694 research outputs found
Takayasu's arteritis: A rare cause of cardiac death in a Caucasian teenage female patient
A Caucasian teenage Dutch schoolgirl with known chronic low visual acuity and albinism, presented with frank acute pulmonary oedema, died after 1 h of cardio-pulmonary resuscitation for bradyarrhythmia and cardiac arrest. Two weeks prior to presentation, during sport training, she complained of oppressive chest pain on exertion accompanied with vomiting without any other systemic symptoms. Post-mortem examination revealed supravalvular stenosis of the pulmonary trunk and ascending aorta with irregular intimal thickening associated with stenosis of the left coronary artery. Microscopic examination demonstrated cellular infiltration of the wall of the aorta and pulmonary trun
Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide
Recently, we developed a technique that allows the in vivo visualization
in man of somatostatin receptor-positive neuroendocrine tumors after i.v.
injection of [125I-Tyr3]octreotide or [111In-DTPA-D-Phe1]octreotide.
Radiotherapy of such tumors using somatostatin analogs coupled to alpha-
or beta-emitting radionuclides has been proposed as an application for
radiolabeled somatostatin analogs. To develop this concept further, it is
of importance to know whether the above-mentioned radiolabeled
somatostatin analogs are internalized by the tumor cells, and whether it
might be possible to manipulate the degree of internalization. In the
present study we investigated the internalization of a stable somatostatin
analog, [125I-Tyr3]octreotide, by mouse AtT20/D16V pituitary tumor cells
and primary cultures of human GH-secreting pituitary tumor cells.
Treatment of the cells with low pH was used to distinguish between
membrane-bound (acid-releasable) and internalize (acid-resistant)
radioligand. [125I-Tyr3]octreotide showed a time-dependent increasing
accumulation in AtT20 cells; after 4 h of incubation, values up to 6-8% of
the dose of radioligand added were obtained. Binding and internalization
of [125I-Tyr3]octreotide were temperature dependent and inhibited by
pertussis toxin. Inhibitors of lysosomal degradation did not increase the
amount of internalized radioligand. After 4 h of incubation, 88% of the
radioactivity present in the cells was still peptide bound, suggesting a
low intracellular breakdown of this radioligand. Six of seven human
GH-secreting adenoma cell cultures also internalized [125I-Tyr3]octreotide
(variation between 0.24-4.98% of the dose radioligand added). Displacement
of binding and internalization of [125I-Tyr3]octreotide by unlabeled
octreotide showed a bell-shaped curve in AtT20 cells. At low
concentrations (0.1 and 1 nM), binding and internalization were increased,
whereas at higher concentrations, saturation occurred. In contrast to
this, binding of [125I-Tyr3]octreotide to a broken cell preparation of
AtT20 cells was displaced in a dose-dependent manner by unlabeled
octreotide, with an IC50 of 0.1 nM. Similar observations were made in the
human GH-secreting adenoma cell cultures. In conclusion, a high amount of
[125I-Tyr3]octreotide is internalized in a specific-, time-, temperature-,
and pertussis toxin-sensitive GTP-binding protein-dependent manner by
mouse AtT20 and human GH-secreting pituitary tumor cells. In the presence
of a low concentration of unlabeled octreotide, a rapid increase in the
amount of [125I-Tyr3]octreotide internalized by AtT20 cells and by the
majority of the human GH-secreting adenoma cell cultures was
found.(ABSTRACT TRUNCATED AT 400 WORDS
Pro-inflammatory cytokines affect pancreatic carcinoma cell. Endothelial cell interactions
OBJECTIVES: The potential role of surgery-induced pro-inflammatory\n cytokines on the development of tumor recurrence in pancreatic cancer was\n investigated. MAIN OUTCOME MEASURES: The adhesion of 3 human pancreatic\n carcinoma cell lines, PanC1, MiaPaCa and BxPC3 to monolayers of\n microvascular endothelial cells after pre-incubation with 0.1 or 10 ng/mL\n IL-1beta, TNF-alpha or IL-6 was assessed in a reproducible human in vitro\n assay. Untreated monolayers served as controls. RESULTS: Pre-incubation of\n microvascular endothelial cells with IL-1beta or TNF-alpha, but not IL-6,\n increased adhesion of all three tumor cell lines as compared to adhesion\n in the control group. Maximally stimulated adhesion for PanC1 reached\n 159%, for MiaPaCa 204% and for BxPC3 155% (all vs. the control, P<0.001).\n Pre-incubation of microvascular endothelial cells with IL-1beta or\n TNF-alpha resulted in a significant up-regulation of E-selectin, ICAM-1\n and VCAM-1 expression. The addition of anti-E-selectin, anti-ICAM-1 or\n anti-VCAM-1 monoclonal antibodies did not decrease adhesion to\n microvascular endothelial cells pre-incubated with IL-1beta. Therefore,\n enhanced tumor cell binding seems to be independent of these adhesion\n molecules. CONCLUSIONS: Pro-inflammatory cytokines derived from surgical\n trauma may enhance tumor cell adhesion to microvascular endothelial cells\n and thus bring about more successful tumor cell implantation resulting in\n an increased risk of metastasis formation
Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature
Rationale: When compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. Methods: Fecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. Results: 87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p < 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. Conclusion: Midgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.</p
Interferon-alpha-2a is a potent inhibitor of hormone secretion by cultured human pituitary adenomas
Interferon-alpha (IFN alpha) may exert direct inhibitory effects on cell
proliferation and on the production of different peptide hormones. We
investigated the effect of IFN alpha on hormone production by 15
GH-secreting pituitary adenomas, 4 clinically nonfunctioning or
gonadotroph pituitary adenomas, and 4 prolactinomas in vitro. In the
GH-secreting pituitary adenoma cultures, a short term (72-h) incubation
with IFN alpha (50-100 U/mL) significantly inhibited GH secretion in 3 of
7 cases and PRL secretion in 6 of 7 cultures. During prolonged incubation
(14 days) with IFN alpha, GH and/or PRL secretion was significantly
inhibited in 7 of 8 cultures (GH, 17-78% inhibition; PRL, 39-88%
inhibition). In the clinically nonfunctioning or gonadotroph cultures
Applying HDACis to increase SSTR2 expression and radiolabeled DOTA-TATE uptake:from cells to mice
Aims: The aim of our study was to determine the effect of histone deacetylase (HDAC) inhibitors (HDACis) on somatostatin type-2 receptor (SSTR2) expression and [111In]In-/[177Lu]Lu-DOTA-TATE uptake in vitro and in vivo. Materials and methods: The human cell lines NCI-H69 (small-cell lung carcinoma) and BON-1 (pancreatic neuroendocrine tumor) were treated with HDACis (i.e. entinostat, mocetinostat (MOC), LMK-235, CI-994 or panobinostat (PAN)), and SSTR2 mRNA expression levels and [111In]In-DOTA-TATE uptake were measured. Furthermore, vehicle- and HDACi-treated NCI-H69 and BON-1 tumor-bearing mice were injected with radiolabeled DOTA-TATE followed by biodistribution studies. Additionally, SSTR2 and HDAC mRNA expression of xenografts, and of NCI-H69, BON-1, NCI-H727 (human pulmonary carcinoid) and GOT1 (human midgut neuroendocrine tumor) cells were determined. Key findings: HDACi treatment resulted in the desired effects in vitro. However, no significant increase in tumoral DOTA-TATE uptake was observed after HDACi treatment in NCI-H69 tumor-bearing animals, whereas tumoral SSTR2 mRNA and/or protein expression levels were significantly upregulated after treatment with MOC, CI-994 and PAN, i.e. a maximum of 2.1- and 1.3-fold, respectively. Analysis of PAN-treated BON-1 xenografts solely demonstrated increased SSTR2 mRNA expression levels. Comparison of HDACs and SSTR2 expression in BON-1 and NCI-H69 xenografts showed a significantly higher expression of 6/11 HDACs in BON-1 xenografts. Of these HDACs, a significant inverse correlation was found between HDAC3 and SSTR2 expression (Pearson r = −0.92) in the studied cell lines. Significance: To conclude, tumoral uptake levels of radiolabeled DOTA-TATE were not enhanced after HDACi treatment in vivo, but, depending on the applied inhibitor, increased SSTR2 expression levels were observed.</p
Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors
Although in situ hybridization has been used to examine the distribution
of messenger RNA for somatostatin receptor subtypes (sst) in human tumors,
the cellular localization of sst1 and sst2A receptors has not been
reported. In this study, we describe the cellular localization of human
sst1 and sst2A receptor proteins in both cryostat- and paraffin-embedded
sections of 25 human tumor tissues using two recently developed polyclonal
antibodies. Six somatostatin (SS) receptor (SSR) positive tumors (two
gastrinomas, three carcinoids, one pheochromocytoma) and one SSR negative
tumor (renal cell carcinoma), selected by positive and negative SSR
autoradiography, respectively, were studied by both immunohistochemistry
and Western blot analysis. The six SSR positive tumors expressed sst2A,
while 4 of 5 expressed sst1 as well. The SSR negative tumor did not
express either sst1 or sst2A. Western blot analysis of wheat germ
agglutinin purified membrane proteins confirmed the presence of the sst1
and sst2A glycosylated receptors. The paraffin-embedded sections gave best
information with respect to the subcellular localization. Sst1
immunoreactivity was observed both on the membrane and in the cytoplasm,
while sst2A showed predominantly membrane-associated immunoreactivity.
This subcellular distribution of sst1 or sst2A receptors was confirmed in
paraffin-embedded sections of 8 additional intestinal carcinoids, 5
gastrinomas and 5 pheochromocytomas. Sst1 receptors were detected in 7 out
of 8 carcinoids, in all gastrinomas, and in 4 out of 5 pheochromocytomas,
while 6 out of 8 carcinoids, all gastrinomas, and 3 out of 5
pheochromocytomas expressed sst2A receptors. In conclusion, sst1 and sst2A
receptors show a differential subcellular localization in human SSR
positive tumors. The use of SSR subtype selective antibodies to detect the
subcellular distribution of SSR subtypes in individual tumor cells is an
important step forward to understand more about the pathophysiological
role of the different SSR subtypes in human tumors
Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system
Cells of the human immune system have been shown to express somatostatin
receptors (sst). The expression of sst suggests a functional role of the
peptide somatostatin (SS). However, SS expression has not been
demonstrated yet in different human immune tissues. Therefore, we
investigated by RT-PCR the expression of both SS and cortistatin (CST), a
SS-like peptide, in various human lymphoid tissues and immune cells. We
detected SS mRNA expression in the human thymus only, while not in
thymocytes. CST mRNA was clearly expressed in the immune cells, lymphoid
tissues, and bone marrow. Using quantitative RT-PCR, significant
differences in expression levels between tissues were demonstrated.
Expression of CST mRNA was up-regulated during differentiation of
monocytes into macrophages and dendritic cells and could be up-regulated
by lipopolysaccharide stimulation. Two differently sized cDNA fragments of
CST were detected in the majority of cells and tissues. However, although
both fragments were detected in nearly all T-cell lines (7 of 8), most of
the B-cell lines expressed the short fragment only (8 of 10). Usin
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