| 1. |
- Falkmer, Ursula G., et al.
(författare)
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Malignant presacral ghrelinoma with long-standing hyperghrelinaemia
- 2015
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Ingår i: Uppsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:4, s. 299-304
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Tidskriftsartikel (refereegranskat)abstract
- Background. A 57-year old man with low-back pain was found to have a 3 x 3 x 3 cm presacral neuroendocrine tumour (NET) with widespread metastases, mainly to the skeleton. His neoplastic disease responded well to peptide receptor radionuclide therapy (PRRT) with the radiotagged somatostatin agonist Lu-177-DOTATATE. During almost 10 years he was fit for a normal life. He succumbed to an intraspinal dissemination. Procedures. A resection of the rectum, with a non-radical excision of the adjacent NET, was made. In addition to computerized tomography (CT), receptor positron emission tomography (PET) with Ga-68-labelled somatostatin analogues was used. Observations. The NET showed the growth pattern and immunoprofile of a G2 carcinoid. A majority cell population displayed immunoreactivity to ghrelin, exceptionally with co-immunoreactivity to motilin. Somatostatin receptor scintigraphy and Ga-68-DOTATATE PET-CT demonstrated uptake in the metastatic lesions. High serum concentrations of total (desacyl-)ghrelin were found with fluctuations reflecting the severity of the symptoms. In contrast, the concentrations of active (acyl-)ghrelin were consistently low, as were those of chromogranin A (CgA).Conclusions. Neoplastically transformed ghrelin cells can release large amounts of desacyl-ghrelin, evoking an array of non-specific clinical symptoms. Despite an early dissemination to the skeleton, a ghrelinoma can be compatible with longevity after adequate radiotherapy.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Tjomsland, Vegard, et al.
(författare)
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IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts
- 2010
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation. The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells. IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.
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| 6. |
- Tjomsland, Vegard, 1978-, et al.
(författare)
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Interleukin 1α sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts
- 2011
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Ingår i: Neoplasia. - : Neoplasia Press. - 1522-8002 .- 1476-5586. ; 13:8, s. 664-675
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Tidskriftsartikel (refereegranskat)abstract
- The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. The aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross-talk between primary PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of primary PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1á, IL-6, CXCL8, VEGFA, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors and tumor cell associated IL-1á was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1á to the active IL-1 receptor (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a positive correlation between IL-1á and CXCL8 expression levels in PDAC tissues and correlation between IL-1á expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1á signaling efficiently diminished the cross-talk induced production of inflammatory factors. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment and we propose that neutralization of the IL-1á signaling might be a potential therapy for this cancer.
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| 7. |
- Tjomsland, Vegard, et al.
(författare)
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Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?
- 2010
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Ingår i: BMC CANCER. - : BioMed Central. - 1471-2407. ; 10:87
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence. Methods: We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls. Results: All groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients similar to 12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival. Conclusions: Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.
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| 8. |
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| 9. |
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| 10. |
- Järhult, Johannes, et al.
(författare)
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First Report on Metastasizing Small Bowel Carcinoids in First-Degree Relatives in Three Generations
- 2010
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 91:4, s. 318-323
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: There is an established association between the multiple endocrine neoplasia type 1 (MEN 1) syndrome and foregut carcinoids. Some registry studies also indicate that offspring to carcinoid patients run an increased risk of developing a carcinoid tumor themselves. However, there are only scattered reports of gastrointestinal carcinoids in two generations. The aim of this study was to describe the clinical characteristics as well as the histopathological, immunohistochemical (IHC) and genetic data of metastasizing ileal carcinoids in three consecutive first-degree relatives. Methods: The histopathological and IHC analyses were performed on newly cut sections of the tumor specimens and included growth pattern, proliferation index (Ki67) as well as expression of established neuroendocrine markers and recently introduced cocaine-amphetamine-regulated transcript (CART). The genetic analyses were focused on establishing whether a connection with the MEN 1 syndrome existed in this family, by means of mutation screening using polymerase chain reaction, multiple ligation-dependent probe amplification, and genotyping using fluorescent-labeled microsatellite markers. Results: Histopathology and IHC revealed that the tumors were virtually identical, with only minor differences in proliferation index and expression of CART. Genetic analyses indicated that the inheritance of the small bowel carcinoids in the family was not linked to the MEN1 gene. Conclusion: Metastasizing small bowel carcinoids have been found in first-degree relatives in three consecutive generations. All three tumors were very similar when characterized by histopathology and IHC. Based on clinical findings and genetic analyses, it seems unlikely, although not completely excluded, that inheritance was linked to the MEN 1 syndrome. Copyright (c) 2010 S. Karger AG, Basel
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| 11. |
- Kaltsas, Gregory, et al.
(författare)
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Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance
- 2011
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Ingår i: Endocrine-Related Cancer. - Uppsala : Uppsala University. - 1351-0088 .- 1479-6821. ; 18:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.
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| 12. |
- Landerholm, Kalle, 1976-
(författare)
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Clinical and immunohistochemical studies of small bowel carcinoid tumours
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small bowel carcinoid tumours arising from enterochromaffin cells in the jejunum and ileum are neuroendocrine tumours (NETs) characterized by secretion of serotonin, tachykinins and other bioactive substances. These substances may lead to the typical carcinoid syndrome as well as pronounced fibrosis locally and in the heart. Although the most frequent histological subtype of malignancy in the small bowel, small bowel carcinoids are rare and therefore difficult to study. We found that previous studies either described selected patients at referral centres, or were based on limited data from large registries. The main objective of this thesis was to investigate small bowel carcinoid patients from a geographically defined cohort with no selection bias.PAPERS I AND IIThe aims of papers I and II were to investigate the incidence, histopathological characteristics, stage atdiagnosis, symptomatology, surgical treatment, prognostic factors and survival of small bowel carcinoid.All patients resident in Jönköping County when diagnosed with small bowel carcinoid between 1960 and2005 were eligible for inclusion. After thorough review of medical records and reexamination of availabletumour specimens, 145 patients were included.A higher incidence of small bowel carcinoid than previously described was found: 1.12 per 100,000 persons and year. The incidence increased during the study period. Symptoms were most often uncharacteristic: the carcinoid syndrome was seen in only 13% of symptomatic patients. Many small bowel carcinoid tumours presented as surgical emergencies without preceding symptoms, often as intestinal obstruction (35%) caused by mesenteric fibrosis. The majority of small bowel carcinoid tumours had metastasized to the mesentery or the liver at diagnosis. Disease-specific survival after 5 years was 75.0% and after 10 years 63.5%. Independent prognostic factors for worse disease-specific survival were higher age at diagnosis, more advanced disease stage at diagnosis and incomplete tumour resection. Completeness of resection was of particular importance in patients with regional metastases.PAPER IIIThere are previous case reports describing small bowel carcinoid in two first-degree relatives, but it is unknown whether this represents hereditary disease forms or chance. Paper III was the first article to describe metastasizing ileal carcinoid tumours in three consecutive generations − strongly suggestive of a hereditary disease form.PAPER IVWe recently demonstrated expression of cocaine- and amphetamine-regulated transcript (CART) in several types of NETs, including small bowel carcinoid. The aim of paper IV was to investigate whether content of CART in small bowel carcinoid tumours is associated with tumour characteristics, symptoms and survival. CART expression was examined in all available tumour specimens from the patients in Papers I and II − 97 patients were included.Presence of CART IR tumour cells was associated with histological grade, but not with stage or age. CART expression in small bowel carcinoid tumours was not associated with clinical symptoms. Increasing levels of CART IR in small bowel carcinoid tumour cells was associated with worse disease-specific survival. CART was also found to increase cell viability in an enteroendocrine cell line in vitro. The results suggest that CART could be used as a prognostic biomarker and that CART is a potential anti-tumour treatment target.
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| 13. |
- Landerholm, Kalle, et al.
(författare)
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Cocaine- and Amphetamine-Regulated Transcript in Neuroendocrine Tumors
- 2011
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 94:3, s. 228-236
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Cocaine-and amphetamine-regulated transcript (CART) is an anorexigenic regulatory peptide highly expressed in the brain's appetite control centers, but also in peripheral neurons and in endocrine cells in the adrenal medulla, thyroid, pancreatic islets, and in the gastrointestinal tract. Plasma levels of CART were recently shown to be elevated in patients with neuroendocrine tumors (NETs), but the cellular sources of CART in NETs have remained unknown. The aim of the study was to establish whether CART is expressed in various types of NETs and, if so, to examine the frequency, distribution and phenotype of CART-expressing cells. Methods: Tumor specimens from 133 NETs originating in the stomach, ileum, rectum, pancreas and thyroid were examined with immunohistochemistry and in situ hybridization. The expression of CART was quantified and the CART-expressing cells were phenotyped by double staining for established markers and hormones. Results: CART-expressing tumor cells were found in the majority of the examined NETs. The expression pattern of CART was highly heterogeneous not only between tumors, but also within individual tumors. In 14% of the NETs, CART was found in a major population of the tumor cells. Conclusion: CART is produced in the majority of NETs, regardless of tumor origin. This likely explains the elevated levels of circulating CART in certain NETs patients, as recently described. CART could therefore prove to be a useful tool in the diagnostics of NETs not only in blood samples, but also in histopathological specimens. Copyright (C) 2011 S. Karger AG, Basel
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| 14. |
- Landerholm, Kalle, et al.
(författare)
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Epidemiology of Small Bowel Carcinoids in a Defined Population
- 2010
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Ingår i: World Journal of Surgery. - : Springer Science Business Media. - 0364-2313 .- 1432-2323. ; 34:7, s. 1500-1505
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Tidskriftsartikel (refereegranskat)abstract
- Background: This retrospective study describes the epidemiology of small bowel carcinoids in a geographically defined population, with no other selection bias. Methods: All patients (n = 145) resident in Jönkoping County when diagnosed with carcinoid in the jejunum or ileum from 1960 to 2005 were included. Medical records were reviewed in detail, and tumor specimens were histopathologically and immunohistochemically reexamined when required (n = 44). Results: The annual age-adjusted incidence of small bowel carcinoids was 1.12 (95% confidence interval 0.95-1.31) per 100,000 persons. Median age at diagnosis was 69 years. The predominating presenting symptom was uncharacteristic abdominal pain (50%), whereas a smaller number suffered from typical flushes (13%). Surprisingly, 14% presented with overt gastrointestinal hemorrhage. Most of the patients diagnosed based on their symptoms had metastases at diagnosis (44% regional, 40% distant). Metastasized tumors by definition belong to World Health Organization (WHO) histopathologic group 2; and when reexamined, most (83%) of the localized tumors were also found to belong to WHO group 2. Conclusions: In comparison to previous reports, a higher age-adjusted incidence of small bowel carcinoids was observed, and the patients were clearly older at the time of diagnosis. Even with metastatic disease, the presenting symptoms were usually uncharacteristic, and the carcinoid syndrome was infrequently seen.
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| 15. |
- Landerholm, Kalle, et al.
(författare)
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Expression of Cocaine- and Amphetamine-Regulated Transcriptis Associated with Worse Survival in Small Bowel Carcinoid Tumors
- 2012
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 18:13, s. 3668-3676
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cocaine- and amphetamine-regulated transcript (CART) peptide exerts several regulatory functions acting both as neurotransmitter and hormone. We recently showed that CART is expressed in various neuroendocrine tumors, including small bowel carcinoid. The main objective of the present study was to examine whether CART expression is associated with survival in small bowel carcinoid patients. Secondary aims were to assess if CART expression is associated with other tumor characteristics or clinical symptoms.Experimental Design: Specimens from 97 patients with small bowel carcinoids were examined for CART expression using immunohistochemistry and in situ hybridization. A CART score was introduced based on the proportion of CART immunoreactive cells. On inclusion, specimens were examined by routine histopathological methods and detailed clinical patient data were retrieved. The effect of CART on cell viability was assessed in vitro using an enteroendocrine cell line.Results: Expression of CART (P = 0.011), and increasing CART score (P = 0.033) were associated with worse disease-specific survival. Adjusting for age, disease stage and tumor grade in multivariable analysis, CART expression was still associated with worse survival (Low CART hazard ratio (HR) 5.47, 95% confidence interval (CI) 0.71 to 42.46; and High CART HR 9.44, 95% CI 1.14 to 78.14). Expression of CART correlated with higher tumor grade, but not with age or disease stage, neither with weight loss or any other symptom. Supporting our clinical data, we found that CART promoted tumor cell viability in vitro.Conclusion: Expression of CART in small bowel carcinoid tumors is associated with worse survival.
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| 16. |
- Landerholm, Kalle, et al.
(författare)
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Ki-67 Index and Solid Growth Pattern as Prognostic Markers in Small Intestinal Neuroendocrine Tumors
- 2015
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 102:4, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- Background/aims: The prognostic value of histopathological grading and the growth pattern of small intestinal neuroendocrine tumors (SI-NET) is unclear. In particular, the cutoff level between grades G1 and G2 at Ki-67 index above 2% is an open issue, and both lower and higher cutoffs have been proposed. The morphological solid growth pattern (SGP) in SI-NET has been reported to be associated with worse survival. The present study investigates whether a Ki-67 index cutoff of 1% has a higher predictive power than one of 2% for disease-specific survival in SI-NET, and whether an SGP is associated with survival.Patients and methods: From a population-based cohort, 127 SI-NET patients with available tumor specimens were included. Medical records and pathology reports were reviewed. Tumor specimens were reexamined to confirm the diagnosis, recalculate the Ki-67 index, and assess the presence of an SGP, introducing an SGP score from 0 to 3+.Results: The current grading system with a G1/G2 cutoff of 2% was more discriminative (HR 2.30; 95% CI 1.20-4.38, p = 0.012) than one with a lower cutoff of 1% (HR 1.65; 95% CI 0.95-2.87, p = 0.078) after adjustment for patient age and clinical stage. SGP score was strongly associated with clinical stage (p = 0.004) and histopathological grade (p < 0.001) but was not an independent prognostic factor for disease-specific survival in SI-NET (p = 0.122) after adjusting for age, stage, and grade.Conclusions: The present grading system of SI-NET is supported by our results. The SGP is not an independent prognostic factor for disease-specific survival in SI-NET.
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| 17. |
- Landerholm, Kalle, et al.
(författare)
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Survival and prognostic factors in patients with small bowel carcinoid tumour
- 2011
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Ingår i: British Journal of Surgery. - : Wiley-Blackwell. - 0007-1323 .- 1365-2168. ; 98:11, s. 1617-1624
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous studies of small bowel carcinoid tumours usually presented overall or relative survival. This study, in addition, evaluated disease-specific survival in a cohort of patients in a geographically defined population.METHODS: Patients diagnosed with carcinoid of the jejunum or ileum in Jönköping County between 1960 and 2005 were eligible for inclusion. Available tumour specimens were re-examined to confirm the diagnosis. Medical records and pathology reports were reviewed in detail.RESULTS: A total of 145 patients were included in the study. One hundred and thirty-five patients underwent surgery in connection with the diagnosis. Resection was considered complete (R0) in 74 patients (54·8 per cent). Only two localized tumours recurred, whereas no patient with distant metastases was cured. Patients with regional metastases who underwent R0 resection had a better survival than patients with incomplete resection (P = 0·005), and a majority of patients remained recurrence-free. Median overall survival was 7·2 years and median disease-specific survival 12·3 years. In multivariable analysis, age 61-74 years (hazard ratio (HR) 3·78, 95 per cent confidence interval 1·86 to 7·68), age 75 years or more (HR 3·96, 1·79 to 8·74), distant metastases (HR 14·44, 1·59 to 131·36) and incomplete tumour resection (HR 2·71, 1·11 to 6·61) were associated with worse disease-specific survival. Later time period of diagnosis (HR 0·45, 0·24 to 0·84) was associated with better disease-specific survival.CONCLUSION: Age, disease stage and complete resection were identified as independent prognostic factors for survival in patients with small bowel carcinoid tumours. The importance of achieving R0 resection is therefore emphasized.
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| 18. |
- Leckström, Arnold
(författare)
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Islet amyloid polypeptide : Perspectives on the storage and plasma concentration of islet amyloid polypeptide (IAPP) in rodent models of obesity and non-insulin-dependent diabetes mellitus and aspects of amyloidogenesis andelimination of IAPP
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study was aimed to investigate plasma concentrations and pancreatic storage of IAPP in relation to that of insulin in four different animal models with hyperglycemia, hyperinsulinemia, obesity and/or NIDDM. The NMRI mice fed a high-fat diet for six months, the Psammomys on high-energy (HE) diet and the genetically obese (ob/ob) mice studied for one year all revealed significantly elevated plasma IAPP concentrations, while the IAPP levels were unchanged in the spontaneously diabetic GK rats during a glucose tolerance test.In the NMRI mice the fasting plasma glucose and insulin concentrations had also increased, suggesting a possible development of insulin resistance. The increase in plasma IAPP concentrations was even greater than that of insulin, which was reflected in an increased plasma IAPP/insulin molar ratio.The Psammomys developed obesity, hyperinsulinemia and hyperglycemia in response to the HE diet. The plasma IAPP concentration was also elevated, but changed in parallel with that of insulin. After vanadyl sulphate treatment the glucose and insulin concentrations were normalized, while IAPP remained elevated.The OK rats showed significantly decreased plasma concentrations of IAPP and insulin during the glucose tolerance test. The insulin response to the glucose load was even lower than that of IAPP, resulting in a modest elevation of the plasma IAPP/insulin ratio. The elevated IAPP/insulin ratios in these three animal models might reflect a negative feedback effect of IAPP on insulin release.In the ob/ob mice the plasma glucose concentration was initially greatly elevated, but had by the end of study returned to almost normal, presumbly due to the tremendous increase in hyperinsulinemia. The plasma IAPP concentration reached extremely high levels, which however was relatively low to that of insulin, resulting in a sudden significant decrease in the plasma IAPP/insulin ratio at 21 weeks of age, possibly indicating a deficiency in the negative feedback effect of IAPP on insulin secretion.IAPP-immunoreactivity was detected in the morning urine of healthy human volunteers and was by reverse phase HPLC-analysis confirmed to be identical to full-length IAPP. This finding gives strong support to the previous suggestions that IAPP is eliminated by the kidneys, why slight disturbances in plasma TAPP/insulin ratios in dynamic situations (as e.g. in the GK rat) should be carefully interpreted.
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| 19. |
- Ma, Zuheng, et al.
(författare)
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Evidence for Presence and Functional Effects of Kv1.1 Channels in beta-Cells: General Survey and Results from mceph/mceph Mice
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Voltage-dependent K+ channels (Kv) mediate repolarisation of beta-cell action potentials, and thereby abrogate insulin secretion. The role of the Kv1.1 K+ channel in this process is however unclear. We tested for presence of Kv1.1 in different species and tested for a functional role of Kv1.1 by assessing pancreatic islet function in BALB/cByJ (wild-type) and megencephaly (mceph/mceph) mice, the latter having a deletion in the Kv1.1 gene. Methodology/Principal Findings: Kv1.1 expression was detected in islets from wild-type mice, SD rats and humans, and expression of truncated Kv1.1 was detected in mceph/mceph islets. Full-length Kv1.1 protein was present in islets from wildtype mice, but, as expected, not in those from mceph/mceph mice. Kv1.1 expression was localized to the beta-cell population and also to alpha-and delta-cells, with evidence of over-expression of truncated Kv1.1 in mceph/mceph islets. Blood glucose, insulin content, and islet morphology were normal in mceph/mceph mice, but glucose-induced insulin release from batch-incubated islets was (moderately) higher than that from wild-type islets. Reciprocal blocking of Kv1.1 by dendrotoxin-K increased insulin secretion from wild-type but not mceph/mceph islets. Glucose-induced action potential duration, as well as firing frequency, was increased in mceph/mceph mouse beta-cells. This duration effect on action potential in beta-cells from mceph/mceph mice was mimicked by dendrotoxin-K in beta-cells from wild-type mice. Observations concerning the effects of both the mceph mutation, and of dendrotoxin-K, on glucose-induced insulin release were confirmed in pancreatic islets from Kv1.1 null mice. Conclusion/Significance: Kv1.1 channels are expressed in the beta-cells of several species, and these channels can influence glucose-stimulated insulin release.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Tsolakis, Apostolos V., et al.
(författare)
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Ghrelin Immunoreactive Cells in Gastric Endocrine Tumors and Their Relation to Plasma Ghrelin Concentration : Ghrelin in Gastric Endocrine Tumors
- 2008
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Ingår i: Journal of Clinical Gastroenterology. - 0192-0790 .- 1539-2031. ; 42:4, s. 381-388
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Tidskriftsartikel (refereegranskat)abstract
- GOALS: Our aim was to elucidate the incidence and distribution pattern of ghrelin-immunoreactive (IR) cells in various types of human gastric endocrine tumors, and their surrounding mucosa, and relate the findings to total ghrelin concentrations in plasma. BACKGROUND: It has been demonstrated previously, that ghrelin-IR cells are present not only in normal human gastric oxyntic mucosa, but also in all types of enterochromaffinlike (ECL) cell carcinoids (ECL-CCs), and in mucosal regions affected by ECL cell hyperplasia. STUDY: Forty-eight gastric endocrine tumors were included in the study: 32 type I ECL-CCs, 3 type II, 9 type III, 1 non-ECL-CC, and 3 poorly differentiated endocrine carcinomas. The tumors were analyzed immunohistochemically with antibodies raised versus chromogranin A, synaptophysin, serotonin, somatostatin, vesicular monoamine transporter 2 and ghrelin. Total ghrelin in plasma was measured in 20 patients, using a commercial radioimmunoassay kit. RESULTS: Ghrelin-IR cells were found in all types I and II ECL-CCs but in only a few cases of the other tumors. Ghrelin-IR cells were also found among the hyperplastic endocrine cells in the mucosa surrounding types I and II, where they showed diffuse, linear, nodular and adenomatoid hyperplasia patterns. In type III ECL-CCs and poorly differentiated endocrine carcinomas, only diffuse and linear ghrelin-IR cell hyperplasia was present in the oxyntic mucosa in about half of the cases, whereas the mucosa of the non-ECL-CC did not show this feature. CONCLUSIONS: Despite the frequent occurrence of ghrelin-IR cells in both the neoplastic parenchyma and the oxyntic mucosa, plasma total ghrelin concentrations remained within the reference range and can therefore not be used as a clinical marker to identify ghrelin expressing ECL-CCs or ghrelin cell hyperplasia.
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| 24. |
- Tsolakis, Apostolos V., et al.
(författare)
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Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours
- 2015
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 21:47, s. 13240-13249
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Tidskriftsartikel (refereegranskat)abstract
- AIM:To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite.METHODS:Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients.RESULTS:In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms.CONCLUSION:Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.
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| 25. |
- Tsolakis, Apostolos V., et al.
(författare)
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Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach
- 2009
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 160:6, s. 941-949
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Obestatin and ghrelin are derived from the same gene and co-expressed in the same endocrine cells. Vesicular monoamine transporter-2 (VMAT-2), a marker for enterochromaffin-like (ECL) cells, is considered to be expressed in ghrelin cells. The aim was to establish if the two peptides and the transporter are co-expressed, both in normal gastric mucosa and in gastric endocrine tumours.Design: An immunohistochemical study was performed on gastric biopsy material and on surgical specimens from 63 patients with gastric endocrine tumours and from individuals with normal gastric mucosa. Cells displaying obestatin immunoreactivity were examined regarding co-localization with ghrelin and VMAT-2. Both single- and double-immunostaining techniques were applied. Obestatin concentration in blood was measured in a subgroup of these patients. The results were correlated to various clinico-pathological parameters.Results:In the normal mucosa, obestatin/ghrelin-immunoreactive cells rarely co-expressed VMAT-2. In most tumour tissue specimens, only a fraction of neoplastic cells displayed immunoreactivity to obestatin, and these cells always co-expressed ghrelin. Neoplastic obestatin-/ ghrelin-IR cells invariably expressed VMAT-2, except for two ghrelinomas. The obestatin concentrations in blood were consistently low and did not correlate to clinico-pathological data.Conclusions:Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. These results indicate that endocrine cells expressing obestatin and ghrelin mainly differ from VMAT-2 expressing cells (ECL-cells) and can develop into pure ghrelinomas. Plasma concentrations of obestatin did not correlate to cellular expression.
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| 26. |
- Westermark, Gunilla, 1958-, et al.
(författare)
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Islet amyloid polypeptide is expressed in the pancreatic islet parenchyma of the teleostean fish, Myoxocephalus (cottus) scorpius
- 2002
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Ingår i: Comparative Biochemistry and Physiology - Part B. - 1096-4959 .- 1879-1107. ; 133, s. 119-
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Tidskriftsartikel (refereegranskat)abstract
- The comparative endocrinology of the 37-amino-acid-residue islet amyloid polypeptide (IAPP) is poorly known, possibly due to the fact that available antisera, raised against mammalian IAPP, fail to give immunoreactivity with islet parenchymal cells of non-mammalian vertebrates. Using reverse transcriptase-linked polymerase chain reaction with degenerate primers, IAPP was identified, and its deduced amino-acid sequence partially characterized, in three species of teleostean fish, i.e. Danio rerio (zebrafish), Salmo salar (Atlantic salmon), and Myoxocephalus (cottus) scorpius (daddy sculpin). The daddy sculpin is a species where the histophysiology of the pancreatic islet parenchyma has previously been comprehensively studied. From the deduced amino-acid sequence, a synthetic peptide, corresponding to positions 20-29 of Salmo IAPP, was synthesized. A mouse antiserum to this peptide gave a distinct immunoreactivity with the insulin-producing beta cells of the sculpin Brockmann bodies and salmon endocrine pancreas. Thus, IAPP belongs to the group of peptide hormones expressed by the islet parenchymal cells in both mammals and non-mammalian vertebrates. Salmo salar IAPP(20-29) was found to give rise to amyloid-like fibrils in vitro.
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