| 61. |
- Hagbom, Marie, et al.
(författare)
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Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting
- 2011
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Ingår i: PLOS PATHOGENS. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca(2+) concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP(3)), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT(3) receptor antagonists.
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| 62. |
- Jakobsen, A M, et al.
(författare)
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Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours.
- 2001
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Ingår i: The Journal of pathology. - : Wiley. - 0022-3417. ; 195:4, s. 463-72
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumours are characterized by their capacity to produce hormones, which are stored in vesicles and secretory granules. Demonstration of granule/vesicle proteins in tumours is taken as evidence of neuroendocrine differentiation. Vesicular monoamine transporters (VMAT1 and VMAT2) mediate the transport of amines into vesicles of neurons and endocrine cells. The expression of VMAT1 and VMAT2 and the usefulness of VMAT1 and VMAT2 in the histopathological diagnosis of gastrointestinal endocrine tumours have not been fully explored. This study therefore investigated the expression of VMAT1 and VMAT2 in 211 human gastrointestinal tumours by immunocytochemistry and western blotting. VMAT1 and/or VMAT2 were demonstrated in the majority of amine-producing endocrine tumours of gastric, ileal, and appendiceal origin. Serotonin-producing endocrine tumours (ileal and appendiceal carcinoids) expressed predominantly VMAT1, while histamine-producing endocrine tumours (gastric carcinoids) expressed VMAT2 almost exclusively. In peptide-producing endocrine tumours such as rectal carcinoids and endocrine pancreatic tumours, only a small number of immunopositive tumour cells were observed. No labelling was found in non-endocrine tumours, including gastric, colorectal and pancreatic adenocarcinomas and gastrointestinal stromal tumours. In conclusion, VMAT1 and VMAT2 are differentially expressed by gastrointestinal endocrine tumours, with a pattern specific for each tumour type, reflecting their neuroendocrine differentiation and origin. VMAT1 and VMAT2 may therefore become valuable markers in the classification of neuroendocrine tumours and may also indicate patients suitable for radioisotope treatment operating via these transporter systems.
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| 63. |
- Janson, Per-Olof, 1940, et al.
(författare)
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Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6.
- 1998
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Ingår i: Clinical endocrinology. - 0300-0664. ; 48:2, s. 243-50
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Tidskriftsartikel (refereegranskat)abstract
- A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500-1800 nmol/l) without diurnal variation. Plasma ACTH levels (200-250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600-1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80-90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.
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| 64. |
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| 65. |
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| 66. |
- Jansson, Svante, 1948, et al.
(författare)
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Treatment of bilateral pheochromocytoma and adrenal medullary hyperplasia.
- 2006
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1073, s. 429-35
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Tidskriftsartikel (refereegranskat)abstract
- The risk for bilateral tumors and long-term outcome after conservative cortical-sparing adrenal surgery was studied in a consecutive single-center series. One hundred fifty-four patients were operated on (1950-2004) for pheochromocytoma (PC=137), or abdominal paraganglioma (PG=17). Twenty had MEN 2 (16 MEN 2A; 4 MEN 2B), 15 von Recklinghausen's disease (VRD), and 1 von Hippel-Lindau (VHL) disease. Twelve patients had, or developed, bilateral adrenal medullary tumors; four with MEN 2A, four with MEN 2B, three with VRD, and one with probably hereditary PC associated with brain tumors/meningioma. Two patients with MEN 2B and one with MEN 2A with had bilateral adrenalectomy (adx). Three VRD patients, two MEN 2B and one MEN 2A patients had cortical-sparing surgery. Two patients were operated on unilaterally, but developed small contralateral tumors; one of these (MEN 2A) had a second asymptomatic PC diagnosed at an older age, so surgery was withheld; the other patient (hereditary PC syndrome) had a small contralateral PC diagnosed at autopsy 9 years later. Only three of nine patients with bilateral operations needed corticosteroid replacement after surgery. Four of six patients died of associated tumors (MTC and meningioma). The mean follow-up was 13 (1-25) years. Twelve MEN 2A patients with unilateral adx have been followed up for 20 (4-36) years without developing a second PC. Cortical-sparing adrenal surgery can safely be performed in the majority of patients with bilateral PC. On the basis of our long-term experience of MEN 2A we perform contralateral adrenal resection only if a second PC is confirmed. Five patients underwent adrenal exploration because of clinical and biochemical findings compatible with PC. Four had asymmetrical positive MIBG scans. They all underwent unilateral adx and diffuse medullary hyperplasia was confirmed (medullary weight estimated morphometrically to 1.0-3.4 g vs. normal weight 0.3-0.5 g in matched controls). These patients have been followed for 19 (5-27) years with normal clinical and biochemical findings. In this rare condition removal of the largest adrenal seems adequate.
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| 67. |
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| 68. |
- Johanson, Viktor, 1958, et al.
(författare)
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A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis
- 2007
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 14:2, s. 433-444
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
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| 69. |
- Johanson, Viktor, 1958, et al.
(författare)
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Antitumoural effects of the pyridyl cyanoguanidine CHS 828 on three different types of neuroendocrine tumours xenografted to nude mice
- 2005
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 82:3-4, s. 171-6
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828, a cyanoguanidine with potent experimental antitumoural activity, inhibits activation of nuclear factor-kappaB. In the present study, marked antitumoural activity of peroral CHS 828 was shown against three different human neuroendocrine tumours, midgut carcinoid (GOT1), pancreatic carcinoid (BON), and medullary thyroid carcinoma (GOT2), transplanted in nude mice. Our results indicate that CHS 828 can be a candidate drug for treatment of neuroendocrine tumours.
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| 70. |
- Johanson, V, et al.
(författare)
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Comparison of survival between malignant neuroendocrine tumours of midgut and pancreatic origin.
- 1999
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 80:8, s. 1259-61
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Tidskriftsartikel (refereegranskat)abstract
- The survival of 64 consecutive patients with disseminated midgut carcinoid tumours was compared in a retrospective study with that of 25 consecutive patients with sporadic malignant endocrine pancreatic tumours treated according to similar surgical principles. The presence of hepatic metastases implied a worse prognosis in neuroendocrine tumours of pancreatic rather than midgut origin. This infers that these tumour types must be separated when treatments are evaluated.
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