Somatostatin receptor scintigraphy in the follow up of neuroendocrine neoplasms of appendix

BACKGROUND Neuroendocrine tumors of appendix(ANETs)known as carcinoids,are rare endocrine neoplasms originated from enterochromaffin cells of gastrointestinal tract.ANETs are the third most frequent(16.7%)gastrointestinal neuroendocrine tumors,with the incidence of 0.08-0.2 cases/100000 during one year.Incidental ANETs occur in 0.2%-0.7%of emergency surgical resections because of suspected appendicitis which is usually the first manifestation of ANET.Although there are a lot of papers about application of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumors,there are very rare sporadic cases described about ANETs particularly.AIM To establish the role of somatostatin receptor scintigraphy(SRS)in the management of patients with neuroendocrine tumors of appendix(ANET).METHODS The total of 35 patients was investigated,23 females and 12 males,average age(43.7±17.3 years).All patients had histological diagnosis of ANET(34 carcinoids of appendix and one tubular carcinoid).Majority of tumors have been found incidentally during surgery of:Acute appendicitis(n=15),perforated appendicitis(n=2),ileus(n=3),hysterectomy(n=3),ruptured ovarian cyst(n=2),caecal volvulus(n=1),while 9 patients had diagnosis of appendiceal tumor before the surgery.Seventeen patients had tumor grade(G)G1,12 G2 and 6 G3.The right hemicolectomy was performed in 13,while the rest of the patients had appendectomy only.SRS was done early(2 h)and late(24 h)after i.v.application of 740 MBq technetium-99 m ethylenediamine-N,N’-diacetic acid Hydrazinonicotinyl-Tyr3-Octreotide(technetium-99 m-Tektrotyd,Polatom,Poland).SRS was performed for restaging in all the patients after surgery.RESULTS There were 12 true positive(TP),19 true negative,3 false positive and 1 false negative SRS result.Sensitivity of the method was 92.31%,specificity was 86.36%,positive predictive value was 80.00%,negative predictive value was 95.00%and accuracy 88.57%.Receiver operating characteristics analysis showed that SRS scintigraphy is a good test for detection TP cases[area under the curve of 0.850,95%confidence interval(CI):0.710-0.990,P<001].Single photon emission computed tomography contributed diagnosis in 7 TP findings.In 10 patients Krenning score was 4 and in 2 was 3.In 8 patients SRS significantly changed the management of the patients(in two surgery was repeated,in 4 somatostatin analogues and in two peptide receptor radionuclide therapy).Median progression-free survival in SRS positive patients was 52 months(95%CI:39.7-117.3 mo)while in SRS negative patients it was 60 months(95%CI:42.8-77.1 mo),without statistically significant difference between the two groups(P=0.434).CONCLUSION In conclusion,our results confirmed the value of SRS in the follow-up of the patients with ANET after surgery,if recurrences or metastases are suspected.

Somatostatin receptor subtypes in hormone-refractory （castration-resistant） prostatic carcinoma

The aim of this study was to examine the tissue expression and Iocalisation of the somatostatin receptors （SSTRs） in hormone-refractory （HR） prostate cancer （PCa）. Five SSTRs were evaluated immunohistochemically in 20 radical prostatectomies （RPs） with Gleason score （GS） 3＋3=6 PCa, in 20 RPs with GS 4＋4=8 and 4＋5=9 PCa, and 20 transurethral resection of the prostate specimens with HR PCa. The mean values in the cytoplasm （all five SSTRs were expressed）, membrane （only SSTR3 and SSTR4 were expressed） and nuclei （only SSTR4 and SSTR5 were expressed） of the glands in HR PCa were 20-70% lower than in the other two groups, the differences being statistically significant. All five SSTRs were expressed in the smooth muscle and endothelial cells of HR PCa, the mean values being lower than in the other two groups. In conclusion, this study expands our knowledge on the expression and Iocalisation of five SSTRs in the various tissue components in the HR PCa compared with hormone-sensitive PCa.

Relationship between somatostatin receptor subtype expression and clinicopathology,Ki-67,Bcl-2 and p53 in colorectal cancer

瞄准：学习 SSTR1， 2， 3， 4，有在颜色的 clinico 病理学的因素，房间增长， Bcl-2 和 p53 表示的 5 表示和他们的关系表面的癌症房间。方法：五种 SSTR 子类型， Ki-67， Bcl-2 和 p53 染色的 Immunohistochemical 被标准 streptavidin-peroxidase (SP ) 执行为 127 颜色的石蜡节的技术表面的癌症。并且在正常的 40 个标本的五种 SSTR 子类型的表示渲染表面的 mucosae 与一样的方法被检测。结果：为五种 SSTR 子类型的积极染色在颜色被观察表面的癌症房间和正常颜色表面的 mucosae。SSTR1 是最占优势的子类型在渲染表面的癌症，正常渲染表面的粘膜，并且第二是 SSTR5 或 SSTR2。作为与正常相比渲染表面的粘膜， SSTR4 更经常在颜色被表示表面的癌症房间(2.5% 对 18.9% ， P【0.05 ) ； SSTR2 的表示， 4 ， 5 在里面中等到很好区分的颜色，表面的腺癌在糟糕区分的( P【0.05 )比那显著地高，在有积极淋巴节点转移的表面的癌症是的颜色的 SSTR1 表示比那显著地高与否定淋巴节点转移(72.2%和54.5%， P【0.05 )。另外，颜色在溃疡的打表面的癌症， SSTR2 表示显然被减少(P【0.05 ) ；关联没到达在五 SSTR 子类型表情和 Dukes'stages (P】0.05 ) 之间的统计意义，但是 SSTR1 表示的频率与 Dukes'stage 增加，当 SSTR3 和 SSTR5 表示与公爵的阶段减少了时。而且，在象年龄那样的五种 SSTR 子类型和另外的 clinicopathological 因素的表示之间没有关联，性别，肿瘤地点，肿瘤深度，远转移。在肤色的增生的索引有 SSTR2 和 SSTR3 的否定表示的表面的癌症房间与积极表示(P【0.05 ) 比那显著地高。在肤色的 Bcl-2 表示有 SSTR1 的积极表示的表面的癌症房间， 2， 3， 5 与否定表示(P【0.05 ) 是比那显著地低的。在五种 SSTR 子类型和 p53 表示之间没有关联。结论：最占优势的 SSTR 子类型是 SSTR1，并且第二是 SSTR2 或 SSTR5。五种 SSTR 子类型在肤色的发展起不同作用表面的癌症。SSTR2 和 SSTR3 能禁止增长并且支持肿瘤房间的 apoptosis。

Gene transfer of somatostatin receptor type 2 by intratumoral injection inhibits established pancreatic carcinoma xenografts

AIM: To investigate the therapeutic effect of somatostatin receptor type 2 (SSTR2) gene transfection on pancreatic carcinoma xenograftsin vivo in experimental cancers.METHODS: Human pancreatic cancer cell line Panc-1 was inoculated subcutaneously into the back of nude mice. When tumor nodules were grown as large as about 5 mm×5 mm days after inoculation, the mice were randomly divided into 3 groups (6 mice in each group). Group Ⅰ served as untreated control group. Group Ⅱ received an intratumoral injection of a combination of human cytomegalovirus promoter-6C (pCMV-6C) and lipofectamine 2000. Group Ⅲ received an intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000. The rate of tumor growth was compared among these three groups. The expression of SSTR2 in these tumors was detected by immunohistochemistry and Western-blot. Apoptosis index (AI) in these tumors was examined by using TUNEL in situ.RESULTS: Intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000 resulted in the expression of SSTR2 protein. The tumor size and weight in group Ⅲ (0.318±0.098 cm3, and 0.523±0.090 g,respectively) were significantly lower than those in group Ⅰ (2.058±0.176 cm3, and 1.412±0.146 g, respectively) and group Ⅱ (2.025±0.163 cm3, and 1.365±0.116 g, respectively)(P＜0.05) The AI in group Ⅲ (1.47±0.13%) was significantly higher than that in group Ⅰ (0.56±0.09%) and group Ⅱ (0.57±0.11%) (P＜0.05). But there were no significant differences between groups Ⅰ and Ⅱ.CONCLUSION: Our data demonstrate that re-expression of SSTR2 gene has antitumor effects on experimental pancreatic cancer. Restoration of SSTR2 gene expression through gene transfer in vivo might be a potential gene therapy strategy for human pancreatic cancer.

Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial

AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49 ± 6 wk) as compared to the control group (28 ± 1 wk) and to the SSTR negative group (28 ± 2 wk), LR = 20.39, df = 2, P < 0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the f irst year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group respectively.CONCLUSION: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.

Somatostatin receptor subtype 2-mediated scintigraphy and localization using ^(99m)Tc-HYNIC-Tyr^3-octreotide in human hepatocellular carcinoma-bearing nude mice

AIM: To investigate the uptake of 99mTc-HYNIC-Tyr3-octreotide (99mTc-HYNIC-TOC) in human hepatocellular carcinoma (HCC), which can provide the localizable diagnosis in hepatic carcinoma.METHODS: The expression of somatostatin receptor 2(SSTR2) messenger RNA (mRNA) in human HCC cell line HepG2 was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Uptake of 99mTc-HYNIC-TOC was evaluated in the human HCC implanted into BALB/c nude mice. ANMIS2000 nuclear medicine analysis system was used to calculate the ratio of 99mTC uptake between tumor tissue and vital organs.RESULTS: We demonstrated the expression of SSTR2mRNA in human HCC cell line HepG2 by RT-PCR. The size of the RT-PCR products was 364 bp detected by sequence analysis of the human SSTR2 mRNA. Scintigraphy proved that 99mTc-HYNIC-TOC was uptaken in the tumor tissue,liver and kidney of the tumor-bearing mice.CONCLUSION: Based on expression of the SSTR2 mRNA in human NCC, 99mTc-NYNIC-TOC can markedly bind with and be uptaken by human HCC tissues as compared with normal liver tissue. The significant retention of radionuclide in kidney and bladder is probably related to non-specific peptide uptake in the tubulus cells of kidney and possibly due to excretion by kidney. Our results show that localizable diagnosis and targeting radiotherapy with radionuclidelabeled somatostatin analog for HCC are of great value to be further studied.

RELATIONSHIP BETWEEN SOMATOSTATIN RECEPTORS AND ACTIVATION OF HEPATIC STELLATE CELL

To investigate the relationship between expression of somatostatin receptors (SSTRs) and activation of rat hepatic stellate cell (HSC). Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation, and then SSTR1-5 mRNA levels in the differentiated frst passage HSCs were detected by means of reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1-5 in normal as well as fibrotic liver was measured by immunohistochemical staining. Results SSTR mRNA and SSTR couM not be found in freshly isolated rat HSCs and normal rat liver. But SSTR1-3 mRNA appeared as HSCs became wholly activated, and SSTR1-3 could also be identified on the membrane of activated HSCs in the perisinusoid space, fibrous septa, etc. Conclusion The expression of SSTRt -3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.

Impact of antagonist peptides and chelators on the diagnostic performance of PET/CT using gallium-68-labeled somatostatin receptor antagonists

Objective: Different SSTR2 antagonists have been developed. This study aims to evaluate the impact of different peptides and chelators on the diagnostic performance of SSTR2 antagonists in well-differentiated NETs.Methods: In this prospective study, participants were equally randomized into 2 arms: arm A, participants would undergo a whole-body^(68)Ga-NODAGA-LM3 PET/CT scan on the first day and^(68)Ga-DOTA-LM3 PET/CT scan on the second day;arm B, participants would undergo a whole-body^(68)Ga-NODAGA-LM3 PET/CT scan on the first day and^(68)Ga-NODAGA-JR11 PET/CT scan on the second day. Biodistribution in normal organs, lesion detection ability, and tumor uptakes were compared within each arm.Results: A total of 40 participants (age, 49.5 ± 13.4, 21 men), 20 in each arm, were recruited in the study. In arm A,^(68)Ga-DOTA-LM3 showed lower background. However, the lesion detection ability (overall lesion detected, 445 vs 548;P = .005) and the lesion uptake (overall lesions SUVmax, 19.8 ± 17.2 vs 35.3 ± 28.8;P < .001) was significantly lower than those of^(68)Ga-NODAGA-LM3. In arm B, both^(68)Ga-NODAGA-LM3 and^(68)Ga-NODAGA-JR11 showed similar biodistribution and lesion uptake (SUVmax, 28.5 ± 23.8 vs 25.0 ± 20.0;P < .001) despite minor differences. The lesion detection ability was the same between these 2 tracers (overall lesion detected, 503 vs 503).Conclusions: The diagnostic performance of SSTR2 antagonists was sensitive to chelators. Both^(68)Ga-NODAGA-LM3 and^(68)Ga-NODAGA-JR11 outperformed^(68)Ga-DOTA-LM3 with higher lesion uptake and detection ability, of which^(68)Ga-NODAGA-LM3 had marginally but significantly higher lesion uptake.

Relationship between expression of somatostatin receptors subtype 2 mRNA and estrogen and progesterone receptors in breast cancer

Objectives To observe the expression of somatostatin receptor subtype 2 (SSTR2) mRNA, and investigate the relationship between the expression of SSTR2 mRNA and the expressions of estrogen and progesterone receptors (ERs and PRs) in benign and malignant breast tissues.Methods Samples from a total of 23 breast carcinomas, 16 mammary hyperplasias, and 9 mammary fibroadenomas were analyzed. SSTR2 mRNA expression was examined by in situ hybridization using multiphase oligoprobes. ER and PR expressions were detected by immunohistochemical staining. A computerized image analysis system was utilized to estimate the relative content of SSTR2 mRNA.Results The rate of expression (87.0%) and relative content (0.47) of SSTR2 mRNA in breast cancer were higher than those in benign breast tissue (64%,0.26) (P<0.05). SSTR2 mRNA expression was closely correlated with ER and PR expressions in breast cancer (P<0.05). SSTR2 mRNA was also positively correlated with ER expression in benign breast tissues.Conclusions SSTR2 mRNA expression is higher or in benign breast tissues than in malignant ones. There is a significant positive correlation between SSTR2 mRNA and ER and PR expressions. Combined antiestrogen and somatostatin analogue in treatment of ER-positive breast cancers should be further investigated.

Relationship between somatostatin receptors and activation of hepatic stellate cells

Background Somafostatin receptors (SSTRs) have been sug gested to involve in mediating the effect of somatostatin on hepatic stellate ce lls (HSCs) in an activation-dependent way. We, therefore, try to investigate th e relationship between expression of SSTRs and activation of rat HSCs.Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation.SSTR 1-5 mRNA levels in the differentiated first passage HSCs were detected by means of a reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR 1-5 in normal as well as fibrotic livers was measured by immunohistochemical staining.Results SSTR mRNA and SSTR could not be found in freshly isolated rat HSCs or normal rat liver. However, SSTR 1-3 mRNA appeared as HSCs became wholly activated, and could also be identified on the membrane of activated HSCs in the perisinusoid space, fibrous septa, etc.Conclusion The expression of SSTR 1-3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.

Highly variable biodistribution of ^(68)Ga labeled somatostatin analogues ^(68)Ga-DOTA-NOC and ^(68)Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT

Background:Somatostatin receptor(SSTR)-targeted positron emission tomography/computed tomography(PET/CT)imaging has risen to the forefront for neuroendocrine tumor(NET)detection and management,yet the variability of significant uptake variability(SUV)as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored.Methods:We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial^(68)Ga-DOTA-NOC and^(68)Ga-DOTA-TATE PET imaging to clinically monitor disease state.Eighty-one patients were enrolled in this retrospective study.Results:Both primary and metastatic hepatic lesions demonstrated SUV(SUVmean 16.5±8.0).The median SUVmean was 16 for the spleen,9.7 for the pituitary,12.6 for the adrenal glands,and 4.8 for the liver.The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5–23.The adrenal gland showed uptake with SUVmax range of 4.1–29.4,which is more than two times greater than liver uptake(SUVmean range,2.3–12.4).Highest physiological uptake seen in the spleen(average SUVmean of 17.3,range of 5.4–34.4).Conclusions:The highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.

Guipi decoction effects on brain somatostatin levels and receptor mRNA expression in rats with spleen deficiency

BACKGROUND： Somatostatin is abundant in the hypothalamus, cerebral cortex, limbic system, and mesencephalon. Somatostatin mRNA expression in the brain of rats with spleen deficiency is noticeably reduced, as well as attenuation of cognitive function. OBJECTIVE： To observe the interventional effect of Guipi decoction on somatostatin level and somatostatin receptor 1 （SSTRl） mRNA expression in different encephalic regions of rats with spleen deficiency, and to compare the interventional effects of Guipi decoction, Chaihu Shugan powder, and Tianwang Buxin pellet. DESIGN： A randomized controlled observation. SETTING： Basic Medical College, Beijing University of Traditional Chinese Medicine. MATERIALS： Fifty adult Wistar male rats, of clean grade, weighing （160 ± 10） g, were provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The protocol was performed in accordance with ethical guidelines for the use and care of animals. Somatostatin 1 polyclonal anti-rabbit antibody and SSTRl in situ hybridization kit were provided by Department of Neuroanatomy, Shanghai Second Military Medical University of Chinese PLA. The drug for developing rat models of spleen deficiency was composed of Dahuang, Houpu and Zhishi, and prepared at 2：1：1. Guipi decoction, Chaihu Shugan powder, and Tianwang Buxin pellet recipes were made according to previous studies. METHODS： This study was performed at the Basic Medical College, Beijing University of Traditional Chinese Medicine from March 2002 to March 2005. The rats were randomly divided into 5 groups, with 10 rats in each group： normal, model, Guipi decoction, Chaihu Shugan powd.er, and Tianwang Buxin pellet groups. Rat models of the latter 4 groups were developed by methods of purgation with bitter and cold nature drugs, improper diet, and overstrain. The rats received 7.5 g/kg of the drugs each morning and were fasted every other day, but were allowed free access to water at all times. The rats were forced to swim in 25 ℃ water until fatigued. Rats in the normal group were intragastrically administered the same amount of normal saline. Rats in the Guipi decoction, Chaihu Shugan powder, and Tianwang Buxin pellet groups were intragastrically administered 7.5 g/kg Guipi decoction, Chaihu Shugan powder, and Tianwang Buxin pellet, respectively, every afternoon. All rats were treated for 6 weeks. MAIN OUTCOME MEASURES： Somatostatin protein and SSTRI mRNA expression in the ventral nucleus of hypothalamus, hippocampal CAl region, and cortex of prefrontal lobe were determined by immunohistochemistry and in situ hybridization, respectively. RESULTS： Fifty rats were included in the final analysis. In the model group, expression of somatostatin protein and SSTRl mRNA in the ventral nucleus of hypothalamus, hippocampal CAl region, and cortex of prefrontal lobe were significantly less than in the normal group （P 〈 0.01）. Above-mentioned indices were identical in the Chaihu Shugan powder and model groups. However, expression of somatostatin protein and SSTRl mRNA were significantly higher in the Guipi decoction group compared to model group （P 〈 0.01）. In the Tianwang Buxin pellet group, SSTRl mRNA expression in rat ventral nucleus of hypothalamus and somatostatin level in rat hippocampal CAl region and cortex of prefrontal lobe, as well as ventral nucleus of hypothalamus, were significantly higher compared to model group （P 〈 0.01 ）. CONCLUSION： Somatostatin level and SSTRl mRNA expression in rats with spleen deficiency were lower than in normal rats. Guipi decoction and Tianwang Buxin pellet up-regulated somatostatin level and SSTRl mRNA expression.

Using Homology Modeling, Molecular Dynamics and Molecular Docking Techniques to Identify Inhibitor Binding Regions of Somatostatin Receptor 1

The G protein coupled receptor（GPCR）, one of the members in the superfamily, which consists of thousands of integral membrane proteins, exerts a wide variety of physiological functions and responses to a large portion of the drug targets. The 3D structure of somatostatin receptor I（SSTR1） was modeled and refined by means of homology modeling and molecular dynamics simulation. This model was assessed by Verify-3D and Vadar, which confirmed the reliability of the refined model. The interaction between the inhibitor cysteamine, somatostatin（SST） and SSTR1 was investigated by a molecular docking program, Affinity. The binding module not only showed the crucial residues involved in the interaction, but also provided important information about the interaction between SSTR1 on the one hand and ligands on the other, which might be the significant evidence for the structure-based design.

Novel gold nanoparticles targeting somatostatin receptor subtype two with near-infrared light for neuroendocrine tumour therapy

Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.

An Experimental Study on Somatostatin Receptors in the Brains of Hepatic Encephaiopathy Rats

The present study was undertaken to evaluate the effect of somatostatin (SS) receptor,a brain-gut peptide receptor which is capable of inhibiting central neurons, on the pathogenesis of hepatic encephalopathy (HE).By means of radioligand binding assay, SS receptors in crude synaptosomal membrane of rat brains were investigated in a rat model of HE induced by partial hepatectomy following carbon tetrachloride intoxication and in controls. Binding to SS receptor was studied using125 I-SS as radiolgand Scatchard analysis of binding data was linear, yielding a dissociation constant (Kd) of 3.99 ±0.22 nmol/L and a maximal binding capacity (Bmax) of 238± 14.2 fmol/mg of protein in HE rats.Only increased Bmax values were observed (P< 0.005),while the Kd values were statistically unchanged (P>0.50),in HE rats as compared with those in controls.The results suggest that the changes of SS receptors in brains play a significant role in the pathogenesis of HE.The mechanism of HE induced by the alterations of SS receptors in the brains was discussed in this paper.

Impact of antagonist peptides and chelators on the diagnostic performance of PET/CT using gallium-68 labeled somatostatin receptor antagonists

Objective:Different SSTR2 antagonists have been developed.This study aims to evaluate the impact of different peptides and chelators on the diagnostic performance of SSTR2 antagonists in well-differentiated NETs.Methods:In this prospective study,participants were equally randomized into two arms:Arm A,participants would undergo a whole-body 68Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68Ga-DOTA-LM3 PET/CT scan on the 2nd day;Arm B,participants would undergo a whole-body 68Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68Ga-NODAGA-JR11 PET/CT scan on the 2nd day.Biodistribution in normal organs,lesion detection ability,and tumor uptakes were compared within each Arm.Results:A total of 40 participants(age,49.5±13.4,21 men),20 in each arm,were recruited in the study.In Arm A,68Ga-DOTA-LM3 showed lower background.However,the lesion detection ability(overall lesion detected,445 versus 548,P=0.005)and the lesion uptake(overall lesions SUVmax,19.8±17.2 versus 35.3±28.8,P<0.001)was significantly lower than those of 68Ga-NODAGA-LM3.In Arm B,both 68Ga-NODAGA-LM3 and 68Ga-NODAGA-JR11 showed similar biodistribution and lesion uptake(SUVmax,28.5±23.8 versus 25.0±20.0,P<0.001)despite minor differences.The lesion detection ability was the same between these two tracers(overall lesion detected,503 versus 503).Conclusions:The diagnostic performance of SSTR2 antagonists was sensitive to chelators.Both 68Ga-NODAGA-LM3 and 68Ga-NODAGA-JR11 outperformed 68Ga-DOTA-LM3 with higher lesion uptake and detection ability,of which 68Ga-NODAGA-LM3 had marginally but significantly higher lesion uptake.

^(99m)Tc-HYNIC-TOC显像和^(131)I-MIBG显像在嗜铬细胞瘤和副神经节瘤中的诊断价值

目的探讨^(99m)Tc标记肼基烟酰胺奥曲肽类似物(^(99m)Tc-HYNIC-TOC)显像与^(131)I-间碘苄胍(^(131)I-MIBG)肾上腺髓质显像对嗜铬细胞瘤和副神经节瘤(PPGL)的临床诊断价值。方法回顾性研究359例经手术病理确诊、临床资料完整的PPGL患者的临床资料,分析^(99m)Tc-HYNIC-TOC生长抑素受体显像与^(131)I-MIBG肾上腺髓质显像的诊断敏感性及影响因素。结果319例行^(99m)Tc-HYNIC-TOC生长抑素受体显像,病灶检出阳性184例,诊断敏感性为57.7%;279例行^(131)I-MIBG肾上腺髓质显像,病灶检出阳性232例,诊断敏感性为83.2%,原发灶位于肾上腺、腹膜后、头颈部、心脏及纵膈、盆腔及膀胱部位的^(99m)Tc-HYNIC-TOC生长抑素受体显像敏感性分别为53.3%、62.5%、95.0%、66.7%、50.0%和11.0%,^(131)I-MIBG肾上腺髓质显像敏感性分别86.7%、88.5%、45.4%、50.0%、75.0%和33.3%。不同遗传背景[包括琥珀酸脱氢酶(SDH)、希佩尔-林道(VHL)及RET原癌基因(RET)基因突变]的PPGL患者中,两种方法诊断PPGL的敏感性差异无统计学意义(P>0.05)。肿瘤最大径的中位数为4.4(3.0,6.1)cm。^(99m)Tc-HYNIC-TOC生长抑素受体显像和^(131)I-MIBG肾上腺髓质显像对较大肿瘤组(≥4.4 cm)的诊断敏感性均显著高于较小肿瘤组(<4.4 cm)(64.0%vs.51.3%;92.3%vs.74.1%)(P<0.01);19例患者(占5.3%)的肿瘤对这两种显像方法均不摄取。结论本研究为迄今中国最大PPGL队列的^(99m)Tc-HYNIC-TOC生长抑素受体显像及^(131)I-MIBG肾上腺髓质显像的研究。总体而言,^(131)I-MIBG肾上腺髓质显像敏感性较^(99m)Tc-HYNIC-TOC生长抑素受体显像高,但对部分部位的肿瘤,如头颈副神经节瘤,后者有明显优势,两者有互补性,临床中需要结合患者的特点进行选用。

生长抑素Ⅱ型受体SSTR2蛋白的理化性质及生物信息学分析

利用生物信息学方法在线分析生长抑素Ⅱ型受体SSTR2的理化性质、信号肽、跨膜结构、分泌蛋白类型、亚细胞定位、磷酸化位点修饰、空间结构及蛋白互作网络等,并通过MEGA5.0软件建立SSTR2蛋白的系统进化树。结果显示,该基因编码369个氨基酸,分子式为C_(1898)H_(2984)N_(470)O_(513)S_(23),相对分子质量为41332.79,等电点理论值为9.15,不稳定系数为37.16。SSTR2是一种碱性稳定亲水蛋白,无信号肽,存在7个跨膜区,作用于质膜结构;二级结构主要为α-螺旋,属7tmGPCRs超家族,且含有1个7tmA_SSTR2结构域;与SSTR2相互作用的蛋白质包括CORT、SST、NPY、GHRL、GNAI1、GNAI2、GNAI3、SHANK1、HIVEP2。SSTR2基因及其编码蛋白在进化上高度保守,可能参与G蛋白偶联受体信号通路,进而发挥其作用。本研究通过对SSTR2蛋白的理化性质及生物学功能进行分析,为深入研究该蛋白在疾病发生中的机制以及为靶向治疗神经内分泌肿瘤等肿瘤药物研发提供理论依据。

生长抑素治疗肥胖的分子机制研究进展

肥胖的患病率逐年升高,是众多慢性病的潜在危险因素。然而,肥胖治疗面临药物选择少、副作用多等问题。生长抑素(SST)在摄食及食欲调节中发挥重要作用。越来越多的证据表明,SST通过影响饱腹感及摄食行为,在肥胖的管理中具有潜在的临床应用价值。SST可与胰岛素、刺鼠相关肽、阿黑皮素原、瘦素、胃饥饿素和脑源性神经营养因子等形成广泛的调节网络,有效调控肥胖及其相关疾病的发生和发展。SST在减重中的作用及机制的深入研究,将为治疗肥胖的新型药物研发开辟新的视角。另外,考虑到天然激素的局限性,SST类似物是治疗肥胖的良好候选药物,有望广泛研发以应用于临床。本文亦根据目前存在的问题,提出未来具体的研究方向,旨在为肥胖治疗提供相关科学依据。

新型非肽类口服生长抑素受体配体paltusotine的临床研究进展

生长抑素类似物相关制剂的研发是内分泌代谢领域的热点。第一代奥曲肽、兰瑞肽,第二代帕瑞肽已批准用于肢端肥大症等神经内分泌肿瘤的治疗。而生长抑素受体配体paltusotine作为一种可口服给药的新型非肽类小分子药物,可抑制生长激素和胰岛素样生长因子1的过度分泌。本文分析总结非肽类口服小分子生长抑素配体paltusotine的药物代谢动力学、药效动力学、临床疗效、耐受性和安全性等研究进展。