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Angioectasias (AD) belong to benign vascular malformations of the gastrointestinal tract and are responsible for about 4-7% of upper non variceal bleeding, 30-40% of small bowel occult bleeding and 3-40% of colonic bleeding episodes. Gastrointestinal haemorrhage secondary to AD represents an important diagnostic and therapeutic problem that negatively impacts on the quality of life of patients and heath care costs. Endoscopic interventions are the mainstay in both diagnosis and treatment of vascular malformations. However, in a substantial percentage of the cases, age of the patients, comorbidities, clinical severity of anaemia and blood loss as well as size, site and number of lesions prevent this therapeutic approach. Hormonal therapy, thalidomide and somatostatin analogues have been investigated for their potential role as rescue therapies in controlling AD bleeding although, thus far, no recommendations have been provided on their use in this clinical setting. In order to implement appropriate prescription of pharmacological agents to manage gastrointestinal bleeding due to ADs, the Italian Society of Gastroenterology (SIGE) nominated a panel of experts who reviewed the available clinical literature and produced practical clinical recommendations.

Acromegaly often involves the presence of different pathologies of the thyroid gland. Long-lasting stimulation of the follicular epithelium by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) can cause disorders in thyroid function, an increase in its mass and the development of goitre. Acromegalic patients present most frequently with non-toxic multinodular goitre. Nodules are more prevalent in patients with active acromegaly. It has been suggested that then thyroid size increases and it can be reduced through treatment with somatostatin analogues. The relationship between thyroid volume and the level of IGF-1 and the duration of the disease is unclear. Each acromegalic patient requires a hormonal and imaging evaluation of the thyroid when the diagnosis is made, and an accurate evaluation during further observation and treatment. Although the data concerning the co-occurrence of acromegaly and thyroid cancer still remain controversial, it is particularly important to diagnose the patient early and to rule out thyroid cancer.

Background: Gastrointestinal cancers account for 20% of all deaths worldwide. Gastric cancer (GC) patients are susceptible to psychological change, especially depression which is commonly induced by chronic stress. Gastric precancerous lesions (GPL) is an important prodromal stage in the occurrence of gastric cancer. Chronic stress influences the prognosis of GC and may influence the process of GPL as well. Methods: Sixty SD rats were randomly divided into a control group, GPL group, and GPL+CUMS group. In the GPL group, 200μg/mL N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) free drinking method combined with intermittent fasting was applied to establish the GPL animal model. Based on this, we combined the GPL rats with chronic unpredicted mild stress (CUMS) to establish a comprehensive model. We then evaluated their behavior by open field tests and sucrose preference tests. We tested the IL-6, IL-10, TNF-α, Ghrelin, Leptin and Somatostatin (SS) levels in serum and observed the expression of Ghrelin and Gastrokine 2(GKN2) in the gastric mucosa of rats with tumors by immunofluorescence. Results: Our results showed that GPL and GPL+CUMS rats all displayed a significantly decreased total distance and mean velocity traveled in the open field test. The percentages of sucrose preference were significantly decreased in the GPL+CUMS group compared to the control group. In addition, IL-6 and TNF-α were significantly increased in both the GPL and GPL+CUMS groups. Furthermore, the GPL+CUMS group showed significantly increased TNF-α levels in serum compared to the GPL rats. Our results showed that the expression of NF-κB, p53, and BCL-2 were significantly increased while BAX was reduced in the GPL and GPL+CUMS groups. Moreover, Ghrelin and Leptin levels in serum were significantly decreased in the GPL and GPL+CUMS groups. SS levels in serum were significantly increased in the GPL+CUMS group. Additionally, we found that the GPL+CUMS rats with tumors not only had strong expression of GKN2 on the luminal side and the lamina propria of the gastric mucosa and tumor, but also had expression of Ghrelin on the luminal side of the gastric mucosa. The areas that showed strong expression of GKN2 and Ghrelin, are all located around the blood vessels in the tumor. Conclusions: GPL rats under chronic stress would aggravate the conditions of GPL, shorten the process of GPL, and increase the risk of tumorigenesis. In addition, the close monitoring of the mental health of cancer survivors and precancerous lesion patients is suggested to be of great significance in the prevention and treatment of cancer.

A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [EMAX] = − 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (EMAX = − 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065. Electronic supplementary material The online version of this article (10.1007/s10928-020-09683-3) contains supplementary material, which is available to authorized users.

The perinatal period, sensitive for newborn survival, is also one of the most critical moments in human brain development. Perinatal hypoxia due to reduced blood supply to the brain (ischemia) is one of the main causes of neonatal mortality. Brain damage caused by perinatal hypoxia–ischemia (HI) can lead to neuro‐ and psychological disorders. However, its impact seems to be region‐dependent, with the hippocampus being one of the most affected areas. Among the neuronal populations of the hippocampus, some interneuron groups – such as somatostatin‐ or neuropeptide Y‐expressing neurons – seem to be particularly vulnerable. The limited information available about the effects of HI in the hippocampus comes mainly from animal models and adult human studies. This article presents an immunohistochemical analysis of somatostatin (SOM) and neuropeptide Y (NPY) expression in the developing human hippocampus after perinatal HI. Two rostrocaudal sections of the body of the hippocampus were analysed, and the number of immunostained cells in the polymorphic layer of the dentate gyrus (DG) and the pyramidal cell layer and stratum oriens of the CA3, CA2 and CA1 fields of the hippocampus proper were quantified. The results showed a lower density of both neuropeptides in hypoxic compared to control cases. In the HI group, the number of SOM‐immunoreactive cell bodies was statistically significantly lower in the pyramidal cell layer and stratum oriens of CA1, while the number of NPY‐expressing neurons was statistically lower in the pyramidal cell layer of CA2. Besides, the number of SOM‐expressing neurons was significantly higher in the stratum oriens of CA1 compared to that in CA2. In sum, we observed a different vulnerability of SOM‐ and NPY‐containing neurons in the developing human hippocampus following perinatal HI damage. Our results could contribute to a better understanding of the behaviour of these neuronal populations under stressful conditions during the perinatal period., Hypoxia‐ischemia during the perinatal period could damage the hippocampal interneuron populations which might lead to the appearance of different problems during subsequent development. Interneurons containing Somatostatin and Neuropeptide Y located in the hippocampal ammonic fields are affected differently, although there is a global reduction after suffering perinatal hypoxia‐ischemia. This work is the first study that describes this issue in depth in the developmental human hippocampus.

Multimodal imaging probes have attracted the interest of ongoing research, for example, for the surgical removal of tumors. Modular synthesis approaches allow the construction of hybrid probes consisting of a radiotracer, a fluorophore and a targeting unit. We present the synthesis of a new asymmetric bifunctional cyanine dye that can be used as a structural and functional linker for the construction of such hybrid probes. 68Ga‐DOTATATE, a well‐characterized radiopeptide targeting the overexpressed somatostatin receptor subtype 2 (SSTR2) in neuroendocrine tumors, was labeled with our cyanine dye, thus providing additional information along with the data obtained from the radiotracer. We tested the SSTR2‐targeting and imaging properties of the resulting probe 68Ga‐DOTA‐ICC‐TATE in vitro and in a tumor xenograft mouse model. Despite the close proximity between dye and pharmacophore, we observed a high binding affinity towards SSTR2 as well as elevated uptake in SSTR2‐overexpressing tumors in the positron emission tomography (PET) scan and histological examination., Multifunctional cyanine dyes: Multimodal imaging agents can be built up based on an asymmetric cyanine dye connecting the radionuclide and targeting unit. Insertion of a cyanine dye into the clinically approved radiopharmaceutical 68Ga‐DOTATATE allowed the identification of cancer tissue in vivo and ex vivo by using radionuclear and fluorescence imaging.

Background: The understanding of the regulation of glucagon secretion by pancreatic islet α-cells remains elusive. We aimed to develop an in vitro model for investigating the function of human α-cells under direct influence of glucose and other potential regulators. Methods: Highly purified human α-cells from islets of deceased donors were re-aggregated in the presence or absence of β-cells in culture, evaluated for glucagon secretion under various treatment conditions, and compared to that of intact human islets and non-sorted islet cell aggregates. Findings: The pure human α-cell aggregates maintained proper glucagon secretion capability at low concentrations of glucose, but failed to respond to changes in ambient glucose concentration. Addition of purified β-cells, but not the secreted factors from β-cells at low or high concentrations of glucose, partly restored the responsiveness of α-cells to glucose with regulated glucagon secretion. The EphA stimulator ephrinA5-fc failed to mimic the inhibitory effect of β-cells on glucagon secretion. Glibenclamide inhibited glucagon secretion from islets and the α- and β-mixed cell-aggregates, but not from the α-cell-only aggregates, at 2.0 mM glucose. Interpretation: This study validated the use of isolated and then re-aggregated human islet cells for investigating α-cell function and paracrine regulation, and demonstrated the importance of cell-to-cell contact between α- and β-cells on glucagon secretion. Loss of proper β- and α-cell physical interaction in islets likely contributes to the dysregulated glucagon secretion in diabetic patients. Re-aggregated select combinations of human islet cells provide unique platforms for studying islet cell function and regulation. Keywords: Human alpha cells glucagon, Insulin inhibition, Somatostatin, Glibenclamide, Paracrine regulation, Cell-to-cell contact

The intestinal microbiota has been demonstrated to influence host metabolism, and has been proposed to affect the development of obesity and type 2 diabetes (T2D), possibly through short-chain fatty acids (SCFAs) produced by fermentation of dietary fiber. There are some indications that SCFAs inhibit glucose-stimulated insulin secretion (GSIS) in rodents, but research on this subject is sparse. However, it has been reported that receptors for SCFAs, free fatty acid receptor 2 (FFAR2) and FFAR3 are expressed not only on gut endocrine cells secreting GLP-1 and PYY, but also on pancreatic islet cells. We hypothesized that SCFAs might influence the endocrine secretion from pancreatic islets similar to their effects on the enteroendocrine cells. We studied this using isolated perfused mouse pancreas which responded adequately to changes in glucose and to infusions of arginine. None of the SCFAs, acetate, propionate and butyrate, influenced glucagon secretion, whereas they had weak inhibitory effects on somatostatin and insulin secretion. Infusions of two specific agonists of FFAR2 and FFAR3, CFMB and Compound 4, respectively, did not influence the pancreatic secretion of insulin and glucagon, whereas both induced strong increases in the secretion of somatostatin. In conclusion, the small effects of acetate, propionate and butyrate we observed here may not be physiologically relevant, but the effects of CFMB and Compound 4 on somatostatin secretion suggest that it may be possible to manipulate pancreatic secretion pharmacologically with agonists of the FFAR2 and 3 receptors, a finding which deserves further investigation.

Using viral optogenetics in transgenic reporter mice, it was revealed that spared nerve injury model of neuropathic pain differentially alters synaptic efficacy of monosynaptic parabrachial inputs targeting distinct regions and neurons in the central amygdala., Dissecting the organization of circuit pathways involved in pain affect is pivotal for understanding behavior associated with noxious sensory inputs. The central nucleus of the amygdala (CeA) comprises distinct populations of inhibitory GABAergic neurons expressing a wide range of molecular markers. CeA circuits are associated with aversive learning and nociceptive responses. The CeA receives nociceptive signals directly from the parabrachial nucleus (PBn), contributing to the affective and emotional aspects of pain. Although the CeA has emerged as an important node in pain processing, key questions remain regarding the specific targeting of PBn inputs to different CeA subregions and cell types. We used a multifaceted approach involving transgenic reporter mice, viral vector-mediated optogenetics, and brain slice electrophysiology to delineate cell-type–specific functional organization of the PBn–CeA pathway. Whole-cell patch clamp recordings of molecularly defined CeA neurons while optogenetically driving long-range inputs originating from PBn revealed the direct monosynaptic excitatory inputs from PBn neurons to 3 major subdivisions of the CeA: laterocapsular (CeC), lateral (CeL), and medial (CeM). Direct monosynaptic excitatory inputs from PBn targeted both somatostatin-expressing (SOM+) and corticotropin-releasing hormone expressing (CRH+) neurons in the CeA. We find that monosynaptic PBn input is preferentially organized to molecularly specific neurons in distinct subdivisions of the CeA. The spared nerve injury model of neuropathic pain differentially altered PBn monosynaptic excitatory input to CeA neurons based on molecular identity and topographical location within the CeA. These results provide insight into the functional organization of affective pain pathways and how they are altered by chronic pain.

Background: Aggregation of the amyloid-beta (Aβ) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading Aβ, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance. Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the Aβ-precursor protein (AβPP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and Aβ were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125. Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound Aβ42 was detected in the hippocampus and the adjacent cortical area after only three injections. Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound Aβ42 in the hippocampus. Being that membrane-bound Aβ triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

BACKGROUND Patients with massive ascites (MA) after liver transplantation (LT, defined here as daily ascitic drainage more than 1000 ml per day for more than 7 days after liver transplantation) are at increased risks of infection, hypoalbuminemia, graft loss, and even mortality. The aim of this retrospective cohort study was to investigate the effects of somatostatin on patients with MA after LT. MATERIAL AND METHODS Twenty-eight patients with liver cirrhosis or hepatocellular carcinoma who underwent LT complicated by MA postoperatively were included. Ten participants were receiving somatostatin therapy. The postoperative course and adverse drug effects were investigated. Daily postoperative ascitic drainage and urine output were also recorded and compared to those in the non-somatostatin group. RESULTS The somatostatin group had significantly less ascites drainage after LT compared to the non-somatostatin group (p=0.002). Urine output was significantly increased after somatostatin administration (p

The aim of this study is to investigate the effect of somatostatin (SST) analogue, Octreotide, on some features of liver injury induced by immobilization stress (IS) in adult male albino rats. Eighteen adult male albino rats were randomly divided into three equal groups: control, IS, and Octreotide-treated stressed groups. Octreotide (40 μg/kg body weight, subcutaneously) was administrated twice daily for 8 days during the exposure to IS. Octreotide was found to reduce the IS significantly and induce elevations in the plasma level of corticosterone, liver transaminases, and tumor necrosis factor α (TNF-α) as compared with IS group. Furthermore, Octreotide administration has significantly elevated the decline in the total antioxidant capacities (TAC) and lowered the elevated malondialdehyde (MDA) levels observed with IS in the hepatic tissue. Additionally, Octreotide treatment provided protection against the histopathological changes in the stressed liver in the form of significant reduction in the mean number of degenerated hepatocytes, the area % of collagen fibers, and glial fibrillary acid protein (GFAP) immunostaining with a significant increase in the mean number of normal hepatocytes. In conclusion, stressed rats showed disturbed liver functions and its oxidant–antioxidant status with highly expression hepatic stellate cells (HSCs), which were all improved by Octreotide administration, SST analogue.

Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.

Everolimus, an oral mammalian target of rapamycin(mTOR) inhibitor, which acts upstream of the phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signaling pathway to downregulate cellular metabolism, growth, proliferation, and angiogenesis, has been shown to significantly prolong the progression-free survival of patients with advanced neuroendocrine tumors. Somatostatin analogues (SSAs) such as octreotide, lanreotide, and pasireotide, have been widely used for symptom control and antiproliferative effects in metastatic or unresectable neuroendocrine tumors. Both everolimus and SSAs have demonstrated antitumor effects in randomized controlled trials (RCTs) involving selected patients with neuroendocrine tumors, but the efficacy and safety of their combined use require further investigation. In this systematic review, we summarize the published studies that have investigated the use of everolimus and SSAs to provide a comprehensive understanding of their combined effects and better guidance for the treatment of neuroendocrine tumors.

Rationale: Pluripotent stem cells (PSCs) are being investigated as a cell source for regenerative medicine since they provide an infinitive pool of cells that are able to differentiate towards every cell type of the body. One possible therapeutic application involves the use of these cells to treat myocardial infarction (MI), a condition where billions of cardiomyocytes (CMs) are lost. Although several protocols have been developed to differentiate PSCs towards CMs, none of these provide a completely pure population, thereby still posing a risk for neoplastic teratoma formation. Therefore, we developed a strategy to (i) monitor cell behavior noninvasively via site-specific integration of firefly luciferase (Fluc) and the human positron emission tomography (PET) imaging reporter genes, sodium iodide symporter (hNIS) and somatostatin receptor type 2 (hSSTr2), and (ii) perform hSSTr2-mediated suicide gene therapy via the clinically used radiopharmacon 177Lu-DOTATATE. Methods: Human embryonic stem cells (ESCs) were gene-edited via zinc finger nucleases to express Fluc and either hNIS or hSSTr2 in the safe harbor locus, adeno-associated virus integration site 1. Firstly, these cells were exposed to 4.8 MBq 177Lu-DOTATATE in vitro and cell survival was monitored via bioluminescence imaging (BLI). Afterwards, hNIS+ and hSSTr2+ ESCs were transplanted subcutaneously and teratomas were allowed to form. At day 59, baseline 124I and 68Ga-DOTATATE PET and BLI scans were performed. The day after, animals received either saline or 55 MBq 177Lu-DOTATATE. Weekly BLI scans were performed, accompanied by 124I and 68Ga-DOTATATE PET scans at days 87 and 88, respectively. Finally, hSSTr2+ ESCs were differentiated towards CMs and transplanted intramyocardially in the border zone of an infarct that was induced by left anterior descending coronary artery ligation. After transplantation, the animals were monitored via BLI and PET, while global cardiac function was evaluated using cardiac magnetic resonance imaging. Results: Teratoma growth of both hNIS+ and hSSTr2+ ESCs could be followed noninvasively over time by both PET and BLI. After 177Lu-DOTATATE administration, successful cell killing of the hSSTr2+ ESCs was achieved both in vitro and in vivo, indicated by reductions in total tracer lesion uptake, BLI signal and teratoma volume. As undifferentiated hSSTr2+ ESCs are not therapeutically relevant, they were differentiated towards CMs and injected in immune-deficient mice with a MI. Long-term cell survival could be monitored without uncontrolled cell proliferation. However, no improvement in the left ventricular ejection fraction was observed. Conclusion: We developed isogenic hSSTr2-expressing ESCs that allow noninvasive cell monitoring in the context of PSC-derived regenerative therapy. Furthermore, we are the first to use the hSSTr2 not only as an imaging reporter gene, but also as a suicide mechanism for radionuclide therapy in the setting of PSC-derived cell treatment. ispartof: Theranostics vol:8 issue:10 pages:2799-2813 ispartof: location:Australia status: published

Glucagon-like peptide (GLP)-1 is released from the intestinal L cells in response to food ingestion and stimulates insulin secretion from the pancreatic B cells, by binding to its specific receptor (GLP-1R), which is expressed on the pancreatic B cells in the mammalian pancreas. Previously, we demonstrated that chicken GLP-1R was expressed on the pancreatic D cells by using a specific antibody against chicken GLP-1R. In the present study, we compared the localization of GLP-1R in the pancreases of three avian species; white leghorn chicken, northern bobwhite, and common ostrich, using the double immunofluorescence technique. We found that the types of pancreatic islets in the northern bobwhite pancreas were similar to those found in the chicken pancreas. The ostrich pancreas contained several types of pancreatic islets. GLP-1R-immunoreactive cells were found in all types of pancreatic islets in both northern bobwhite and ostrich and expressed somatostatin immunoreactivity. The present results indicate that the pancreatic D cells are the target cells of GLP-1, and GLP-1 might play a physiological role via somatostatin in the avian species.

// Sander R. Dubovy 1,3,* , Maria P. Fernandez 1,* , Jose J. Echegaray 1,5,* , Norman L. Block 3,4 , Noriyuki Unoki 1 Roberto Perez 2,4 , Irving Vidaurre 2 , Richard K. Lee 1 , Mehrdad Nadji 3 and Andrew V. Schally 2,3,4 1 Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, Florida, USA 2 Miami Veterans Affairs Medical Center, Miami, Florida, USA 3 Department of Pathology, University of Miami, Miller School of Medicine, Miami, Florida, USA 4 Divisions of Hematology/Oncology, Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA 5 Department of Ophthalmology, University of Puerto Rico School of Medicine, San Juan, PR, USA * These authors have contributed equally to this work Correspondence to: Andrew V. Schally, email: // Keywords : eye neuropeptides, ocular endocrinology, hormone-analog therapy Received : May 07, 2017 Accepted : May 20, 2017 Published : June 03, 2017 Abstract Extrapituitary roles for hypothalamic neurohormones have recently become apparent and clinically relevant, based on the use of synthetic peptide analogs for the treatment of multiple conditions including cancers, pulmonary edema and myocardial infarction. In the eye, it has been suggested that some of these hormones and their receptors may be present in the ciliary body, iris, trabecular meshwork and retina, but their physiological role has yet to be elucidated. Our study intends to comprehensively demonstrate the expression of some hypothalamic neuroendocrine hormones and their receptors within different retinal and extraretinal structures of the human eye. Immunofluorescence, Western blot analysis, and RT-PCR were used to evaluate the qualitative and quantitative expression of Luteinizing Hormone Releasing Hormone (LHRH), Growth Hormone Releasing Hormone (GHRH), Thyrotropin Releasing Hormone (TRH), Gastrin Releasing Peptide (GRP) and Somatostatin as well as their respective receptors (LHRH-R, GHRH-R, TRH-R, GRP-R, SST-R1) in cadaveric human eye tissue and in paraffinized human eye tissue sections. The hypothalamic hormones LHRH, GHRH, TRH, GRP and Somatostatin and their respective receptors (LHRH-R, GHRH-R, TRH-R, GRPR/BB2 and SST-R1), were expressed in the conjunctiva, cornea, trabecular meshwork, ciliary body, lens, retina, and optic nerve.

The prevalence of neuroendocrine tumors (NETs) has recently been increasing. Although various drugs such as Octreotide and its analogs show certain efficacy, NETs in many patients progress and metastasize. It is desirable to develop new interventions to improve the therapy. Here we show that human neuroendocrine tumor BON cells are resistant to several drugs commonly used for NET therapy, including Octreotide that activates somatostatin receptor-induced anti-proliferation, and Capecitabine and Temozolimide that damage DNA. In contrast, an inhibitor (IBET) to an epigenetic regulator, Brd4 that binds acetylated histones and upregulates transcription of multiple genes including protooncogene c-Myc, potently inhibited the NET cells. We found that IBET increased the protein levels of cyclin-dependent kinase (CDK) inhibitor p27kip/cip (or p27), but not its mRNA levels. Moreover, the p27 induction at protein level by IBET was at least partly through increasing the protein stability of p27. The increased protein stability of p27 likely resulted from IBET-mediated suppression of Skp2, an E3 ligase that can mediate p27 degradation by increasing its ubiquitinylation. These findings unravel a new mechanism whereby the IBET-induced repression of proliferation of neuroendocrine cells.

Limited penetration of chemotherapeutic drugs through the blood brain barrier (BBB), and the increased chemo-resistance of glioma cells due to macroautophagy/autophagy, result in high tumor recurrence and extremely limited survival of glioma patients. Ultrasound-targeted microbubble destruction (UTMD) is a technique of transient and reversible BBB disruption, which greatly facilitates intracerebral drug delivery. In addition, sonodynamic therapy (SDT) based on ultrasound stimulation and a sonosensitizer, can be a safe and noninvasive strategy for treating glioma. We innovatively designed a smart “all-in-one” nanosensitizer platform by incorporating the sonoactive chlorin e6 (Ce6) and an autophagy inhibitor-hydroxychloroquine (HCQ) into angiopep-2 peptide-modified liposomes (designated as ACHL), which integrates multiple diagnostic and therapeutic functions. ACHL selectively accumulated in the brain tumors during the optimal time-window of transient UTMD-mediated BBB opening. The nanosensitizer then responded to a second ultrasonic stimulation, and simultaneously unloaded HCQ and generated ROS in the glioma cells. The sonotherapy triggered apoptosis as well as MAPK/p38-PINK1-PRKN-dependent mitophagy, in which the antioxidant relieved the sonotoxicity and MAPK/p38 activation, while the inhibition of MAPK/p38 attenuated the progression toward mitophagy by compromising redistribution of PRKN. Moreover, HCQ blocking autophagosome degradation, augmented intracellular ROS production and resulted in an oxidative-damage regenerative loop. ACHL-SDT treatment using this construct significantly inhibited the xenograft-tumor growth and prolonged the survival time of tumor-bearing mice, exhibiting an improved therapeutic efficiency. All together, we demonstrated a precision sonotherapy with simultaneous apoptosis induction and mitophagy inhibition, which served as an intelligently strategic sense of working alongside, providing new insights into the theranostics of brain tumors. Abbreviations ACHL: Angiopep-2-modified liposomes loaded with Ce6 and hydroxychloroquine; ACL: Angiopep-2-modified liposomes loaded with Ce6; BBB: blood brain barrier; Ce6: chlorin e6; CHL: liposomes loaded with Ce6 and hydroxychloroquine; CL: liposomes loaded with Ce6; CNS: central nervous system; DDS: drug delivery system; EB: Evans blue; FUS: focused ultrasound; HCQ: hydroxychloroquine; LRP1: low density lipoprotein receptor-related protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MBs: microbubbles; MTG: MitoTracker Green; MTR: MitoTracker Red; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS: phosphate-buffered saline; PDI: polydispersity index; PINK1: PTEN induced kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; SDT: sonodynamic therapy; SQSTM1: sequestome 1; TA: terephthalic acid; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling; US: ultrasound; UTMD: ultrasound-targeted microbubble destruction.

Background and Purpose Specific, high potency receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent, insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist, (Pro3)GIP, and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. Experimental Approach Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using 125I-human GIP. Using isolated perfused pancreata both from wild type and GIP receptor-deficient rodents, insulin-releasing, glucagon-releasing and somatostatin-releasing properties in response to species-specific GIP and (Pro3)GIP analogues were evaluated. Key Results Human (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (Emax) for cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata in the presence of 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion, corresponding to the partial agonist activities observed in cAMP production. Conclusions and Implications When evaluating new compounds, it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models, human GIP is a comparatively weak partial agonist. Human (Pro3)GIP was not an antagonist at human GIP receptors, so there is still a need for a potent antagonist in order to elucidate the physiology of human GIP.

Background: Growth hormone-secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also downregulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve insulin-like growth factor I (IGF-I) normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenoma tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pretreatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization during postsurgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression was lower in patients pretreated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment-naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization.

We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.

Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, βIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound.

Purpose Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734). Methods ACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. Patients received pasireotide long-acting release 40 mg administered intramuscularly every 28 days. The primary outcome was the proportion of patients having a treatment-emergent grade ≥3 or serious adverse event. Efficacy data were not collected. Results Forty-four adult patients with active acromegaly were enrolled in the study for an average of 37.6 weeks (range, 4–70 weeks). Twenty-five grade ≥3 treatment-emergent adverse events were reported in 11 patients (25.0 %), 3 of whom (27.3 %) experienced grade ≥3 hyperglycemia. In patients treated with pasireotide long-acting release for ≥3 months (n = 42), mean glycated hemoglobin and fasting plasma glucose levels increased significantly from 5.9 % and 100.4 mg/dL at baseline to 6.8 % and 135.9 mg/dL at 3 months, respectively. Ten patients (22.7 %) were treated with pasireotide long-acting release for ≥15 months, after which mean glycated hemoglobin and fasting plasma glucose levels were 6.3 % and 123 mg/dL, respectively. Twenty-one patients (48 %) initiated antidiabetic medication. Conclusions Grade ≥3 adverse events (primary outcome) were reported in 25.0 % of acromegaly patients treated with pasireotide long-acting release in a clinical setting. Hyperglycemia-related adverse events were reported in 45.5 % of patients, but were typically manageable, supporting the role of pasireotide long-acting release as a safe treatment option for acromegaly patients.

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)–hypoxia-inducible factor-1α (HIF-1α)–vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK–HIF-1α–VEGF signaling pathway. Electronic supplementary material The online version of this article (doi:10.1007/s10456-016-9522-9) contains supplementary material, which is available to authorized users.

GABAergic interneurons are positioned to powerfully influence the dynamics of neural activity, yet the interneuron-mediated circuit mechanisms that control spontaneous and evoked neocortical activity remains elusive. Vasoactive intestinal peptide (VIP+) interneurons are a specialized cell class which synapse specifically on other interneurons, potentially serving to facilitate increases in cortical activity. In this study, using in vivo Ca2+ imaging, we describe the interaction between local network activity and VIP+ cells and determine their role in modulating neocortical activity in mouse visual cortex. VIP+ cells were active across brain states including locomotion, nonlocomotion, visual stimulation, and under anesthesia. VIP+ activity correlated most clearly with the mean level of population activity of nearby excitatory neurons during all brain states, suggesting VIP+ cells enable high-excitability states in the cortex. The pharmacogenetic blockade of VIP+ cell output reduced network activity during locomotion, nonlocomotion, anesthesia, and visual stimulation, suggesting VIP+ cells exert a state-independent facilitation of neural activity in the cortex. Collectively, our findings demonstrate that VIP+ neurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus evoked neocortical activity.

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and relatively rare neoplasms that present many clinical challenges. They characteristically synthesize, store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndromes, including the carcinoid syndrome, insulinoma, glucagonoma or VIPoma, although many are clinically silent until late presentation with mass effects. Management strategies include surgery and cytoreduction with chemotherapy and the use of somatostatin analogues to control symptoms from peptide neurotransmitter release. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five G-protein-coupled somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Clinically used somatostatin analogues including octreotide and lanreotide are effective medical tools in treatment and show selectivity for SSTR2 and SSTR5. During treatment, disappearance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion are observed. The addition of interferon (INF) to somatostatin analogues may improve the antiproliferative effects. Patients who received the combination therapy had a significantly lower risk of progressive disease. On the other hand, the major toxicity of INF including temporary flu-like symptoms, tiredness, anorexia and leukopenia should be considered. Telotristat etiprate is an orally bioavailable, tryptophan hydroxylase (TPH) inhibitor with potential antiserotoninergic activity. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and, as such, is a promising potential new treatment for patients with carcinoid syndrome. Pancreatic functioning neuroendocrine tumors include insulinoma, gastrinoma, glucagonoma and VIPoma. Medical management in patients with insulinoma and severe hypoglycemic attacks includes diazoxide, which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma includes both proton pump inhibitors (PPIs) and histamine H2-receptor antagonists. Octreotide and lanreotide can also control acid hypersecretion. In patients with glucagonomas hyperglycemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas somatostatin analogues are effective in controlling necrolytic migratory erythema. Severe cases of the VIPoma syndrome require supplementation of fluid losses. Octreotide reduces tumoral VIP secretion and controls secretory diarrhea. Further control of diarrhea can be achieved with loperamide, opiates and glucocorticoids.

The Lake Van fish (Alburnus tarichi) is a species that is endemic to Turkey’s Lake Van basin. In this study, the regional distribution, volume density, and relative frequency of some pancreatic endocrine cells in Lake Van fish were investigated via immunohistochemistry using specific mammalian antibodies. The pancreatic tissue was observed to be surrounded by adipose tissue, which was adjacent to the gall bladder or extrahepatic bile duct, or dispersed in the adipose tissue ranked among coils of post-esophageal swelling and intestine. The pancreatic endocrine cells were examined, including the islets, exocrine pancreas, and pancreatic ducts. According to the modified aldehyde fuchsin staining and immunohistochemistry, insulin-secreting beta cells were observed to localize throughout the islets. Glucagon immune-reactive (IR) cells were observed to be situated moderately on the islet periphery, and were rarely determined in the islet central region. A small number of somatostatin-IR cells were observed in the islet centers and peripheries. Similar distributions of those 3 endocrine cells were also determined in the secondary islets. Additionally, the endocrine cell percentages did not differ between the primary and secondary islets; insulin-, glucagon- and somatostatin-IR cells comprised approximately 54%, 29%, and 11% of the endocrine cells in the principal islets, whereas they comprised 52%, 27%, and 14% in the secondary islets, respectively. Insulin-, glucagon- and somatostatin-IR cells were also determined among the epithelium and subepithelial connective tissue in the pancreatic ducts or exocrine areas of the pancreas. With this study, the existence, regional distribution, and relative frequency of the insulin-, glucagon- and somatostatin-IR cells were first investigated in the pancreatic tissue of Lake Van fish and the results were discussed.

Key points There is a rapid interneuronal response to focal activity in cortex, which restrains laterally propagating activity, including spreading epileptiform activity.The interneuronal response involves intense activation of both parvalbumin‐ and somatostatin‐expressing interneurons.Interneuronal bursting is time‐locked to glutamatergic barrages in the pre‐ictal period.Ca2+ imaging using conditional expression of GCaMP6f provides an accurate readout of the evolving firing patterns in both types of interneuron.The activation profiles of the two interneuronal classes are temporally offset, with the parvalbumin population being activated first, and typically, at higher rates. Abstract Previous work has described powerful restraints on laterally spreading activity in cortical networks, arising from a rapid feedforward interneuronal response to focal activity. This response is particularly prominent ahead of an ictal wavefront. Parvalbumin‐positive interneurons are considered to be critically involved in this feedforward inhibition, but it is not known what role, if any, is provided by somatostatin‐expressing interneurons, which target the distal dendrites of pyramidal cells. We used a combination of electrophysiology and cell class‐specific Ca2+ imaging in mouse brain slices bathed in 0 Mg2+ medium to characterize the activity profiles of pyramidal cells and parvalbumin‐ and somatostatin‐expressing interneurons during epileptiform activation. The GCaMP6f signal strongly correlates with the level of activity for both interneuronal classes. Both interneuronal classes participate in the feedfoward inhibition. This contrasts starkly with the pattern of pyramidal recruitment, which is greatly delayed. During these barrages, both sets of interneurons show intense bursting, at rates up to 300Hz, which is time‐locked to the glutamatergic barrages. The activity of parvalbumin‐expressing interneurons appears to peak early in the pre‐ictal period, and can display depolarizing block during the ictal event. In contrast, somatostatin‐expressing interneuronal activity peaks significantly later, and firing persists throughout the ictal events. Interictal events appear to be very similar to the pre‐ictal period, albeit with slightly lower firing rates. Thus, the inhibitory restraint arises from a coordinated pattern of activity in the two main classes of cortical interneurons., Key points There is a rapid interneuronal response to focal activity in cortex, which restrains laterally propagating activity, including spreading epileptiform activity.The interneuronal response involves intense activation of both parvalbumin‐ and somatostatin‐expressing interneurons.Interneuronal bursting is time‐locked to glutamatergic barrages in the pre‐ictal period.Ca2+ imaging using conditional expression of GCaMP6f provides an accurate readout of the evolving firing patterns in both types of interneuron.The activation profiles of the two interneuronal classes are temporally offset, with the parvalbumin population being activated first, and typically, at higher rates.

Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

The present study has demonstrated the galaninergic innervation of the endocrine pancreas including sources of the galaninergic nerve fibers, and the influence of galanin receptor agonists on blood glucose level in the zebrafish. For the first time, a very abundant galaninergic innervation of the endocrine pancreas during development is shown, from the second day post-fertilization to adulthood. The fibers originated from ganglia consisting of galanin-IR, non-adrenergic (non-sensory) neurons located rostrally to the pancreatic tissue. The ganglia were found on the dorsal side of the initial part of the anterior intestinal segment, close to the intestinal branch of the vagus nerve. The galanin-IR neurons did not show immunoreactivity for applied antibodies against tyrosine hydroxylase, choline acetyltransferase, and vesicular acetylcholine transporter. Intraperitoneal injections of galanin analog NAX 5055 resulted in a statistically significant increase in the blood glucose level. Injections of another galanin receptor agonist, galnon, also caused a rise in blood glucose level; however, it was not statistically significant. The present findings suggest that, like in mammals, in the zebrafish galanin is involved in the regulation of blood glucose level. However, further studies are needed to elucidate the exact mechanism of the galanin action.

// Daniel Kaemmerer 1 , Tina Trager 1, 2 , Maike Hoffmeister 3 , Bence Sipos 3 , Merten Hommann 1 , Jorg Sanger 4 , Stefan Schulz 2 , Amelie Lupp 2 1 Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany 2 Department of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany 3 Institute of Pathology, University Hospital Tuebingen, Germany 4 Institute of Pathology and Cytology, Bad Berka, Germany Correspondence to: Daniel Kaemmerer, e-mail: Daniel.Kaemmerer@zentralklinik.de Keywords: somatostatin receptor, neuroendocrine tumor, neuroendocrine carcinoma, chemokine receptor, CXCR4 Received: April 13, 2015 Accepted: July 03, 2015 Published: July 14, 2015 ABSTRACT Introduction: Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods: SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 ( n = 31), G2 ( n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results: Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion: We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies.