk factors for different subtypes vary markedly. Westernized populations are more likely to have factors that increase the risk for the luminal A type, while risk factors for the triple-negative type are more frequent in local populations. Copyright © 2012 UICC.

Interferon-alpha subtype 11 activates NK cells and enables control of retroviral infection.

Directory of Open Access Journals (Sweden)

Kathrin Gibbert

Full Text Available The innate immune response mediated by cells such as natural killer (NK cells is critical for the rapid containment of virus replication and spread during acute infection. Here, we show that subtype 11 of the type I interferon (IFN family greatly potentiates the antiviral activity of NK cells during retroviral infection. Treatment of mice with IFN-α11 during Friend retrovirus infection (FV significantly reduced viral loads and resulted in long-term protection from virus-induced leukemia. The effect of IFN-α11 on NK cells was direct and signaled through the type I IFN receptor. Furthermore, IFN-α11-mediated activation of NK cells enabled cytolytic killing of FV-infected target cells via the exocytosis pathway. Depletion and adoptive transfer experiments illustrated that NK cells played a major role in successful IFN-α11 therapy. Additional experiments with Mouse Cytomegalovirus infections demonstrated that the therapeutic effect of IFN-α11 is not restricted to retroviruses. The type I IFN subtypes 2 and 5, which bind the same receptor as IFN-α11, did not elicit similar antiviral effects. These results demonstrate a unique and subtype-specific activation of NK cells by IFN-α11.

Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2, and T3 tumors.

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Parise, Carol A; Caggiano, Vincent

2017-10-01

The purpose of this study was to assess differences in breast cancer-specific mortality within tumors of the same size when breast cancer was defined using the three tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We identified 104,499 cases of node-negative primary female invasive breast cancer from the California Cancer Registry. Tumor size was categorized as T1a, T1b, T1c, T2, and T3. Breast cancer was defined using ER, PR, and HER2. Kaplan-Meier Survival analysis was conducted and Cox Regression was used to compute the adjusted risk of mortality for the ER+/PR+/HER2+, ER-/PR-/HER2- (TNBC), and ER-/PR-/HER2+ (HER2-overexpressing) subtypes when compared with the ER+/PR+/HER2-. Separate models were computed for each tumor size. Unadjusted survival analysis showed that for all tumor sizes, the ER+/PR+ subtypes regardless of HER status have better breast cancer-specific survival than ER-/PR- subtypes. Subtype was not an important factor for risk of mortality for T1a tumors. The ER+/PR+/HER2+ subtype was only a risk for mortality in T1b tumors that were unadjusted for treatment. For all other tumor sizes, the ER+/PR+/HER2+ had the same mortality as the ER+/PR+/HER2- subtype regardless of adjustment for treatment. The HER2-overexpressing subtype had a higher risk of mortality than the ER+/PR+/HER2- subtype except for T1b tumors that were adjusted for treatment. For all tumor sizes, the TNBC had higher hazard ratios than all other subtypes. T1a tumors have the same risk of mortality regardless of ER/PR/HER2 subtype, and ER and PR negativity plays a stronger role in survival than HER2 positivity for tumors of all size.

Risk Differences Between Prediabetes And Diabetes According To Breast Cancer Molecular Subtypes.

Science.gov (United States)

Crispo, A; Augustin, L S A; Grimaldi, M; Nocerino, F; Giudice, A; Cavalcanti, E; Di Bonito, M; Botti, G; De Laurentiis, M; Rinaldo, M; Esposito, E; Riccardi, G; Amore, A; Libra, M; Ciliberto, G; Jenkins, D J A; Montella, M

2017-05-01

Hyperglycemia and hyperinsulinemia may play a role in breast carcinogenesis and prediabetes and diabetes have been associated with increased breast cancer (BC) risk. However, whether BC molecular subtypes may modify these associations is less clear. We therefore investigated these associations in all cases and by BC molecular subtypes among women living in Southern Italy. Cases were 557 patients with non-metastatic incident BC and controls were 592 outpatients enrolled during the same period as cases and in the same hospital for skin-related non-malignant conditions. Adjusted multivariate logistic regression models were built to assess the risks of developing BC in the presence of prediabetes or diabetes. The analyses were repeated by strata of BC molecular subtypes: Luminal A, Luminal B, HER2+, and Triple Negative (TN). Prediabetes and diabetes were significantly associated with higher BC incidence after controlling for known risk factors (OR = 1.94, 95% CI 1.32-2.87 and OR = 2.46, 95% CI 1.38-4.37, respectively). Similar results were seen in Luminal A and B while in the TN subtype only prediabetes was associated with BC (OR = 2.43, 95% CI 1.11-5.32). Among HER2+ patients, only diabetes was significantly associated with BC risk (OR = 3.04, 95% CI 1.24-7.47). Furthermore, when postmenopausal HER2+ was split into hormone receptor positive versus negative, the association with diabetes remained significant only in the former (OR = 5.13, 95% CI 1.53-17.22). These results suggest that prediabetes and diabetes are strongly associated with BC incidence and that these metabolic conditions may be more relevant in the presence of breast cancer molecular subtypes with positive hormone receptors. J. Cell. Physiol. 232: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group

DEFF Research Database (Denmark)

Kyndi, M.; Sorensen, F.B.; Overgaard, M.

2008-01-01

. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec- as both ER- and PgR-. The four subgroups were Rec+/HER-2-, Rec......+/HER-2+, Rec-/HER-2- (triple negative), and Rec-/HER-2+. Results A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall...... after PMRT were found for ER- and PgR- tumors compared with the ER+ and PgR+ tumors (P = .003 and 04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec-/HER-2- subtype. Conclusion Hormonal receptor status, HER-2, and the constructed...

Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group

DEFF Research Database (Denmark)

Kyndi, Marianne; Sørensen, Flemming Brandt; Knudsen, Helle