| 1. |
- Carpten, JD, et al.
(författare)
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HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome
- 2002
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 32:4, s. 676-680
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Tidskriftsartikel (refereegranskat)abstract
- We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
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| 2. |
- Chen, D, et al.
(författare)
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Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice
- 2004
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 126:2, s. 476-487
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Three pathways control gastric acid secretion: the gastrin-enterochromaffin-like (ECL) cell axis, the vagus-parietal cell axis, and the cholecystokinin (CCK)-D cell axis. Mice lacking gastrin or both gastrin and CCK were examined to determine the role of the hormones. Methods: Acid was measured after pylorus ligation, and biopsies from gastrin knockout (KO), gastrin-CCK double-KO, and wild-type (WT) mice were collected for biochemical, immunocytochemical, and electron-microscopic examination. Results: The ECL cells were inactive in both groups of mutant mice but the cell number was unaffected. Both parietal cell number and level of H+/K+-ATPase messenger RNA (mRNA) were reduced in the mutant strains, but gastrin-CCK double-KO mice displayed more active parietal cells and larger acid output than the gastrin KO mice. The acid response to histamine in double-KO mice was unchanged whereas that to gastrin was diminished, but it could be restored by infusion of gastrin. Oxyntic D-cell density was the same in both mutant strains, but the D cells were more active in the gastrin KO than in the double-KO mice. CCK infusion in gastrin-CCK double-KO mice raised the somatostatin mRNA level and inhibited acid secretion to the level seen in gastrin KO mice. Vagotomy and atropine abolished acid secretion in all 3 groups of mice. Conclusions: Lack of gastrin impairs the gastrin-ECL axis, whereas lack of gastrin and CCK impairs both hormonal pathways. In the gastrin-CCK double-KO mice, acid secretion is only controlled by cholinergic vagal stimulation, which normalizes the acid output.
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| 3. |
- Chen, DA, et al.
(författare)
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Differentiation of gastric ECL cells is altered in CCK2 receptor-deficient mice
- 2002
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 123:2, s. 577-585
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Gastrin stimulation of the type 2 cholecystokinin (CCK2) receptor results in ECL cell proliferation and histamine secretion. This report describes the effects of targeted disruption of the CCK2 receptor gene on ECL cell morphology and function. Methods: The ECL cells in the oxyntic mucosa of CCK2 receptor-deficient (knockout [KO]) vs. wild-type (WT) mice were investigated by immunocytochemical and biochemical approaches, as well as by electron microscopy. Results: Immunocytochemistry demonstrates similar numbers (cells per millimeter of horizontal length of mucosa) of pancreastatin- or vesicle monoamine transporter-2 (VMAT-2)-immunoreactive cells in WT mice and KO mice. However, only WT mice harbor histamine-immunoreactive ECL cells. The mucosal histamine content in KO mice (likely originating from mast cells) is only a minute fraction of that present in WT animals. The activity of the histamine forming enzyme, histidine decarboxylase (a marker of ECL cells), was undetectable in the oxyntic mucosa of KO mice yet was readily apparent in the mucosa from WT animals. Electron microscopy revealed numerous ECL cells in WT mice. In KO animals, these cells were replaced by an "ECL-like" cell type, characterized by a lack of secretory vesicles (a hallmark feature of normal ECL cells) and the presence of dense-core granules and microvesicles in numbers comparable to those found in WT ECL cells. Based on ultrastructural features, the ECL-like cells in KO mice can be readily distinguished from other gastric endocrine cells, including A-like cells and D cells. Conclusions: Absence of a single gene product, the CCK2 receptor, alters the differentiation and function of gastric ECL cells.
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| 4. |
- Chen, D, et al.
(författare)
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Gastric phenotypic abnormality in cholecystokinin 2 receptor null mice
- 2002
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Ingår i: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 91:6, s. 375-381
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Tidskriftsartikel (refereegranskat)abstract
- Gastrin, released from antral G-cells, plays an important role in the regulation of gastric acid secretion and is trophic for the stomach, The cholecystokinin type 2 (CCK)(2) receptor (previously referred to as CCK-B/gastrin receptors) is expressed in both parietal cells and ECL cells in the oxyntic mucosa of stomach. Gastric phenotypic abnormality has been observed in CCK2 receptor null (gene knock-out) mice. Such mice displayed markedly impaired gastric acid secretion, atrophy of the oxyntic mucosa and hypergastrinaemia. The impaired acid secretion may be the result of a reduced parietal cell mass, a reduced proportion of actively secreting parietal cells (with secretory canaliculi), and a replacement of ECL cells by histamine-free ECL-like cells. The ECL-like cells, observed in the CCK2 receptor null mice, lacked the hallmark features of wild-type ECL cells, i.e. histamine and cytoplasmic secretory vesicles. However, they had the features of endocrine cells, such as the content of pancreastatin (a fragment of chromogranin A), with cytoplasmic small dense-core granules and microvesicles. We propose that the replacement of ECL cells by ECL-like cells in the mutant mice reflects an altered differentiation of the same precursors that develop into ECL cells in wild-type mice. Thus, studies of CCK2 receptor null mice demonstrate the importance of the receptor in the regulation of gastric acid secretion and in the differentiation of ECL cells in the oxyntic mucosa of stomach.
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| 5. |
- Chen, W, et al.
(författare)
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Structure, luminescence, and dynamics of Eu2O3 nanoparticles in MCM-41
- 2002
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 106:28, s. 7034-7041
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Tidskriftsartikel (refereegranskat)abstract
- The structure, luminescence spectroscopy, and lifetime decay dynamics of Eu2O3 nanoparticles formed in MCM-41 have been investigated. Both X-ray diffraction and high-resolution transmission electron microscopic observations indicate that Eu2O3 nanoparticles of monoclinic structure are formed inside channels of MCM-41 by heating at 140 degreesC. However, heat treatment at 600 or 700 degreesC causes migration of Eu2O3 from the MCM-41 channels, forming nanoparticles of cubic structure outside the MCM-41 channels. After heating to 900 degreesC, some of the cubic Eu2O3 particles change to monoclinic Eu2O3, and the MCM-41 structure breaks down and a different or disordered phase is formed. The feature of the hypersensitive D-5(0) --> F-7(2) emission profile of Eu3+ is used to follow the structural changes. In the luminescence spectrum of the sample prepared at 140 degreesC, the emission spectrum is dominated by peaks at 615 and 623 nm, while in the other samples a peak at 612 nm is prevalent. Photoluminescence lifetimes show the existence of short (<1 mus) and long (microsecond to millisecond) components for each sample. The fast decay is attributed to quenching by surface states of the nanoparticles or energy transfer to the MCM-41, while the longer time decays show the effects of concentration quenching. The monoclinic sample prepared at 140 degreesC shows a higher luminescence intensity than the cubic samples or the bulk powder. These observations indicate that MCM-41 as a template can be used for making and stabilizing monoclinic rare earth oxides, which normally are stable only at high temperatures and high pressures. More importantly, the nanophase Eu2O3/MCM-41 composite materials formed at low temperatures might represent a new type of efficient luminescence material with fast response, with potential applications in lighting and displays.
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| 6. |
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| 7. |
- Zhao, CM, et al.
(författare)
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Chronic Helicobacter pylori infection results in gastric hypoacidity and hypergastrinemia in wild-type mice but vagally induced hypersecretion in gastrin-deficient mice
- 2003
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Ingår i: Regulatory Peptides. - 1873-1686. ; 115:3, s. 161-170
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori infection is a causal factor of gastric cancer (which is associated with low gastric acid secretion) or duodenal ulcer (high acid secretion). Parietal cells and ECL cells in the stomach are controlled by gastrin, which plays a crucial role in the regulation of acid secretion. The present study was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells to chronic H. pylori infection. Wild-type (C57BL/6J) gastrin(+/+) mice and gastrin(-/-) knockout mice, generated through targeted gene disruption and backcrossed eight times to C57BL/6J, were infected with H. pylori for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to alpha-subunit of H+/K+-ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. In infected gastrin(+/+) mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20-30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin(-/-) mice had lower the acid output than uninfected gastrin(+/+) mice, there was a higher acid output (similar to 3 times) in infected gastrin(-/-) mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin(-/-) mice. In conclusion, chronic H. pylori infection results to impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but leads to vagally induced hypersecretion in gastrin-deficient mice. (C) 2003 Elsevier B.V All rights reserved.
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| 8. |
- Zhao, CM, et al.
(författare)
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Histamine and histidine decarboxylase are hallmark features of ECL cells but not G cells in rat stomach
- 2004
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 118:1-2, s. 61-66
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Tidskriftsartikel (refereegranskat)abstract
- The oxyntic mucosa of the rat stomach is rich in ECL cells which produce and secrete histamine in response to gastrin. Histamine and the histamine-forming enzyme histidine decarboxylase (HDC) have been claimed to occur also in the gastrin-secreting G cells in the antrum. In the present study, we used a panel of five HDC antisera and one histamine antiserum to investigate whether histamine and HDC are exclusive to the ECL cells. By immunocytochemistry, we could show that the ECL cells were stained with the histamine antiserum and all five HDC antisera. The G cells, however, were not stained with the histamine antiserum, but with three of the five HDC antisera. Thus, histamine and HDC coexist in the ECL cells (oxymic mucosa) but not in G cells (antral mucosa). Western blot analysis revealed a typical pattern of HDC-immunoreactive bands (74, 63 and 54 kDa) in oxymic mucosa extracts with all five antisera. In antral extracts, immunoreactive bands were detected with three of the five HDC antisera (same as above); the pattern of immunoreactivity differed from that in oxymic mucosa. Food intake or treatment with the proton pump inhibitor omeprazole raised the HDC activity and the HDC protein content of the oxyntic mucosa but not of the antral mucosa; the HDC activity in the antrum was barely detectable. We suggest that the HDC-like immunoreactivity in the antrum represents a cross-reaction with non-HDC proteins and conclude that histamine and HDC are hallmark features of ECL cells but not of G cells. (C) 2003 Elsevier B.V. All rights reserved.
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| 9. |
- Zhao, CM, et al.
(författare)
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Rat stomach ECL cells: mode of activation of histidine decarboxylase
- 2003
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Ingår i: Regulatory Peptides. - 1873-1686. ; 114:1, s. 21-27
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Tidskriftsartikel (refereegranskat)abstract
- Histidine decarboxylase (HDC) occurs in ECL cells in the oxyntic mucosa of rat stomach. It is activated by gastrin. Refeeding of fasted rats or treatment with the proton pump inhibitor omeprazole promptly raised the serum gastrin concentration and consequently the HDC activity and the HDC protein content of the oxyntic mucosa. The food- and omeprazole-induced increase in HDC mRNA expression in the oxyntic mucosa was modest by comparison. Blockade of translation (cycloheximide) but not transcription (actinomycin D) prevented the postprandial rise in HDC activity. The half-life of HDC activity (after blockade of translation) was 94 min in omeprazole-treated rats and 55 min in fasted controls. The rate of enzyme synthesis was estimated to be 15 times higher in omeprazole-treated rats than in fasted controls. Inhibition of histamine uptake into ECL-cell granules by reserpine, a blocker of the vesicular monoamine transporter type-2, lowered the HDC activity and prevented the gastrin-induced HDC activation. We suggest that HDC activation reflects enhanced transcription, translation and/or posttranslational enzyme activation as well as stabilization, and that a high cytosolic histamine concentration suppresses HDC activation. (C) 2003 Elsevier Science B.V. All rights reserved.
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