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B Sandstedt

Publications and source records attributed to B Sandstedt.

At least 55 records · Page 3Linked to original sources
PubMed1998

Developmental gene expression of sympathetic nervous system tumors reflects their histogenesis.

Comparisons of the developing human sympathetic nervous system (SNS) to tumors presumed to derive from these cells may suggest tumor progenitors and predict tumor biologic behavior. Classic neuroblastoma (NB) and its more highly differentiated stroma-rich subtypes, extra-adrenal sympathetic paraganglioma, and pheochromocytoma were examined for the presence of the developmentally characterized gene products NSE, S-100, CD44, Bcl-2, HNK-1, PNMT, TrkA, IGF2, and tyrosine hydroxylase. The marker gene expression profiles of these tumors were compared with those similarly determined for a number of normal prenatal and postnatal human SNS cell types. Sympathetic paraganglioma, pheochromocytoma, and stroma-rich NB display marker expression profiles mimicking those of childhood sympathetic paraganglia, adrenal chromaffin cells, and sympathetic neurons, respectively. A selection of differentiating, extra-adrenal NB tumors with prognostically favorable features possess marker gene expression profiles paralleling that observed for fetal extra-adrenal sympathetic paraganglia/small intensely fluorescent cells. In contrast, undifferentiated, clinically aggressive NB tumors manifest characteristics mirroring that of embryonic/early fetal sympathetic neuroblasts of sympathetic ganglia and of the adrenal gland. These findings suggest that clinical features, such as primary tumor location and age at diagnosis, provide prognostic information for NB patients by virtue of the existence and biology of the presumed tumor progenitor cell type.

Adrenal Gland Neoplasms↗
PubMed1997

Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis.

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility. NBCCS is caused by mutations in the human homologue (PTCH) of the Drosophila patched gene, a developmental regulator implicated in signaling of hedgehog and smoothened. The PTCH gene was found to contain somatic mutations also in sporadic basal cell carcinomas and medulloblastomas, tumors seen in NBCCS, consistent with PTCH acting as a tumor suppressor. Because basal cell carcinomas have been observed to develop in association with benign trichoepitheliomas (TEs) in the same lesions, patients, and families and may share the same cell of origin, we have analyzed PTCH for mutations and expression in TEs. We report frameshift and in-frame somatic deletions in this gene and a consistent overexpression of PTCH mRNA in TEs. These findings provide the first evidence of a gene mutation in TEs and identify a common pathogenic pathway for histopathologically similar but prognostically distinct skin tumors. Moreover, these results support the presence of a gatekeeper mechanism in multistep skin tumorigenesis exerted by the altered PTCH signaling pathway.

Adult↗
PubMed1997

Inactivation of H19, an imprinted and putative tumor repressor gene, is a preneoplastic event during Wilms' tumorigenesis.

Genetic evidence shows that the parent of origin-dependent expression patterns of the Igf2 and H19 genes is coordinated in mouse, such that H19 controls the activity of Igf2 in cis. Equally compelling evidence for a similar situation in humans is absent, although the frequently observed activation of the maternal IGF2 allele (ie., loss of imprinting) in Wilms' tumors has been attributed to the silencing of the maternal H19 locus. We show here that loss of H19 activity is generally a preneoplastic event, which may be linked with an overgrowth lesion that has been proposed to be permissive for tumor formation. Although our results document one instance in which a postneoplastic loss of H19 activity correlates with loss of IGF2 imprinting at the cellular level, it appears that inactivation of H19 is more generally independent of loss of imprinting of IGF2, at least in our specimens. Our results imply that inactivation of H19 correlates with blastema overgrowth and can be independent of a regulatory role with respect to IGF2 imprinting status in cis.

Alleles↗
PubMed1997

In vivo spontaneous neuronal to neuroendocrine lineage conversion in a subset of neuroblastomas.

Neuroblastoma is an embryonal tumor derived from the sympathetic nervous system. Although all neuroblastomas have a neuronal character, a subset of tumors also show evidence of extra-adrenal neuroendocrine differentiation in discrete cell layers. A characterization of the cells of the developing human sympathetic nervous system was performed, identifying growth-associated protein-43, neuropeptide tyrosine, and Bcl-2 as marker genes for sympathetic neurons. Whereas all neuroblastomas express growth-associated protein-43, neuropeptide tyrosine, and Bcl-2, tumors with differentiating cells with neuroendocrine features expressed these genes only in the morphologically immature, proliferating cells. Thus, with neuroendocrine tumor cell differentiation, neuronal marker gene expression vanished and proliferation ceased and was succeeded by expression of chromogranin A/B and insulin-like growth factor-2, markers of neuroendocrine chromaffin differentiation. These tumors appear to provide examples of spontaneous lineage conversion from a neuronal to a neuroendocrine phenotype.

Cell Differentiation↗
PubMed1997

Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis.

To explore possible physiologic functions for the metalloproteinase collagenase-3, we have examined its temporal and spatial expression during human fetal development. Except for mesenchymal cells in the umbilical cord at 4 weeks of gestation, signal for collagenase-3 mRNA was confined to mineralizing skeletal tissue and detected in hypertrophic chondrocytes and osteoblastic cells involved in ossification beginning at 10 weeks and continuing through gestation. These cells were also immunoreactive with collagenase-3 antiserum, indicating their ability to produce collagenase-3 protein. In osteoblastic cells, the expression of membrane-type 1 metalloproteinase and 72-kd gelatinase mRNA, which have the capacity to activate collagenase-3 in vitro, colocalized with that of collagenase-3. In postnatal tissues, collagenase-3 was re-expressed in processes involving skeletal remodeling, such as bone cysts and ectopic bone and cartilage formation. Multinucleated osteoclasts were consistently negative for collagenase-3. Furthermore, in patients with seropositive rheumatoid arthritis, expression of collagenase-3 was prominent in articular cartilage, and collagenase-3 protein was detected by immunoblotting in synovial fluids. Consistent with its substrate specificities, a plausible function for collagenase-3 in these processes is to preferentially degrade type II collagen, thus serving a role during primary ossification, in skeletal remodeling, and in destructive joint disease.

Aged↗
PubMed1996

Proctocolitis in exclusively breast-fed infants.

UNLABELLED: We present nine exclusively breast-fed, full-term infants with mild rectal bleeding due to proctocolitis. The mean age at the onset of symptoms was 5 weeks (range 1-8 weeks). Rectosigmoidoscopic examination was performed in all the children within 2 days after admission, showing inflammatory changes such as oedematous mucosa with petechial haemorrhages. Rectal mucosal biopsy specimens were obtained in eight cases and revealed intra-epithelial eosinophilic granulocytes in seven and a diffuse increase of eosinophils in the lamina propria in six. Allergy to cow's milk protein transferred to the infants via the breast milk was believed to be the cause of the inflammation. The intake of cow's milk protein was then restricted in seven mothers. Following this regimen, symptoms were relieved within 4 weeks in the six infants who were seen at follow up. One child recovered spontaneously without dietary restrictions. Considering the beneficial effect of the diet regimen in addition to the histological findings, allergy to cow's milk protein is possibly the aetiology of the proctocolitis seen in these nine exclusively breast-fed babies, although no challenge tests were performed to confirm this suspicion. CONCLUSION: This report shows that proctocolitis occurs in exclusively breast-fed infants. It is speculated that allergy to cow's milk protein may have played a role in the pathogenesis.

Animals↗
PubMed1996

Rhabdoid tumour of the kidney: a clinicopathological study of 22 patients from the International Society of Paediatric Oncology (SIOP) nephroblastoma file.

We present 22 (0.9%) cases of rhabdoid tumour of the kidney diagnosed amongst 2392 renal tumours in children. The patients ages ranged from 3 weeks to 94 months (median 7 months) and the female:male ration was 1.2:1. Clinically, they presented with an abdominal mass but four (18%) children also had hypercalcaemia and one (4.5%) developed a brain tumour (primitive neuroectodermal tumour). None of the children presented with stage I disease, five (23%) had stage II, ten (46%) stage III, and five (23%) stage IV disease. Two (9%) patients had bilateral tumours. Histologically, the vast majority (20/22) of the tumours exhibited a classical pattern but other histological patterns were also noted. Immunohistochemical studies performed in 12 cases showed vimentin positivity in all cases, CAM 5.2 in eight, epithelial membrane antigen in six, neuron specific enolase in four, S-100 protein in eight, and desmin in one case. In only 12 of the 22 tumours was there agreement between the reporting pathologist and the panel on a diagnosis of rhabdoid tumour of the kidney. Eight tumours originally diagnosed as rhabdoid tumour of the kidney were found to be other renal tumours and in another ten cases the initial diagnosis was changed by the panel to rhabdoid tumour. Metastases developed in 18 (82%) of the children--in eight they were present at the time of diagnosis and in 10 they developed from 2 weeks to 9 months after initial diagnosis. Metastases were found in the lung, abdomen, lymph nodes, liver, bone and brain. Of the 19 children with adequate follow-up, only two (10.5%) with stage II disease are alive, while 17 (89.5%) died 2 weeks to 20 months after the diagnosis.

Adolescent↗
PubMed1996

Stromelysin-3 mRNA associated with myofibroblasts is overexpressed in aggressive basal cell carcinoma and in dermatofibroma but not in dermatofibrosarcoma.

Stromelysin-3 is produced in the stroma of various malignant tumors, and in breast carcinoma there seems to be a positive correlation between aggressive disease and intensity of stromelysin-3 expression, suggesting that stromelysin-3 participates in the tumor spread. In basal cell carcinoma, previous findings on stromelysin-3 have been inconclusive in this respect. Our study was undertaken to determine the pattern of stromelysin-3 production in relation to different histologic subtypes and stromal reactions in basal cell carcinoma. By in situ hybridization, stromelysin-3 mRNA was detected in stromal fibroblastic cells in 51/56 samples. Furthermore, there was a significant correlation between strong signal for stromelysin-3 mRNA and infiltrative tumor growth. In all tumors, there was ongoing collagen synthesis as shown by a signal for procollagen I mRNA; this signal co-localized with stromelysin-3 around tumor nests. Our findings suggest a link between stromelysin-3 and fibrotic stromal response, which prompted us to evaluate the expression of stromelysin-3 in other fibrotic skin tumors. Interestingly, stromelysin-3, co-localizing with procollagen I mRNA, was consistently expressed in lesional cells in dermatofibromas (19/19), but not in dermatofibrosarcomas (0/7). Thus, our results indicate that in addition to being a marker for malignant disease, stromelysin-3 is produced by fibroblastic cells associated with benign fibrosis. A subset of cells producing stromelysin-3 appears to be myofibroblasts as demonstrated by immunoreactivity for alpha smooth muscle actin in both basal cell carcinoma and dermatofibroma.

Actins↗
PubMed1996

Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters.

We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The P1 promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts.

Adult↗
PubMed1996

A developmental model of neuroblastoma: differentiating stroma-poor tumors' progress along an extra-adrenal chromaffin lineage.

The prognosis of children with neuroblastoma (NB) is dependent upon the patient's age at diagnosis, the location of the primary tumor, and histologic tumor cell differentiation. These characteristics, as well as the presumption that NB results from clonal expansion of primitive cells involved in sympathetic nervous system (SNS) development, predict that a model of tumorigenesis based upon normal fetal SNS histogenesis might indicate tumor progenitor status and define biologic and clinical behavior. Immunohistochemistry and in situ hybridization were used to examine a panel of marker gene products predicted or shown to be expressed during SNS development in the normal human fetal SNS from 8 to 24 weeks' gestational age. A similar analysis was performed in a selection of clinical NB tumors, and the results were compared. In a subset of differentiating, often extra-adrenal NB tumors in patients who frequently had a favorable outcome; advancing morphologic tumor cell differentiation spatially paralleled an advancing fetal extra-adrenal chromaffin marker gene expression phenotype (ie, increasing TrkA, TrkC, TH, IGF-2, and neuron-specific enolase expression but a lack of phenylethanolamine N-methyltransferase expression). In these tumors, expression of gene products associated with normal fetal sympathetic ganglionic differentiation (ie, Bcl-2, HNK-1, and neuropeptide Y) was lost with morphologic tumor cell differentiation. In contrast, undifferentiated tumors, the majority of which were high stage, adrenal in origin, and prognostically unfavorable, displayed marker expression characteristics mirroring that of an early fetal ganglionic lineage. Thus, we show that morphologic differentiation in stroma-poor NB tumors, long held as an important prognostic feature in tumor grading systems, often corresponds to an extra-adrenal chromaffin rather than a ganglion cell or adrenal medullary chromaffin phenotype. Understanding the biology of extra-adrenal chromaffin tissues may provide an explanation for the clinically less aggressive nature of differentiating NB tumors and suggest potential mechanisms for spontaneous regression and/or treatment response.

Biomarkers, Tumor↗
PubMed1995

Constitutional and somatic mutations in the WT1 gene in Wilms' tumor patients.

Wilms' tumor development, like most tumors, involves multiple genetic alterations affecting diverse genes. Only one of these has thus far been identified, the Wilms' tumor 1 (WT1) gene on 11p13, which functions as a tumor suppressor gene. We assessed the involvement of the WT1 gene constitutionally and somatically in 26 Wilms' tumor patients. Of these, the clinical data suggest a constitutional pre-disposition in 12 bilateral cases and 7 cases with early onset. We employed Southern blot analysis and PCR-based markers for analyses of somatic allelic losses in chromosome bands 11p13, 11p15 and 16q and screened for point mutations in exons 2-10 of the WT1 gene with denaturing gradient gel electrophoresis (DGGE). Of the 12 cases with multiple tumors, 1 exhibited a constitutional 11p13 deletion and a somatic stop mutation in exon 4 of the WT1 gene and 2 harbored constitutional mutations in the WT1 gene: a pre-mature stop codon in exon 6 in a boy with bilateral cryptorchidism and bilateral Wilms' tumors and an intragenic deletion in a girl with bilateral WT. Three additional bilateral tumors displayed WT1 rearrangements or allelic losses with 11p13 markers. Four of 7 patients with an early onset of unilateral tumor had losses of 11p13, though no WT1 mutations were detected. Two of the remaining cases that did not show any somatic or constitutional 11p13 alterations had Beckwith-Wiedemann syndrome, known to involve the 11p15 region.

Alleles↗
PubMed1995

Expression, promoter usage and parental imprinting status of insulin-like growth factor II (IGF2) in human hepatoblastoma: uncoupling of IGF2 and H19 imprinting.

We have studied the promoter utilization and parental imprinting status of human IGF2 in three genetically informative hepatoblastomas from patients ranging in age from 9 months to 3 years. In all three cases, there is a downregulation of promoter P1 in the tumor tissues while the P2 and P3 promoters are upregulated compared to the normal liver. One of three patients displayed loss of imprinting (LOI) of IGF2 in the tumor tissue. We also investigated the expression of the H19 gene in all three cases and the methylation pattern in H19 from the patient with LOI of IGF2. The expression of H19 was greatly reduced in all tumors. Monoallelic H19 expression however, was retained even in the case which showed LOI of IGF2. Unlike the situation in Wilms' tumor, no differences in the methylation pattern between the normal liver and tumor tissues were observed in the H19 promoter or 3' region, using HpII analysis. We show here, that in contrast to the situation in Wilms' tumor, H19 expression is not a prerequisite for maintaining a monoallelic IGF2 expression.

Alleles↗
PubMed1995

Biochemical evidence for a mature phenotype in morphologically poorly differentiated neuroblastomas with a favourable outcome.

Neuroblastoma is an embryonal tumour of the sympathetic nervous system with marked heterogeneity in terms of histological maturity and clinical course. A previous study revealed that high tumour levels of the csrc protein, particularly its neuronal isoform (pp60csrcN), correlated with favourable outcome. To test whether this feature reflects a higher degree of neuronal maturation in these tumours, an extended series (47 consecutive neuroblastomas and 10 ganglioneuromas) were analysed for levels of csrc protein isoforms, neuron-specific enolase, and synaptophysin. Immunoblotting and radioimmunoassay techniques were employed. The results were compared with conventional histological signs of neuronal maturation. High pp60csrcN levels were specific for prognostically favourable neuroblastomas and correlated with high neuronal marker levels. However, signs of histological maturation correlated poorly with these parameters. It is therefore concluded that low stage tumours are highly differentiated in biochemical terms despite their frequently immature histology. Furthermore, the clinical usefulness of these biochemical parameters as prognostic markers was compared with established parameters in a multivariate analysis. Stage 4 disease, MYCN amplification, and age above 18 months at diagnosis was the most powerful combination of variables found for predicting a poor outcome. As expected, none of the neuronal differentiation markers investigated could add to the prediction of aggressive disease when compared with this model. However, high expression of pp60csrcN appeared to be useful in predicting long-term survival in high stage infant neuroblastoma.

Age Factors↗
PubMed1995

Tolerance and effects of almokalant, a new selective Ik blocking agent, on ventricular repolarization and on sino-atrial and atrioventricular nodal function in the heart: a study in healthy, male volunteers utilizing transesophageal atrial stimulation.

Almokalant, (4-(3-ethyl(3-propylsulfinyl)propyl)amino)-2-hydroxy-propoxy)- benzonitrile), is a newly developed Ik channel blocker that exhibits pure class III effects. Using a noninvasive approach with transesophageal atrial stimulation (TAS), we wished to identify the dose of almokalant, given as an intravenous bolus infusion, that prolonged ventricular repolarization in the healthy human heart to an extent of potential clinical interest. Furthermore, we defined the electrophysiological effects of this dose on the heart, as well as the pharmacokinetics, safety, and tolerance throughout a wide dosing range. In the titration part, increasing doses were given to identify the dose that produced a reproducible QTend prolongation of approximately 20%. This dose (12.8 mumol) was then given in a placebo-controlled, double-blind, cross-over fashion. In the double-blind part, almokalant significantly prolonged the QTend intervals during sinus rhythm and during TAS at 100 beats/min and increased the effective refractory period of the atria (AERP). There was no alteration in either the cardiac conduction (PQ and QRS), or blood pressure (BP) sinus node function, or the ERP of the atrioventricular (AV) node. Therefore, almokalant exhibited pure class III effects with no signs of beta-blockade or unwanted hemodynamic effects. The plasma concentration-time curve showed a biexponential decrease with a terminal half-life (t1/2) of approximately 3 h. There was a large interindividual variation in the plasma concentration at the end of infusion, Cmax. This variability diminished considerably 60 min after infusion, and the pharmacokinetic characteristics studied appeared to be proportional to the dose. The drug was well tolerated, and the only side effect noted was a brief metallic taste after a dose of 25.6 mumol. Corresponding to high plasma peak values, T-wave morphology changes of short duration were observed, sometimes with the development of pronounced, biphasic T waves.

Adult↗
PubMed1995

Circulating granulocyte antibodies in first attacks of colitis.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) have recently been demonstrated in the sera of patients with inflammatory bowel disease (IBD). METHODS: The presence of ANCA was studied in 107 sera obtained during 1 year from 48 patients with a first attack of IBD and in 33 such sera from 19 patients with infectious or infectious-type colitis (non-relapsing colitis (NRC)). RESULTS: In 65% (31 of 48) of the IBD patients positive immunofluorescence reactivity against granulocytes was observed, compared with in 5% of the NRC patients. No significant difference in granulocyte reactivity was found either between patients with colonic Crohn's disease and those with ulcerative colitis or between active and inactive phases of the disease. Most of the sera showed a perinuclear immunofluorescence staining pattern (68%), in contrast to the classical cytoplasmic staining pattern seen in Wegener's granulomatosis. In sera obtained at the first visit from the 31 IBD patients with positive granulocyte reactivity a hitherto unknown antibody against beta-glucuronidase was found in 42%, whereas in 45% the specificity was not identified. Other antibodies, rarely seen, were directed against myeloperoxidase, lactoferrin, elastase, and cathepsin G. No antibody directed against lysozyme was detected. CONCLUSIONS: Positive granulocyte reactivity practically excluded NRC and was seen in more than half of IBD patients. Antibodies against beta-glucuronidase were common, but still almost half of the antibodies remained unknown.

Adult↗