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Biomedical subjects

G Nilsson

Publications and source records attributed to G Nilsson.

At least 19 recordsLinked to original sources
PubMed2000

Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53: functional impact.

We investigated the functional impact of p53 on insulin-like growth factor I receptor (IGF-IR) expression in malignant cells. Using the BL-41tsp53-2 cell line, a transfectant carrying temperature-sensitive (ts) p53 and endogenous mutant p53 (codon 248), we demonstrated a drastic down-regulation of plasma membrane-bound IGF-IRs on induction of wild-type p53. However, a similar response was obtained by treatment of BL-41tsp53-2 cells expressing mutant ts p53 with a p53 antisense oligonucleotide. Thus, even if the negative effect of wild-type p53 predominates under a competitive condition, these data indicate that mutant p53 may be important for up-regulation of IGF-IR. To further elucidate this issue, three melanoma cell lines (BE, SK-MEL-5, and SK-MEL-28) that overexpressed p53 were investigated. The BE cell line has a "hot spot" mutation (codon 248) and expresses only codon 248-mutant p53. SK-MEL-28 has a point mutation at codon 145. SK-MEL-5 cells did not exhibit any p53 mutations, but the absence of p21Waf1 expression suggested functionally aberrant p53. Our data suggest that interaction with Mdm-2 may underlie p53 inactivation in these cells. Using p53 antisense oligonucleotides, we demonstrated a substantial down-regulation of cell surface expression of IGF-IR proteins in all melanoma cell lines after 24 h. This was paralleled by decreased tyrosine phosphorylation of IGF-IR and growth arrest, and, subsequently, massive cell death was observed (this was also seen in BL-41tsp53-2 cells with mutant conformation of ts p53). Taken together, our results suggest that up-regulation of IGF-IR as a result of expression of aberrant p53 may be important for the growth and survival of malignant cells.

Acetylcysteine↗
PubMed2000

Tamoxifen-induced cell death in malignant melanoma cells: possible involvement of the insulin-like growth factor-1 (IGF-1) pathway.

Recent data indicate that the estrogen receptor (ER) blocker tamoxifen (TAM) can induce cell death in malignant melanoma cells. However, as shown in the present study and several other studies melanoma cells usually do not express classical ERs. In the present study we investigated whether the cytotoxic effect of TAM on melanoma cells could depend on interference with the expression or function of the insulin-like growth factor-1 receptor (IGF-1R), a plasma membrane receptor important for cell survival in this tumor cell type. Several melanoma cell lines were included in the analysis. Administration of TAM at a concentration of 15 microm or more resulted in cell death of the melanoma cells within 48 h. TAM treatment was correlated to a slight to moderate inhibition of IGF-1 binding to IGF-1R. Since it has been reported that TAM can increase the release of IGF binding proteins (IGFBPs) we then investigated whether this mechanism could underly the decreased IGF-1 binding. However, we could demonstrate that the amount of released IGFBPs were unchanged or decreased in TAM-treated cells. Whereas TAM did not have any strong effect on IGF-1 binding and the expression of IGF-1R at the cell surface, it was was found to efficently block tyrosine phosphorylation of IGF-1R beta-subunit. Taken together, our data suggest that TAM-induced cytotoxicity of malignant melanoma cells can be due to inactivation of IGF-1R.

Antineoplastic Agents, Hormonal↗
PubMed2000

Human mast cell migration in response to members of the transforming growth factor-beta family.

Mast cells are known to accumulate at sites of inflammation, however, the chemotaxins involved remain largely undefined. Transforming growth factor-beta (TGF-beta) isoforms regulate numerous cellular functions, including cell growth and differentiation, formation of extracellular matrix, and the immune response. In this study we have compared the potency of different members of the TGF-beta family as human mast cell chemotaxins, and analyzed the expression of TGF-beta binding proteins on human mast cells. We were able to demonstrate that the maximal chemotactic response was attained at approximately 40 fM for the three TGF-beta isoforms, with TGF-beta3 being more effective than TGF-beta1 and TGF-beta2 at this concentration. This effect was observed in both the HMC-1 human mast cell line and in cultured primary mast cells. In addition, TGF-beta1, TGF-beta2, and less efficiently, TGF-beta3 inhibited the proliferation of HMC-1 cells. The migratory response is probably mediated through interaction with the TGF-beta serine/threonine type I and II receptors that were found to be expressed on the cells. No expression of TGF-beta type III receptor, endoglin, or the endothelial TGF-beta type I receptor ALK-1 could be detected. These results provide evidence that TGF-beta isoforms are highly potent chemotaxins for human mast cells and can play an important role in the recruitment of mast cells in inflammatory reactions.

Activin Receptors, Type I↗
PubMed2000

Effects of cholecystokinin on acid formation in glands and cells isolated from rabbit and rat gastric mucosa.

Isolated gastric glands and isolated cells prepared from rabbit and rat were studied to analyse the influence of cholecystokinin octapeptide (CCK 8) on histamine stimulated parietal cell acid formation as assessed by [14C]aminopyrine sequestered in acid tissue compartments. In rabbit gastric glands, CCK 8 evoked 32+/-6% (P<0. 01) inhibition of histamine stimulated acid formation, whereas in glands prepared from rat no inhibition was recorded. Instead, CCK 8 seemed to induce a variable increase of the histamine stimulation in rat gastric glands as the aminopyrine accumulation was increased by 110+/-46% (P<0.1). Further studies on cell preparations derived from rabbit gastric mucosa revealed dual properties of CCK 8, eliciting either inhibition or stimulation of the parietal cell depending on the presence of endocrine cells. The results show that paracrine communication may be effective in glandular preparations, but seems to vary depending on species.

Aminopyrine↗
PubMed2000

Aerosolized surfactant in lung-lavaged adult rats: factors influencing the therapeutic response.

OBJECTIVE: To evaluate the effect of aerosolized modified natural surfactant in adult rats with respiratory failure. METHODS: Lung-lavaged adult rats were treated with aerosolized surfactant, aerosolized saline or a bolus of surfactant. Surfactant was labelled with dimyristoylphosphatidylcholine (DMPC) and human serum albumin was given intravenously for evaluation of lung protein leakage. Blood gases and dynamic compliance were measured intermittently. At the end of ventilation, the lungs were either fixed by vascular perfusion for histological examination or washed for determination of total phospholipids, DMPC and human albumin in the lavage fluid. RESULTS: Treatment with bolus surfactant led to a quick and sustained restoration of pre-lavage blood gas values in most animals. The response to aerosolized surfactant varied considerably, with an overall moderate improvement of gas exchange. The saline-treated group failed to show any significant recovery of lung function. No histopathological differences were found between any of the groups. On average 0.46% of total administered aerosolized surfactant could be recovered. Vascular-to-alveolar leakage of human albumin averaged 11%, with no significant differences between the groups. Final values for PaO2 were significantly correlated with total phospholipids in the lavage fluid, and inversely related to the vascular-to-alveolar leakage of albumin. CONCLUSION: Neither bolus nor aerosolized surfactant influenced lung morphology. Nebulized surfactant improved lung function but the effect was inferior to that obtained with bolus surfactant, and the outcome depended on the balance between the combined pool size of exogenous and endogenous surfactant and the vascular-to-alveolar leakage of serum protein.

Aerosols↗
PubMed2000

Dual mode antimony electrode for simultaneous measurements of PO2 and pH.

BACKGROUND: In biomedical research and clinical medicine there is a demand for potent sensors to measure the components that make up blood gas analyses. Today, as when the electrochemical PO2, PCO2 and pH electrodes were first introduced, these measurements are usually made with the same type of sensor technology. The aims of the present study were, firstly, to find out whether the platinum cathode in the Clark electrode can be replaced by antimony for oxygen measurements (amperometry (A)); secondly, whether, during oxygen measurements, the inherent corrosion potential of the antimony metal can be used for measurement of pH in the same measurement area (potentiometry (P)). METHODS: An electrode of purified, crystallographically orientated monocrystalline antimony (COMA) connected to a reference electrode (silver-silver chloride) was used for the P measurements. Measurements of A (at -900 mV) and P were made in an aqueous environment regulated for oxygen, pH, and temperature. RESULTS: Reproducible oxygen sensitivities of 0.925 nA/% oxygen (2% CV (coefficient of variation)) (A), 10.7 mV/% (P), and 0.7 mV/% (P) were found in the oxygen range: 0-21%, <5%, and above 5%, respectively. The pH sensitivity was 57 mV/pH unit (P). Oxygen and pH measurements were less accurate at oxygen concentrations close to 0%. CONCLUSIONS: Both the oxygen and pH part of the composite electrode signal can be identified by this dual mode technique (A and P). The sensor seems to be promising as it provides measurements of two separate variables (oxygen and pH) and also has the desirable characteristics of a solid state sensor.

Antimony↗
PubMed2000

Effect of nervous excitation on acid secretion in horses.

Nervous excitation was induced by various means in horses provided with a gastric cannula. Insulin hypoglycaemia profoundly inhibited the basal acid output and volume secreted from the stomach. No clear effect on acid secretion was noted after administration of bethanechol, as the acid output was covered by the copious secretion of saliva. Atropine almost abolished the basal acid output. Sensoric stimulation by teasing caused a slight but not significant increase in the total acid output. These data suggest that cholinergic excitation might play a role in the stimulation of both volume and acid secretion in the horse. The inhibitory effect seen on these two parameters after insulin hypoglycaemia may hypothetically be ascribed to inhibitory impulses carried in peptide neurones of the vagal nerves or to inhibitory impulses in adrenergic nerves acting directly or indirectly on the parietal cells.

Animals↗
PubMed2000

Randomized clinical trial of laparoscopic versus open fundoplication: blind evaluation of recovery and discharge period.

BACKGROUND: There is a widespread belief that introduction of the laparoscopic technique in antireflux surgery has led to easier postoperative recovery. To test this hypothesis a prospective randomized clinical trial with blind evaluation was conducted between laparoscopic and open fundoplication. METHODS: Sixty patients with gastro-oesophageal reflux disease were randomized to open or laparoscopic 360 degrees fundoplication. The type of operation was unknown to the patient and the evaluating nurses after operation. RESULTS: The operating time was longer in the laparoscopy group, median 148 versus 109 min (P < 0.0001). The need for analgesics was less in the laparoscopically operated patients, 33.9 versus 67.5 mg morphine per total hospital stay (P < 0.001). There was no significant difference in postoperative nausea and vomiting. On the first day after operation patients in the laparoscopy group had better respiratory function: forced vital capacity 3.2 versus 2. 2 litres (P = 0.004) and forced expiratory volume 2.6 versus 2.0 litres (P = 0.008). Postoperative hospital stay was shorter in the laparoscopic group, median (range) 3 (2-6) versus 3 (2-10) days (P = 0.021). No difference was found in the duration of sick leave. CONCLUSION: Laparoscopic fundoplication was associated with a longer operating time, better respiratory function, less need for analgesics and a shorter hospital stay, while no reduction in the duration of postoperative sick leave was found compared with open surgery.

Adult↗
PubMed2000

IgE receptor-mediated release of nerve growth factor by mast cells.

BACKGROUND: It has previously been demonstrated that the level of nerve growth factor (NGF) is increased in serum from humans with allergic diseases and asthma. AIM: A question raised by these observations is whether NGF could be released from degranulating mast cells during an allergic reaction. The aim of this study was to investigate if NGF is released from mast cells after activation through cross-linkage of the high-affinity IgE receptor. METHODS: Mouse and human in vitro cultured mast cells were activated by IgE and specific antigen, stem cell factor or lipopolysaccharide. Release of NGF was measured by ELISA and mRNA expression was detected by RT PCR. RESULTS: We found that mast cells not only express NGF transcripts, but also release NGF polypeptide in response to IgE and specific antigen. Activation of mouse mast cells for 30 min induced significant release of NGF (32.9 +/- 1.3 pg/2 x 106 cells) compared to spontaneous release (13.9 +/- 2.7 pg/2 x 106 cells) (P < 0.01). Similarly, activation of human cultured mast cells also resulted in a significant increase of NGF release (733 +/- 310 pg/3 x 105 cells) compared to spontaneous release (9.2 +/- 4. 0 pg/3 x 105 cells). Two other mast cell secretogogues studied, stem cell factor and lipopolysaccharide, were not able to induce release of NGF. CONCLUSION: This study provides evidence that NGF could be specifically released by stimuli causing an allergic reaction, and mast cells can thereby be the source of NGF in IgE-mediated allergic diseases. Our findings add further support for a close correlation between NGF and mast cells that could be of importance for the allergic inflammation.

Animals↗
PubMed2000

Demonstration that platelet-activating factor is capable of activating mast cells and inducing a chemotactic response.

Platelet-activating factor (PAF) is generated in a variety of inflammatory conditions in which mast cells accumulate. However, little is known about the ability of PAF to influence mast cell function directly. In this study we examine the ability of PAF to activate mast cells and regulate mast cell chemotaxis. PAF was found to induce intracellular calcium mobilization and chemotactic responses in both murine and human mast cells. PAF induced transient increases in intracellular Ca2+ concentrations with a 50% effective dose of 1 nM and induced significant migratory responses at PAF concentrations of 1 nM to 1 microM in the human leukaemia mast cell line (HMC-1). Using signal transduction inhibitors, both PAF-induced calcium mobilization and migration of mast cells were shown to require activation of pertussis toxin-sensitive G proteins. PAF-induced calcium and chemotactic responses were cross-desensitized by C5a. Together, these data demonstrate that PAF is capable of activating distinct signalling pathways in mast cells associated with calcium mobilization and cell migration; and that PAF may thus contribute to the regulation of mast cell responses and hyperplasia at sites of inflammation.

Animals↗
PubMed2000

Demonstration of mast cell chemotactic activity in bronchoalveolar lavage fluid collected from asthmatic patients before and during pollen season.

BACKGROUND: Mast cells are versatile effector cells of primary importance in asthma and airway inflammation. During inflammation mast cells accumulate in the bronchial epithelium. The mechanism for this increase in mast cell number has not been defined. OBJECTIVES: The aim of this study was to examine the presence of mast cell chemotactic activity in bronchoalveolar lavage (BAL) fluid taken before and at the end of 2 pollen seasons from patients with allergic asthma. METHODS: To measure mast cell chemotactic activity, we used a modified Boyden chamber and the human mast cell line HMC-1 or in vitro-developed mast cells as responder cells. RESULTS: A total of 27 patients were investigated, of which 8 exhibited mast cell chemotactic activity in their BAL fluid collected before season. A significant increase in the activity was found in 18 of 27 BAL fluids sampled at the end of the pollen season. No difference was found between patients treated with immunotherapy or placebo. The presence of stem cell factor could be detected in all BAL fluids analyzed. Blocking antibodies against stem cell factor or transforming growth factor-beta partially blocked the activity in some of the BAL fluids. Treatment of the responder cells with pertussis toxin reduced the migratory activity in 13 of 14 BAL fluids collected during pollen season. CONCLUSION: This study demonstrates the presence of mast cell chemotactic activity in BAL fluids from patients with allergic asthma, with a significant increase in activity during pollen season. The major part of this activity consisted of factors mediating their effect through G(i)-protein coupled receptors. This activity may be responsible for the mast cell accumulation in the intraepithelial layer seen in allergic asthmatic patients.

Asthma↗
PubMed2000

Postmortem findings of gastric ulcers in Swedish horses older than age one year: a retrospective study of 3715 horses (1924-1996).

The present study was performed to estimate retrospectively the prevalence of gastric ulceration in necropsied Swedish horses and to evaluate some potential risk factors. Horses (n = 3715) older than age one year and necropsied 1924-1996 were included. Information about breed, gender, age, season of death, clinical signs of colic, Gasterophilus larvae and documentation of diseases in different organs was recorded. Data on size, number and anatomical distribution of gastric ulcers were also obtained. The cold-blooded horses and the Standardbreds were the 2 most dominating breeds in our material. Gastric ulcers/erosions were seen in 633 (17%) of the horses. The highest prevalence was found in Thoroughbreds (19%) and Standardbreds (19%), whereas only 7% of the cold-blooded horses were affected. The cutaneous region along the margo plicatus was the most commonly affected area (52%). Multiple ulcers were seen in 62% of the horses with gastric ulcers and concurrent ulcers in the oesophagus were reported in 6%. In the bivariate analysis, significant associations were found between gastric ulcers and signs of colic (P<0.001) and gender (P<0.001), as well as between concomitant bowel (P<0.001), liver (P<0.05) and oesophageal (P<0.01) lesions. Using a multivariate logistic regression model, only year of necropsy and breed were found significantly to influence the risk of gastric ulceration by decreasing the Log Likelihood test value. The present study shows clearly that gastric ulceration has been present in Swedish horses throughout the 20th century, which also may be the situation worldwide.

Age Factors↗
PubMed2000

Inhibition of N-linked glycosylation down-regulates insulin-like growth factor-1 receptor at the cell surface and kills Ewing's sarcoma cells: therapeutic implications.

The insulin-like growth factor-1 receptor (IGF-1R) has been shown to be of critical importance for tumor development and tumor cell survival of various types of malignancies. We have previously demonstrated that an adequate N-linked glycosylation of IGF-1R is required for its translocation to the cell surface in melanoma cells. This raises the possibility of using glycosylation inhibitors as therapeutic agents against IGF-1R-dependent malignancies. In this study we show that inhibition of N-linked glycosylation using tunicamycin or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin resulted in down-regulation of IGF-1R at the cell surface in Ewing's sarcoma cell lines (RD-ES and ES-1 cells). The down-regulation of plasma membrane-bound IGF-1R was correlated with a drastic decrease in IGF-1R autophosphorylation, suggesting biochemical inactivation of the receptor. Whereas RD-ES and ES-1 cells responded differently with regard to DNA synthesis, the decrease in IGF-1R expression was accompanied by a rapid and substantial decrease in survival of both cell lines. Our data suggest that relatively untoxic HMG-CoA reductase inhibitors (e.g. lovastatin) could have therapeutic significance in IGF-1R-dependent neoplasms like Ewing's sarcoma.

Antineoplastic Agents↗
PubMed1999

Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype.

It is well known that insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in proliferation and survival of transformed cells. Overexpression of IGF-1R in certain tumors has been reported, but there is still little known about its importance in vivo. Here, we evaluated the IGF-1R levels in 35 human synovial sarcoma tumors by Western blot and reverse transcriptase-PCR. In 18 of these, IGF-1R was detectable by Western blot, whereas 17 were nondetectable. There was a significant association between the amount of receptor proteins and mRNA transcripts. Furthermore, we found that the IGF-1R Western blot-positive tumors were associated with a high incidence of lung metastases. Eleven of 18 (61%) developed metastases in the IGF-1R detectable group, compared to 3 of 17 (18%) in the nondetectable group (P = 0.01). Moreover, in the detectable group of IGF-1R, 12 of 18 (67%) exhibited a high tumor cell proliferative rate, compared to 5 of 16 (31%) in the nondetectable group (P = 0.04). On the other hand, no association was found between the IGF-1R and type of fusion gene transcript (SYT-SSX1 or SYT-SSX2). Our results suggest that expression of IGF-1R can underlie an aggressive phenotype in synovial sarcoma.

Adult↗
PubMed1999

The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome.

Cytogenetically, synovial sarcoma (SS) is characterized by the translocation t(X;18)(p11.2;q11.2), resulting in a fusion between the SYT gene on chromosome 18 and SSX1 or SSX2 on the X chromosome and the formation of new chimeric genes, SYT-SSX1 or SYT-SSX2. We examined the potential clinical relevance of SYT-SSX1 and SYT-SSX2 fusion transcripts together with tumor proliferation. In a series of 33 patients with primary SS, the type of fusion transcript was assessed by reverse transcription-PCR and sequence analysis. The proliferation rate was analyzed using anti-Ki-67 antibodies. One case carrying an atypical transcript with a 57-bp insert was excluded, leaving 13 SYT-SSX1 and 19 SYT-SSX2 cases for analysis. The hazard ratio (with respect to metastasis-free survival for patients with SYT-SSX1 versus patients with SYT-SSX2 fusion transcripts was 7.4 (95% confidence interval, 1.5-36; log-rank P = 0.004). There was also an association with reduced overall survival for patients with SYT-SSX1 compared to patients with SYT-SSX2 (hazard ratio, 8.5; 95% confidence interval, 1.0-73; log-rank P = 0.02). The 5-year metastasis-free survival for patients with SYT-SSX1 was 42% versus 89% for patients with SYT-SSX2. There was a significant association between SYT-SSX1 and a high tumor proliferation rate (P = 0.02). We conclude that the findings suggest that the type of SYT-SSX fusion transcript determines the proliferation rate and is an important predictor of clinical outcome in patients with SS.

Adolescent↗
PubMed1999

Mast cell migratory response to interleukin-8 is mediated through interaction with chemokine receptor CXCR2/Interleukin-8RB.

To explore the role of chemokines in mast cell chemotaxis and accumulation at sites of inflammation, we first investigated the response of human mast cells to 18 different chemokines by induction of intracellular calcium mobilization in the human mast cell line, HMC-1. Only a subgroup of CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR) tripeptide motif, which included interleukin-8 (IL-8), growth-regulated oncogene alpha (GROalpha), neutrophil-activating peptide-2 (NAP-2), and epithelial cell-derived neutrophil activating peptide-78 (ENA-78), induced calcium flux in the cells. These observations suggested that the receptor CXCR2 (IL-8RB) should be expressed on the surface of these cells. Using the RNAse protection assay, CXCR2 mRNA, but not CXCR1 (IL-8RA) mRNA expression was detected in HMC-1 cells. Flow cytometry analysis documented the surface expression of CXCR2. A binding analysis performed with 125I-IL-8 determined that there were approximately 3,600 high affinity IL-8 binding sites per HMC-1 cell, with a calculated kd of 1.2 to 2 nmol/L. The activity of this receptor was further explored using IL-8, which was found to induce dose-dependent chemotactic and haptotactic responses in both HMC-1 cells and in vitro cultured human cord blood-derived mast cells. These results show the expression of functional CXCR2 receptors on the surface of human mast cells, which may play an important role in mast cell recruitment during the genesis of an inflammatory response.

Amino Acid Sequence↗