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2.
Nat Commun ; 10(1): 4923, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664021

RESUMO

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.


Assuntos
Hipocampo/metabolismo , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Comportamento Impulsivo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Animais , Hormônios Hipotalâmicos/genética , Masculino , Melaninas/genética , Vias Neurais , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Hormônios Hipofisários/genética , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo
3.
Neurochem Res ; 44(11): 2670-2680, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31630317

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR4) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR4 agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aß phagocytosis, amyloid-beta (Aß)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aß phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aß-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aß phagocytosis and clearance, further supporting SSTR4 as a treatment target for AD.


Assuntos
Encéfalo/metabolismo , Microglia/metabolismo , RNA Mensageiro/metabolismo , Receptores de Somatostatina/metabolismo , Doença de Alzheimer/patologia , Aminopiridinas/farmacologia , Animais , Encéfalo/citologia , Catalase/genética , Regulação para Baixo/efeitos dos fármacos , Insulisina/genética , Camundongos Transgênicos , Neprilisina/genética , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Receptores Depuradores Classe A/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Tioureia/análogos & derivados , Tioureia/farmacologia , Regulação para Cima/efeitos dos fármacos
4.
Clin Nucl Med ; 44(11): 851-854, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31524686

RESUMO

PURPOSE: To measure the SUVs in the tail of the pancreas compared with normal liver parenchyma and somatostatin receptor-positive lesions. MATERIALS AND METHODS: Ga-DOTATATE PET/low mAs CT of 35 patients were reviewed. RESULTS: There was no significant difference (P = 0.59) between the SUVaverage of normal liver and the SUVpeak of normal tail. Five patients had uptake in the tail slightly above that of normal liver that were interpreted equivocally. In one of these patients with Ga-DOTATATE uptake in a peripancreatic lymph node, proven neuroendocrine tumor underwent a distal pancreatectomy and pathologic examination revealed islet cell hyperplasia. CONCLUSIONS: Ga-DOTATATE uptake in the tail of the pancreas above that of normal liver indicates a somatostatin receptor-avid lesion. Uptake in the tail of the pancreas equal to the liver can be normal. Patients with uptake equivalent to the liver should undergo further anatomical imaging before procedural intervention.


Assuntos
Compostos Organometálicos/metabolismo , Pâncreas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Pâncreas/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/metabolismo
5.
Endocrinology ; 160(12): 2849-2860, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556942

RESUMO

The gut-pancreas axis plays a key role in the regulation of glucose homeostasis and may be therapeutically exploited to treat not only type 2 diabetes but also hypoglycemia and hyperinsulinemia. We identify a novel enteroendocrine cell type expressing the peptide hormone urotensin 2B (UTS2B). UTS2B inhibits glucagon-like peptide-1 (GLP-1) secretion in mouse intestinal crypts and organoids, not by signaling through its cognate receptor UTS2R but through the activation of the somatostatin receptor (SSTR) 5. Circulating UTS2B concentrations in mice are physiologically regulated during starvation, further linking this peptide hormone to metabolism. Furthermore, administration of UTS2B to starved mice demonstrates that it is capable of regulating blood glucose and plasma concentrations of GLP-1 and insulin in vivo. Altogether, our results identify a novel cellular source of UTS2B in the gut, which acts in a paracrine manner to regulate GLP-1 secretion through SSTR5. These findings uncover a fine-tuning mechanism mediated by a ligand-receptor pair in the regulation of gut hormone secretion, which can potentially be exploited to correct metabolic unbalance caused by overactivation of the gut-pancreas axis.


Assuntos
Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Hormônios Peptídicos/metabolismo , Receptores de Somatostatina/metabolismo , Animais , Glucose/metabolismo , Jejuno/citologia , Jejuno/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Comunicação Parácrina
6.
Pharm Res ; 36(10): 143, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385111

RESUMO

PURPOSE: Pancreatic Polypeptide-secreting tumor of the distal pancreas (PPoma) is a rare, difficult and indolent type of cancer with a survival rate of 5-year in only 10% of all cases. The PPoma is classified as a neuroendocrine tumor (NET) not functioning that overexpresses SSTR 2 (somatostatin receptor subtype 2). Thus, in order to improve the diagnosis of this type of tumor, we developed nanoparticulate drug carriers based on poly-lactic acid (PLA) polymer loaded with octreotide and radiolabeled with Technetium-99 m (99mTc). METHODS: PLA/PVA octreotide nanoparticles were developed by double-emulsion technique. These nanoparticles were characterized by Atomic Force Microscopy (AFM) and Dynamic Light Scattering (DLS) and radiolabeled with 99mTc by the direct via forming 99mTc-PLA/PVA octreotide nanoparticles. The safety of these nanosystems was evaluated by the MTT cell toxicity assay and their in vivo biodistribution was evaluated in xenografted inducted animals. RESULTS: The results showed that a 189 nm sized nanoparticle were formed with a PDI of 0,097, corroborating the monodispersive behavior. These nanoparticles were successfully radiolabeled with 99mTc showing uptake by the inducted tumor. The MTT assay corroborated the safety of the nanosystem for the cells. CONCLUSION: The results support the use of this nanosystem (99mTc-PLA/PVA octreotide nanoparticles) as imaging agent for PPoma. Graphical Abstract Polypeptide-Secreting Tumor of the Distal Pancreas (PPoma) Radiolabeled Nanoparticles for Imaging.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Nanopartículas/química , Octreotida/química , Neoplasias Pancreáticas/diagnóstico por imagem , Polipeptídeo Pancreático/metabolismo , Poliésteres/química , Compostos Radiofarmacêuticos/química , Tecnécio/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/metabolismo , Octreotida/metabolismo , Pâncreas/diagnóstico por imagem , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Tamanho da Partícula , Cintilografia/métodos , Compostos Radiofarmacêuticos/metabolismo , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Distribuição Tecidual
7.
Drug Dev Ind Pharm ; 45(10): 1707-1715, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31418304

RESUMO

Numerous normal and tumors cells are well-known to express the somatostatin receptors (SSTRs) on their surface which makes the receptor be useful for tumor scintigraphy. Thus, the identification of SSTRs is beneficial, especially SSTR2. The somatostatin analog, Octreotide (OCT), was chosen as a ligand, as it is known to selectively bind to SSTR2. Moreover, polyethylene glycol (PEG), 8armPEG, was used as a branched PEG to provide a low nonspecific cell binding and easily chemical modification. OCT and fluorescein (Flu) were conjugated to branched PEG using a water-soluble carbodiimide (EDC) and N-hydroxy succinimide (NHS) so as to activate its carboxylic acid group. 8armPEG-tagged Flu and OCT was characterized by gel permeation chromatography (GPC) to proof the conjugation of OCT to 8armPEG. Finally, cellular uptake was studied using pancreatic cancer cells with well-expressed somatostatin receptors using a confocal laser scanning microscope (CLMS) and fluorescence activated cell sorting (FACS). GPC showed increases in molecular mass since it showed a difference in elution time of 8armPEG itself and 8armPEG labeled with Flu. CLMS and FACS showed high binding with the positive SSTR2 cells expression and showed negative results with negative expressing SSTR2. These bindings were decreased when the receptors were occupied with free OCT which confirms the specific binding to SSTR2. Therefore, we formulated a novel model to easily identify SSTR2 and other receptors which serves as a promising platform for identification of tumor cells overexpressing the SSTR2, which would be a hopeful target for cancer therapy and tumor scintigraphy.


Assuntos
Octreotida/metabolismo , Polietilenoglicóis/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Células HCT116 , Humanos , Células MCF-7 , Neoplasias Pancreáticas/metabolismo , Cintilografia/métodos
8.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412614

RESUMO

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Receptores de Somatostatina/metabolismo , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Tumores Neuroendócrinos/etiologia , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Ligação Proteica , Multimerização Proteica , Receptores de Somatostatina/química , Transdução de Sinais , Resultado do Tratamento
9.
Clin Nucl Med ; 44(9): 687-694, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274560

RESUMO

PURPOSE: This pilot study aimed to prove the complementary value of a novel Gallium-labeled heterodimeric peptide, Ga-NOTA-3P-TATE-RGD, in detection and evaluation of tumors with somatostatin receptor subtype 2 or integrin αvß3 overexpression, including non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), neuroendocrine tumor (NET), and neuroendocrine carcinoma (NEC). METHODS: With institute review board approval and written informed consent, 32 patients with pathologically diagnosed lung cancer (18 NSCLC, 14 SCLC) and 12 patients with neuroendocrine neoplasm (8 NET, 4 NEC) patients were recruited to undergo Ga-NOTA-3P-TATE-RGD PET/CT. For comparison, the NSCLC patients also underwent Ga-NOTA-TATE PET/CT, the SCLC patients underwent Ga-NOTA-RGD PET/CT, and the neuroendocrine neoplasm patients underwent F-FDG PET/CT within 3 days. The maximum standardized uptake value (SUV) of the primary tumor (T) and mean SUV of the blood pool (B) were measured, and the T/B ratios were calculated for comparison. RESULTS: In the primary tumors of NSCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-TATE (4.54 ± 3.00 versus 4.10 ± 2.83, P = 0.0058). In SCLC, the T/B ratios of Ga-NOTA-3P-TATE-RGD were significantly higher than those of Ga-NOTA-RGD (6.06 ± 6.09 versus 2.65 ± 1.19, P = 0.0344). In NET, the T/B ratios of Ga-NOTA-3P-TATE-RGD were 36.13 ± 33.84, significantly higher than those of F-FDG (2.91 ± 1.71, P = 0.0234). In NEC, there were no significant difference between the T/B ratios of Ga-NOTA-3P-TATE-RGD (4.80 ± 0.85) and those of F-FDG (3.56 ± 0.74, P = 0.1833). CONCLUSIONS: This proof-of-concept study preliminarily demonstrates the efficacy of the dual targeting Ga-NOTA-3P-TATE-RGD PET/CT in the evaluation of lung cancer and neuroendocrine neoplasm in a single scan.


Assuntos
Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/metabolismo
10.
Nanoscale ; 11(30): 14400-14409, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31334537

RESUMO

Somatostatin receptor subtype 2 (SSTR2) is highly expressed in pulmonary neuroendocrine tumors, which account for approximately 25% of all lung cancers including small-cell lung cancer (SCLC). It is possible to establish SCLC-specific imaging agents for multimodal imaging to obtain tumor integrity information. Herein, we constructed novel multifunctional organic melanin nanoparticles (MNPs) as a carrier and surface-loaded somatostatin analog octreotide to produce a human small-cell lung cancer-targeted nanoprobe OCT-PEG-MNPs. MNPs have an excellent photoacoustic imaging (PAI) function and can be directly chelated with the magnetic resonance contrast agent Mn2+, and N-bromo succinimide (NBS) can be used as an oxidant to label the nanoparticles with the long half-life radionuclide 124I by an electrophilic substitution reaction. Therefore, (124I, Mn) OCT-PEG-MNPs can not only be used for PAI but also be used for positron emission tomography (PET) and magnetic resonance imaging (MRI). The NCI-H69 SCLC tumor xenograft model with high SSTR2 expression was constructed to evaluate the multimodal imaging ability of (124I, Mn) OCT-PEG-MNPs. This nanoprobe showed good imaging abilities in PAI, MRI and PET. The PA images showed that the photoacoustic signal in the NCI-H69 tumor site gradually increased with time, and the NCI-H69 xenograft showed a clear increase in the T1-weighted signal intensity after injection of Mn-OCT-PEG-MNPs at 24 h compared to that in the prescan. MicroPET and biodistribution studies showed that the uptake of NCI-H69 tumors (8.03 ± 0.37% ID g-1) was significantly higher than that in the control A549 model (3.35 ± 0.54% ID g-1) after injection of (124I, Mn) OCT-PEG-MNPs at 24 h. The (124I, Mn) OCT-PEG-MNPs were successfully applied to multimodal imaging in a small-cell lung cancer model with high SSTR2 expression. This nanoprobe may be considered for clinical trials since it combines the numerous advantages of organic nanoparticles.


Assuntos
Carcinoma de Células Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Melaninas/química , Nanopartículas/química , Receptores de Somatostatina/química , Animais , Carcinoma de Células Pequenas/diagnóstico por imagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Radioisótopos do Iodo/química , Neoplasias Pulmonares/diagnóstico por imagem , Imagem por Ressonância Magnética , Manganês/química , Melaninas/metabolismo , Camundongos , Camundongos Nus , Nanopartículas/toxicidade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores de Somatostatina/metabolismo , Transplante Heterólogo
11.
Clin Nucl Med ; 44(10): 777-783, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31283601

RESUMO

PURPOSE: Somatostatin receptor (SSTR) PET has become a mainstay in the diagnosis of neuroendocrine tumors (NETs) and for selecting patients for SSTR-based therapy; however, no consensus has yet been reached in terms of prognosis. A systematic review and meta-analysis was performed on the prognostic value of the maximum standardized uptake value (SUVmax) for Ga-SSTR PET in patients with NETs. PATIENTS AND METHODS: We performed a systematic search using the following keywords: PET, SSTR, NET, and prognosis. The inclusion criteria were the use of Ga-SSTR PET as an imaging tool, studies limited to NETs, studies that reported progression-free survival (PFS) and/or overall survival (OS), and studies that included SUVmax as a prognostic parameter. The effect of SUVmax on PFS and OS was measured in terms of the hazard ratio (HR). RESULTS: Eight eligible studies with 474 patients were finally included and analyzed. The combined HR of SUVmax on PFS was 2.31 with significance (95% confidence interval [CI], 1.34-4.00; P = 0.003). The trim and fill adjusted analysis for SUVmax on PFS demonstrated the combined HR as 1.81 with significance (95% CI, 1.11-2.95; P = 0.017), as the publication bias was found (Egger P = 0.004). The combined HR of SUVmax on OS was 2.97 with significance (95% CI, 1.71-5.15; P = 0.0001), without publication bias (Egger P = 0.929). The subgroup analysis revealed that well-differentiated NETs (grade 1 or 2) on PFS showed significance (P = 0.03); however, all grades of NETs (including grade 3) on PFS did not reach significance (P = 0.11). Tumor site and type of radiotracer did not affect the prognostic value of SUVmax. CONCLUSIONS: Low SUVmax of Ga-SSTR PET was associated with a worse prognosis for PFS and OS in patients with NETs. Well-differentiated NETs had more prognostic value compared with all grades of NETs. The SUVmax of Ga-SSTR PET could be used as an objective prognosis predictor.


Assuntos
Radioisótopos de Gálio , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Somatostatina/metabolismo , Humanos , Modelos Biológicos , Prognóstico
12.
Clin Nucl Med ; 44(10): 795-796, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306201

RESUMO

A 61-year-old man, with a history of prior clear cell renal cell carcinoma in remission, was referred to Ga-DOTATATE PET/CT for the further evaluation of pancreatic tail mass. Ga-DOTATATE PET/CT showed pathologically intense uptake on the pancreatic mass; subsequent biopsy of the pancreatic mass confirmed the diagnosis of clear cell renal cell carcinoma metastasis. Ga-DOTATATE uptake is not specific for neuroendocrine tumors. In the presence of prior malignancy, it should be kept in mind that malignancies apart from neuroendocrine tumors express somatostatin receptors, and they can show Ga-DOTATATE uptake.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Tumores Neuroendócrinos/diagnóstico por imagem , Compostos Organometálicos/metabolismo , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Transporte Biológico , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo
13.
Clin Nucl Med ; 44(10): 810-811, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306203

RESUMO

Ga-DOTATATE PET/CT, a functional imaging modality for assessment of well-differentiated neuroendocrine tumors, targeting the somatostatin receptors, has essentially replaced the conventional gamma camera-based imaging with In-labeled octreotide. Physiologic distribution, normal variations, and common pitfalls with Ga-DOTATATE imaging have been well described in the literature. Here, we describe uptake of Ga-DOTATATE in 2 different patients at cervicothoracic junction within the stellate ganglia.


Assuntos
Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Gânglio Estrelado/diagnóstico por imagem , Gânglio Estrelado/metabolismo , Transporte Biológico , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Receptores de Somatostatina/metabolismo
14.
Clin Nucl Med ; 44(11): 927-928, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31306208

RESUMO

Ga-DOTATATE PET/CT was performed to determine the cause of endogenous Cushing syndrome in a 10-year-old boy whose MRI studies did not reveal pituitary or adrenal gland abnormality. The PET/CT images demonstrated an intense activity in a small soft tissue nodule in the left upper abdomen where splenules are commonly located. Heat-damaged Tc-labeled red blood cell imaging showed that this soft tissue nodule did not have increased red blood cell activity, which indicated that this lesion was a true somatostatin receptor-rich lesion. The pathology result following surgical resection of the lesion confirmed adrenocorticotropic hormone-producing neuroendocrine tumor.


Assuntos
Eritrócitos/patologia , Temperatura Alta , Interpretação de Imagem Assistida por Computador , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Criança , Humanos , Imagem por Ressonância Magnética , Masculino , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Receptores de Somatostatina/metabolismo
15.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234481

RESUMO

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.


Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Animais , Antineoplásicos Hormonais/uso terapêutico , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Tumores Neuroendócrinos/metabolismo , Octreotida/metabolismo , Octreotida/farmacologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Receptores de Somatostatina/metabolismo , Transdução de Sinais , Somatostatina/metabolismo , Somatostatina/farmacologia , Somatostatina/uso terapêutico
16.
Biomed Pharmacother ; 117: 109056, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31181441

RESUMO

Chronic low back pain (LBP) ranks among the most common reasons for patient visits to healthcare providers. Drug treatments often provide only partial pain relief and are associated with considerable side-effects. J-2156 [(1'S,2S)-4amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4"-methyl-1"-naphthalenesulfonylamino)butanamide] is an agonist that binds with nanomolar affinity to the rat and human somatostatin receptor type 4 (SST4 receptor). Hence, our aim was to assess the efficacy of J-2156 for relief of chronic mechanical LBP in a rat model. Male Sprague Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but without disc puncture. For LBP-rats, noxious pressure hyperalgesia developed in the lumbar axial deep tissues from day 7 to day 21 post-surgery, which was maintained until study completion. Importantly, mechanical hyperalgesia did not develop in the lumbar axial deep tissues of sham-rats. In LBP-rats, single intraperitoneal (i.p.) injection of J-2156 (3, 10, 30 mg kg-1) alleviated primary and secondary hyperalgesia in the lumbar axial deep tissues at L4/L5 and L1, respectively. This was accompanied by a reduction in the otherwise augmented lumbar (L4-L6) dorsal root ganglia expression levels of the pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK and a reduction in pp38 MAPK in the lumbar enlargement of the spinal cord. The SST4 receptor is worthy of further investigation as a target for discovery of novel analgesics for the relief of chronic LBP.


Assuntos
Butanos/uso terapêutico , Dor Crônica/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Naftalenos/uso terapêutico , Receptores de Somatostatina/agonistas , Sulfonas/uso terapêutico , Animais , Butanos/química , Butanos/farmacologia , Modelos Animais de Doenças , Masculino , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Naftalenos/química , Naftalenos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Sulfonas/química , Sulfonas/farmacologia , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
AJR Am J Roentgenol ; 213(3): 683-688, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31120789

RESUMO

OBJECTIVE. The objective of our study was to investigate the impact of point-spread function (PSF) reconstruction and lesion size on 68Ga-tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate (DOTATATE) PET/CT quantitative parameters. MATERIALS AND METHODS. A total of 38 patients with 42 68Ga-DOTATATE PET/CT studies and 125 lesions were included. Scans were reconstructed with and without PSF modulation. For each lesion, the maximum standardized uptake value (SUVmax) and peak standardized uptake value (SUVpeak), metabolic tumor volume (MTV), total lesion somatostatin avidity, and tumor somatostatin receptor expression heterogeneity using the AUC method were measured. Intraclass correlation coefficient (ICC) and Bland-Altman analyses were used to compare PSF and non-PSF values. A subgroup analysis was performed to determine the impact of lesion size. RESULTS. Of the 125 lesions, 51 were in the liver, 31 in lymph nodes, 17 in bone, eight in pancreas, four in lung, and 14 in other sites. The ICCs between PSF and non-PSF values were excellent for SUVmax, SUVpeak, MTV, and total lesion somatostatin avidity (ICC = 0.97-0.99), and the ICC was good for tumor somatostatin receptor expression heterogeneity (ICC = 0.81). Comparison of PSF with non-PSF values showed a bias (mean percentage change ± SD) of 27.5% ± 14.7% for SUVmax, 15.5% ± 9.5% for SUVpeak, -18.6% ± 37.6% for MTV, 0.8% ± 28.1% for total lesion somatostatin avidity, and -7.1% ± 11.0% for tumor somatostatin receptor expression heterogeneity. Comparison of PSF with non-PSF values for lesions less than 2 cm (n = 75) showed corresponding biases greater than those for lesions 2 cm or larger (n = 50). CONCLUSION. PSF reconstruction effected higher values for SUVmax and SUVpeak, produced decreased values for tumor somatostatin receptor expression heterogeneity, and had a variable effect on MTV and total lesion somatostatin avidity depending on lesion size.


Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Receptores de Somatostatina/metabolismo , Sensibilidade e Especificidade
18.
Clin Imaging ; 56: 146-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31121520

RESUMO

Somatostatin receptors (SSTR) are upregulated in the cells of origin that define numerous neuroendocrine neoplasms. PET imaging with 68Ga-DOTATATE allows specific targeting of SSTR2A, a single species of SSTR receptor, which is commonly overexpressed in a variety of gastroenteropancreatic neuroendocrine tumors, as well as pulmonary carcinoid and head and neck tumors. Due to more specific targeting of SSTR2 as well as lower radiation dose, shorter study length, ability to quantify uptake, and lower cost, 68Ga-DOTATATE has demonstrated superior imaging attributes when compared to 111In-pentetreotide. As with any novel imaging modality, dedicated training, increasing experience and staying up-to-date with scientific publications are required to provide optimal patient care. The purpose of this review is to summarize the current state of the art in SSTR-targeted molecular imaging and discuss ongoing and future potential diagnostic and therapeutic applications.


Assuntos
Imagem Molecular/métodos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Compostos Organometálicos , Tomografia por Emissão de Pósitrons/métodos , Receptores de Somatostatina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo
19.
PLoS One ; 14(5): e0216781, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091247

RESUMO

AIM: Purpose of this study was to evaluate the association of the spatial heterogeneity (asphericity, ASP) in intra-therapeutic SPECT/ CT imaging of somatostatin receptor (SSR) positive metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) for morphological treatment response to peptide receptor radionuclide therapy (PRRT). Secondly, we correlated ASP derived form a pre-therapeutic OctreoScan (ASP[In]) and an intra-therapeutic [177Lu]-SPECT/CT (ASP[Lu]). MATERIALS AND METHODS: Data from first therapy cycle [177Lu-DOTA0-Tyr3]octreotate ([177Lu]-DOTATATE)-PRRT was retrospectively analyzed in 33 patients (m = 20; w = 13; median age, 72 [46-88] years). The evaluation of response to PRRT was performed according to RECIST 1.1 in responding lesions [RL (SD, PR, CR), n = 104] and non-responding lesions [NRL (PD), n = 27]. The association of SSR tumor heterogeneity with morphological response was evaluated by Kruskal-Wallis test and receiver operating characteristic curve (ROC). The optimal threshold for separation (RL vs. NRL) was calculated using the Youden-index. Relationship between pre- and intra-therapeutic ASP was determined with Spearman's rank correlation coefficient (ρ) and Bland-Altman plots. RESULTS: A total of 131 lesions (liver: n = 59, lymph nodes: n = 48, bone: n = 19, pancreas: n = 5) were analyzed. Lesions with higher ASP values showed a significantly poorer response to PRRT (PD, median: 11.3, IQR: 8.5-15.5; SD, median: 3.4, IQR: 2.1-4.5; PR, median 1.7, IQR: 0.9-2.8; CR, median: 0.5, IQR: 0.0-1.3); Kruskal-Wallis, p<0.001). ROC analyses revealed a significant separation between RL and NRL for ASP after 4 months (AUC 0.85, p<0.001) and after 12 months (AUC 0.94, p<0.001). The optimal threshold for ASP was >5.45% (sensitivity 96% and specificity 82%). The correlation coefficient of pre- and intra-therapeutic ASP revealed ρ = 0.72 (p <0.01). The mean absolute difference between ASP[In] and ASP[Lu] was -0.04 (95% Limits of Agreement, -6.1-6.0). CONCLUSION: Pre- and intra-therapeutic ASP shows a strong correlation and might be an useful tool for therapy monitoring.


Assuntos
Neoplasias Gastrointestinais , Proteínas de Neoplasias/metabolismo , Tumores Neuroendócrinos , Octreotida/análogos & derivados , Receptores de Somatostatina/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Intervalo Livre de Doença , Feminino , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/mortalidade , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Octreotida/administração & dosagem , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida
20.
Neuropharmacology ; 151: 112-126, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981749

RESUMO

Glycine-proline-glutamate (GPE) is a cleaved tripeptide of IGF-I that can be processed to cycloprolylglycine (cPG) in the brain. IGF-I protects the hippocampal somatostatinergic system from ß-amyloid (Aß) insult and although neither IGF-I-derived peptides bind to IGF-I receptors, they exert protective actions in several neurological disorders. As their effects on the hippocampal somatostatinergic system remain unknown, the objective of this study was to evaluate if cPG and/or GPE prevent the deleterious effects of Aß25-35 infusion on this system and whether changes in intracellular-related signaling and interleukin (IL) content are involved in their protective effect. We also determined the effect of cPG or GPE co-administration with Aß25-35 on IL secretion in glial cultures and the influence of these ILs on signaling activation and somatostatin synthesis in neuronal cultures. cPG or GPE co-administration reduced Aß-induced cell death and pro-inflammatory ILs, increased IL-4 and partially avoided the reduction of components of the somatostatinergic system affected by Aß25-35. GPE increased activation of Akt and CREB and reduced GSK3ß activation and astrogliosis, whereas cPG increased phosphorylation of extracellular signal-regulated kinases. Both peptides converged in the activation of mTOR and S6 kinase. Co-administration of these peptides with Aß25-35 to glial cultures increased IL-4 and reduced IL-1ß; this release of IL-4 could be responsible for activation of Akt and increased somatostatin in neuronal cultures. Our findings suggest that cPG and GPE exert protective effects against Aß on the somatostatinergic system by a reduction of the inflammatory environment that may activate different pro-survival pathways in these neurons.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Somatostatina/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/metabolismo , Inflamação/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Somatostatina/metabolismo , Transdução de Sinais/efeitos dos fármacos
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