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[PMID]:28911153
[Au] Autor:Øystese KA; Casar-Borota O; Normann KR; Zucknick M; Berg JP; Bollerslev J
[Ad] Endereço:Department of Endocrinology, Section of Specialized Endocrinology, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway.
[Ti] Título:Estrogen Receptor α, a Sex-Dependent Predictor of Aggressiveness in Nonfunctioning Pituitary Adenomas: SSTR and Sex Hormone Receptor Distribution in NFPA.
[So] Source:J Clin Endocrinol Metab;102(9):3581-3590, 2017 Sep 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Nonfunctioning pituitary adenomas (NFPAs) are fairly common and require a multidisciplinary approach. Reliable markers of a clinically aggressive course are lacking. Medical treatment is not available, and transsphenoidal surgery is the preferred primary treatment. Objective: We aimed to characterize the somatostatin, estrogen, and progesterone receptor distribution for NFPAs and compare it with factors of tumor aggressiveness. Design: Tumor samples for immunohistochemistry (n = 145) and quantitative reverse transcription polymerase chain reaction (n = 106) analyses of somatostatin receptor (SSTR) 1, SSTR2, SSTR3, SSTR5, estrogen receptor α (ERα), and progesterone receptor (PR) were measured by immunoreactive score (IRS) and messenger RNA relative quantity and retrospectively compared with variables of aggressiveness. Setting: All patients were operated at the same tertiary referral center. Participants: A total of 164 patients with NFPA and tumor tissue from the primary operation were included. Results: SSTR3 was expressed abundantly by immunohistochemistry in all NFPAs. The IRS of ERα correlated with that of SSTR2 in male patients only (males, P < 0.001; females, P = 0.8). Low ERα level was linked to a higher reintervention rate (P = 0.001) and earlier reintervention (P = 0.004) in male patients only (females, P = 0.95 and P = 0.65, respectively). Absence of ERα together with age provided a good prediction model for reintervention in male patients with gonadotroph adenomas. Conclusions: SSTR3 is expressed abundantly in NFPAs and is therefore a possible target for medical treatment. Absence of ERα together with young age may predict tumor recurrence in groups of NFPAs. Further validation in systematic prospective studies is needed.
[Mh] Termos MeSH primário: Adenoma/patologia
Biomarcadores Tumorais/sangue
Receptor alfa de Estrogênio/metabolismo
Neoplasias Hipofisárias/patologia
Receptores de Progesterona/metabolismo
Receptores de Somatostatina/metabolismo
[Mh] Termos MeSH secundário: Adenoma/metabolismo
Adenoma/mortalidade
Idoso
Estudos de Coortes
Intervalo Livre de Doença
Feminino
Seres Humanos
Masculino
Meia-Idade
Invasividade Neoplásica/patologia
Estadiamento de Neoplasias
Neoplasias Hipofisárias/metabolismo
Neoplasias Hipofisárias/mortalidade
Valor Preditivo dos Testes
Prognóstico
Estudos Prospectivos
Fatores Sexuais
Análise de Sobrevida
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Estrogen Receptor alpha); 0 (Receptors, Progesterone); 0 (Receptors, Somatostatin); 0 (somatostatin receptor subtype 2, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00792


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[PMID]:28905400
[Au] Autor:Pedraza-Arévalo S; Hormaechea-Agulla D; Gómez-Gómez E; Requena MJ; Selth LA; Gahete MD; Castaño JP; Luque RM
[Ad] Endereço:Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.
[Ti] Título:Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer.
[So] Source:Prostate;77(15):1499-1511, 2017 Nov.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known. METHODS: PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell-proliferation, migration, signaling-pathways, and androgen-signaling. RESULTS: We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines. CONCLUSIONS: Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/biossíntese
Neoplasias de Próstata Resistentes à Castração/metabolismo
Receptores de Somatostatina/biossíntese
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/genética
Linhagem Celular Tumoral
Seres Humanos
Masculino
Meia-Idade
Terapia de Alvo Molecular
Neoplasias de Próstata Resistentes à Castração/diagnóstico
Neoplasias de Próstata Resistentes à Castração/genética
Neoplasias de Próstata Resistentes à Castração/terapia
Receptores de Somatostatina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Receptors, Somatostatin); 0 (somatostatin receptor type 1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1002/pros.23426


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[PMID]:28864614
[Au] Autor:Fani M; Nicolas GP; Wild D
[Ad] Endereço:Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland.
[Ti] Título:Somatostatin Receptor Antagonists for Imaging and Therapy.
[So] Source:J Nucl Med;58(Suppl 2):61S-66S, 2017 Sep.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the introduction of peptide receptor radionuclide therapy with radiolabeled sstr agonists, such as [ Y-DOTA ,Tyr ]octreotide or [ Lu-DOTA ,Tyr ]octreotide ( Y- or Lu-DOTATOC, respectively) and [ Lu-DOTA ,Tyr ]octreotate ( Lu-DOTATATE). PET/CT with Ga-labeled sstr agonists, such as Ga-DOTATOC, Ga-DOTATATE, and [ Ga-DOTA,1-Nal ]octreotide ( Ga-DOTANOC), plays an important role in staging and restaging neuroendocrine tumors. Most importantly, sstr scintigraphy and sstr PET/CT can distinguish patients who will qualify for and benefit from peptide receptor radionuclide therapy. This characteristic of sstr targeting is important because it allows a personalized treatment approach (theranostic approach). Until recently, it was thought that internalization of the radiolabeled agonist was mandatory for sstr-mediated imaging and therapy. It was Ginj et al. who proposed in 2006 the paradigm shift that radiolabeled sstr antagonists may perform better than agonists despite the lack of internalization. Despite the rather limited number of head-to-head comparisons of sstr antagonists and agonists, the superiority of sstr antagonists was demonstrated in several cases. From a small library of sstr antagonists, the analog JR11 (Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH ), an antagonist with selectivity for sstr subtype 2, showed the best overall characteristics for sstr subtype 2 targeting and was therefore selected for clinical translation. JR11 is under clinical development as a PET imaging agent when labeled with Ga ( Ga-NODAGA-JR11 or Ga-OPS202) and as a therapeutic agent when labeled with Lu ( Lu-DOTA-JR11 or Lu-OPS201). In this article, we discuss the development and current status of radiolabeled sstr antagonists. Evidence based on preclinical work, on quantitative in vivo autoradiography of human tumor slices, and on human data now supports a shift to sstr antagonists.
[Mh] Termos MeSH primário: Diagnóstico por Imagem/métodos
Descoberta de Drogas/métodos
Terapia de Alvo Molecular/métodos
Receptores de Somatostatina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Marcação por Isótopo
Receptores de Somatostatina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Somatostatin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.116.186783


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[PMID]:28864613
[Au] Autor:Smit Duijzentkunst DA; Kwekkeboom DJ; Bodei L
[Ad] Endereço:Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; and d.smitduijzentkunst@erasmusmc.nl.
[Ti] Título:Somatostatin Receptor 2-Targeting Compounds.
[So] Source:J Nucl Med;58(Suppl 2):54S-60S, 2017 Sep.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic compounds. Whole-body scintigraphy with In-pentetreotide has revolutionized the diagnosis and staging of NETs and the evaluation of treatment outcomes. At present, diagnostic accuracy with positron-emitting radionuclides is greater than 90%. Peptide receptor radionuclide therapy (PRRT) has become a well-accepted treatment for patients with well-differentiated inoperable or metastatic NETs and disease progression after first-line treatment. Disease control rates (complete or partial remission or stable disease in patients with formerly progressive disease) of up to 95%, with a low incidence of long-term hematologic and renal toxicity, have been reported. In a recently published randomized trial, compared with intensified treatment of midgut NETs with long-acting and repeatable octreotide, PRRT reduced the hazard of disease progression and death by 79%. Upcoming developments in PRRT include the use of somatostatin receptor antagonists and α-emitting radionuclides, which may further enhance treatment outcomes.
[Mh] Termos MeSH primário: Descoberta de Drogas/métodos
Terapia de Alvo Molecular
Receptores de Somatostatina/metabolismo
[Mh] Termos MeSH secundário: Animais
Diagnóstico por Imagem
Seres Humanos
Segurança
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Somatostatin); 0 (somatostatin receptor 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.117.191015


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[PMID]:28800359
[Au] Autor:Nölting S; Rentsch J; Freitag H; Detjen K; Briest F; Möbs M; Weissmann V; Siegmund B; Auernhammer CJ; Aristizabal Prada ET; Lauseker M; Grossman A; Exner S; Fischer C; Grötzinger C; Schrader J; Grabowski P; GERMAN NET-Z study group
[Ad] Endereço:Department of Internal Medicine II, Klinikum der Universität München (KUM), Ludwig-Maximilians-Universität München, München, Bavaria, Germany.
[Ti] Título:The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.
[So] Source:PLoS One;12(8):e0182852, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Everolimo/farmacologia
Regulação Neoplásica da Expressão Gênica
Pâncreas/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Cromogranina A/genética
Cromogranina A/metabolismo
Classe I de Fosfatidilinositol 3-Quinases/genética
Classe I de Fosfatidilinositol 3-Quinases/metabolismo
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Quinase 3 da Glicogênio Sintase/genética
Quinase 3 da Glicogênio Sintase/metabolismo
Seres Humanos
Pâncreas/metabolismo
Pâncreas/patologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptores de Somatostatina/genética
Receptores de Somatostatina/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Chromogranin A); 0 (NVP-BYL719); 0 (Protein Kinase Inhibitors); 0 (Receptors, Somatostatin); 0 (Thiazoles); 0 (somatostatin receptor 5); 0 (somatostatin receptor subtype 2, human); 0 (somatostatin receptor type 1); 9HW64Q8G6G (Everolimus); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.26 (Glycogen Synthase Kinase 3); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (CASP7 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182852


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[PMID]:28787594
[Au] Autor:Guo J; Otis JM; Higginbotham H; Monckton C; Cheng J; Asokan A; Mykytyn K; Caspary T; Stuber GD; Anton ES
[Ad] Endereço:UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
[Ti] Título:Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity.
[So] Source:Dev Cell;42(3):286-300.e4, 2017 Aug 07.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Appropriate growth and synaptic integration of GABAergic inhibitory interneurons are essential for functional neural circuits in the brain. Here, we demonstrate that disruption of primary cilia function following the selective loss of ciliary GTPase Arl13b in interneurons impairs interneuronal morphology and synaptic connectivity, leading to altered excitatory/inhibitory activity balance. The altered morphology and connectivity of cilia mutant interneurons and the functional deficits are rescued by either chemogenetic activation of ciliary G-protein-coupled receptor (GPCR) signaling or the selective induction of Sstr3, a ciliary GPCR, in Arl13b-deficient cilia. Our results thus define a specific requirement for primary cilia-mediated GPCR signaling in interneuronal connectivity and inhibitory circuit formation.
[Mh] Termos MeSH primário: Interneurônios/metabolismo
Transdução de Sinais
Sinapses/metabolismo
Potenciais Sinápticos
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/genética
Fatores de Ribosilação do ADP/metabolismo
Animais
Células Cultivadas
Cílios/metabolismo
Interneurônios/citologia
Interneurônios/fisiologia
Camundongos
Neurogênese
Receptores de Somatostatina/genética
Receptores de Somatostatina/metabolismo
Sinapses/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arl13b protein, mouse); 0 (Receptors, Somatostatin); 0 (somatostatin receptor 3); EC 3.6.5.2 (ADP-Ribosylation Factors)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


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[PMID]:28782576
[Au] Autor:Li J; Chen C; Bi X; Zhou C; Huang T; Ni C; Yang P; Chen S; Ye M; Duan S
[Ad] Endereço:Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China; The Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China.
[Ti] Título:DNA methylation of CMTM3, SSTR2, and MDFI genes in colorectal cancer.
[So] Source:Gene;630:1-7, 2017 Sep 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer (CRC) is increasingly common worldwide, including in China. Therefore, there is an increasing need to detect CRC at an early stage and to discover and evaluate diagnostic and prognostic biomarkers. DNA methylation of genes in CRC is a potential epigenetic biomarker for the early detection of CRC. This study was performed to analyze the methylation frequency of six candidate genes, CMTM3, SSTR2, MDFI, NDRG4, TGFB2, and BCL2L11, in fresh-frozen CRC tissues and adjacent normal colorectal tissues, from 42 patients with CRC. DNA isolation, bisulphite modification, and pyrosequencing were performed. The sensitivity, specificity, and the area under the receiver operator characteristic (ROC) curve (AUC) were evaluated to determine whether these genes showed any associations with tumor grade, stage, or diagnostic features. Among the tested genes, three genes, CMTM3, SSTR2, and MDFI were significantly methylated in CRC tissues when compared with adjacent normal colorectal tissues. The ROC analysis showed that a multigene model, including CMTM3, SSTR2, and MDFI, had a sensitivity of 81% and a specificity of 91% with an AUC value of 0.92. The findings of this study have shown that DNA methylation of the genes, CMTM3, SSTR2, and MDFI should be studied further with a view to determining their potential role as biomarkers for CRC.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Contactinas/genética
Metilação de DNA
Fatores de Regulação Miogênica/genética
Receptores de Somatostatina/genética
[Mh] Termos MeSH secundário: Proteína 11 Semelhante a Bcl-2/genética
Neoplasias Colorretais/patologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Proteínas Musculares/genética
Proteínas do Tecido Nervoso/genética
Fator de Crescimento Transformador beta2/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2L11 protein, human); 0 (Bcl-2-Like Protein 11); 0 (Biomarkers, Tumor); 0 (CNTN3 protein, human); 0 (Contactins); 0 (Muscle Proteins); 0 (Myogenic Regulatory Factors); 0 (NDRG4 protein, human); 0 (Nerve Tissue Proteins); 0 (Receptors, Somatostatin); 0 (TGFB2 protein, human); 0 (Transforming Growth Factor beta2); 0 (somatostatin receptor subtype 2, human); 183511-66-2 (MDFI protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE


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[PMID]:28732021
[Au] Autor:Chan HS; de Blois E; Morgenstern A; Bruchertseifer F; de Jong M; Breeman W; Konijnenberg M
[Ad] Endereço:Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
[Ti] Título:In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy.
[So] Source:PLoS One;12(7):e0181473, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Absorbed doses for α-emitters are different from those for ß-emitters, as the high linear energy transfer (LET) nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE) at 10% survival was calculated. RESULTS: IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found for 177Lu-DOTATATE and also below the 5 Gy after 137Cs external exposure. CONCLUSION: 213Bi-DTPA and 213Bi-DOTATATE lead to a factor 6 advantage in cell killing compared to 177Lu-DOTATATE. The RBE at 10% survival by 213Bi-ligand compared to 137Cs was 2.0 whereas the RBE for 177Lu-DOTATATE was 0.3 in the CA20948 in vitro model.
[Mh] Termos MeSH primário: Absorção de Radiação
Bismuto
Lutécio
Octreotida/análogos & derivados
Octreotida/farmacologia
Radioisótopos
Compostos Radiofarmacêuticos
Receptores de Somatostatina/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular/efeitos da radiação
Relação Dose-Resposta à Radiação
Seres Humanos
Cinética
Transferência Linear de Energia
Modelos Biológicos
Método de Monte Carlo
Compostos Organometálicos/administração & dosagem
Compostos Organometálicos/farmacologia
Radioisótopos/administração & dosagem
Radioisótopos/farmacocinética
Radiometria
Compostos Radiofarmacêuticos/administração & dosagem
Compostos Radiofarmacêuticos/farmacocinética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organometallic Compounds); 0 (Radioisotopes); 0 (Radiopharmaceuticals); 0 (Receptors, Somatostatin); 0 (somatostatin receptor subtype 2, human); 5H0DOZ21UJ (Lutetium); RWM8CCW8GP (Octreotide); U015TT5I8H (Bismuth)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181473


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[PMID]:28697189
[Au] Autor:Lawal IO; Ololade KO; Lengana T; Reyneke F; Ankrah AO; Ebenhan T; Vorster M; Sathekge MM
[Ad] Endereço:Department of Nuclear Medicine, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa. mike.sathekge@up.ac.za.
[Ti] Título:Gallium-68-dotatate PET/CT is better than CT in the management of somatostatin expressing tumors: First experience in Africa.
[So] Source:Hell J Nucl Med;20(2):128-133, 2017 May-Aug.
[Is] ISSN:1790-5427
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: In this study we aimed to present our experience on the use of Gallium-68-dotatate with positron emission tomography, computed tomography ( Ga-dotatate PET/CT) in the management of neuroendocrine tumors (NET) and other somatostatin expressing tumors. SUBJECTS AND METHODS: We retrospectively reviewed patients with histologically confirmed or biochemically suspected NET and other somatostatin expressing (SSTR) tumors imaged at our department with Ga-dotatate PET/CT. We determined the performance of this imaging technique as well as its impact on patients management. A total of 203 patients were studied: 103 females, 100 males median age 52years. RESULTS: The commonest tumor type was gastroenteropancreatic NET (41% of patients) and the commonest sites of distant metastases were lymph nodes and the liver 34.0% and 30.5% respectively. Positron emission tomography detected foci of disease in 19 patients where CT was falsely negative. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of Ga-dotatate PET/CT imaging of NET and other SST expressing tumors were 94.16%, 91.89%, 95.55%, 89.47% and 96.55% respectively. CONCLUSION: Gallium-68-dotatate PET/CT was better than CT in detecting primary sites of the disease and highly sensitive and specific for diagnosis and treatment of NET and other SSTR expressing tumors.
[Mh] Termos MeSH primário: Tumores Neuroendócrinos/diagnóstico por imagem
Tumores Neuroendócrinos/metabolismo
Compostos Organometálicos
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos
Receptores de Somatostatina/metabolismo
Tomografia Computadorizada por Raios X/métodos
[Mh] Termos MeSH secundário: África
Feminino
Seres Humanos
Aumento da Imagem/métodos
Masculino
Meia-Idade
Projetos Piloto
Compostos Radiofarmacêuticos
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organometallic Compounds); 0 (Radiopharmaceuticals); 0 (Receptors, Somatostatin); 9L17Y0H71P (dotatate gallium ga-68)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1967/s002449910553


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[PMID]:28542563
[Au] Autor:Holmboe S; Hansen PL; Thisgaard H; Block I; Müller C; Langkjær N; Høilund-Carlsen PF; Olsen BB; Mollenhauer J
[Ad] Endereço:Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense, Denmark.
[Ti] Título: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.
[So] Source:PLoS One;12(5):e0178286, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Aptâmeros de Nucleotídeos/farmacologia
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Compostos Heterocíclicos com 1 Anel/química
Células-Tronco Neoplásicas/efeitos dos fármacos
Fosfoproteínas/antagonistas & inibidores
Proteínas de Ligação a RNA/antagonistas & inibidores
Receptores de Somatostatina/metabolismo
Somatostatina/análogos & derivados
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Carcinoma Pulmonar de Células não Pequenas/patologia
Proliferação Celular/efeitos dos fármacos
Sistemas de Liberação de Medicamentos
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Células-Tronco Neoplásicas/metabolismo
Células-Tronco Neoplásicas/patologia
Somatostatina/farmacologia
Células Tumorais Cultivadas
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aptamers, Nucleotide); 0 (Heterocyclic Compounds, 1-Ring); 0 (Phosphoproteins); 0 (RNA-Binding Proteins); 0 (Receptors, Somatostatin); 0 (nucleolin); 0 (somatostatin receptor 2); 1HTE449DGZ (1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid); 51110-01-1 (Somatostatin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178286



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