Biomedical subjects

P Möller

Publications and source records attributed to P Möller.

At least 37 records · Page 2Linked to original sources

PubMed2001

MHC-II-independent CD4+ T cells induce colitis in immunodeficient RAG-/- hosts.

CD4(+) alpha beta T cells from either normal C57BL/6 (B6) or MHC-II-deficient (A alpha(-/-) or A beta(-/-)) B6 donor mice engrafted into congenic immunodeficient RAG1(-/-) B6 hosts induced an aggressive inflammatory bowel disease (IBD). Furthermore, CD4(+) T cells from CD1d(-/-) knockout (KO) B6 donor mice but not those from MHC-I(-/-) (homozygous transgenic mice deficient for beta(2)-microglobulin) KO B6 mice induced a colitis in RAG(-/-) hosts. Abundant numbers of in vivo activated (CD69(high)CD44(high)CD28(high)) NK1(+) and NK1(-) CD4(+) T cells were isolated from the inflamed colonic lamina propria (cLP) of transplanted mice with IBD that produced large amounts of TNF-alpha and IFN-gamma but low amounts of IL-4 and IL-10. IBD-associated cLP Th1 CD4(+) T cell populations were polyclonal and MHC-II-restricted when derived from normal B6 donor mice, but oligoclonal and apparently MHC-I-restricted when derived from MHC-II-deficient (A alpha(-/-) or A beta(-/-)) B6 donor mice. cLP CD4(+) T cell populations from homozygous transgenic mice deficient for beta(2)-microglobulin KO B6 donor mice engrafted into RAG(-/-) hosts were Th2 and MHC-II restricted. These data indicate that MHC-II-dependent as well as MHC-II-independent CD4(+) T cells can induce a severe and lethal IBD in congenic, immunodeficient hosts, but that the former need the latter to express its IBD-inducing potential.

Adoptive Transfer↗

PubMed2001

CD95 ligand-expressing tumors are rejected in anti-tumor TCR transgenic perforin knockout mice.

CD95 (APO-/Fas) ligand (CD95L) is a member of the TNF family predominantly expressed by activated T and NK cells but also by tumors of diverse cellular origin. CD95L trimerizes surface CD95 expressed by target cells that subsequently undergo apoptosis. The role of the CD95/CD95L system in the down-regulation of an immune response (activation-induced cell death) is established. However, it is so far unclear why tumors express CD95L. To investigate whether tumors use the CD95L to down-regulate an anti-tumor immune response, we established a transgenic (tg) mouse model consisting of 1) apoptosis-resistant tumor cells, designated LKC-CD95L, which express functional CD95L and the model tumor Ag K(b); and 2) perforin knockout (PKO) anti-K(b) TCR tg mice. L1210-Fas antisense expressing K(b), crmA, and CD95L (LKC-CD95L) killed CD95(+) unrelated tumor targets and Con A-activated splenocytes from anti-K(b) TCR tg PKO mice by a CD95L-dependent mechanism in vitro. However, we could not detect any cytotoxic activity against anti-tumor (anti-K(b)) T cells in vivo. We also observed reduced growth of LKC-CD95L in nude mice and rapid rejection in anti-K(b) TCR tg PKO mice. Because the tumor cells are resistant to CD95L-, TNF-alpha-, and TNF-related apoptosis-inducing ligand-induced apoptosis and the mice used are perforin-deficient, the involvement of these four cytotoxicity mechanisms in tumor rejection can be excluded. The histological examination of tumors grown in nude mice showed infiltration of LKC-CD95L tumors by neutrophils, whereas L1210-Fas antisense expressing K(b) and crmA (LKC) tumor tissue was neutrophil-free. Chemotaxis experiments revealed that CD95L has no direct neutrophil-attractive activity. Therefore, we conclude that LKC-CD95L cells used an indirect mechanism to attract neutrophils that may cause tumor rejection.

Animals↗

PubMed2001

Nuclear fission modes and fragment mass asymmetries in a five-dimensional deformation space.

Nuclei undergoing fission can be described by a multi-dimensional potential-energy surface that guides the nuclear shape evolution--from the ground state, through intermediate saddle points and finally to the configurations of separated fission fragments. Until now, calculations have lacked adequate exploration of the shape parameterization of sufficient dimensionality to yield features in the potential-energy surface (such as multiple minima, valleys, saddle points and ridges) that correspond to characteristic observables of the fission process. Here we calculate and analyse five-dimensional potential-energy landscapes based on a grid of 2,610,885 deformation points. We find that observed fission features--such as the distributions of fission fragment mass and kinetic energy, and the different energy thresholds for symmetric and asymmetric fission--are very closely related to topological features in the calculated five-dimensional energy landscapes.

Journal Article↗

PubMed2001

Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line.

Primary mediastinal B-cell lymphoma (MBL) is an aggressive Non-Hodgkin's Lymphoma, which has been recognized as a distinct disease entity. We performed a comprehensive molecular cytogenetic study analyzing 43 MBLs. By comparative genomic hybridization (CGH), the most common aberrations were gains of chromosome arms 9p and Xq, which were present in 56% and 40% of cases, respectively. Based on the limited resolution of CGH, this technique may underestimate the real incidence of aberrations. Therefore, we also did an interphase cytogenetic study with eight DNA probes mapping to chromosome regions frequently altered in B-cell lymphomas. With this approach, both 9p and Xq gains were found in more than 70% of cases (75% and 87%, respectively). The findings were compared with results obtained in 308 other B-cell lymphomas. Gains in 9p were identified in only six of the 308 cases, and only one of these lymphomas with 9p gains was not primarily extranodal in origin (P < 10-(20) for CGH data and P < 10-(11) for fluorescence in situ hybridization data). We also present a novel MBL cell line, MedB-1, which carries the genetic aberrations characteristic of this entity.

Adolescent↗

PubMed2001

Molecular-cytogenetic comparison of mucosa-associated marginal zone B-cell lymphoma and large B-cell lymphoma arising in the gastro-intestinal tract.

Extranodal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type may represent a model of lymphoma progression, because a small cell component frequently occurs in the large cell variants. We studied 52 extranodal B-cell lymphomas: 18 extranodal marginal zone B-cell lymphomas of MALT type (MZBL,MT), 7 MZBL,MT of the gastro-intestinal tract with a diffuse large B-cell component (giMZBLplusLBCL), and 27 diffuse large B-cell lymphomas of the gastro-intestinal tract without small cell component (giLBCL). Analytical techniques were comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). The translocation t(11;18) was found as the sole aberration in two MZBL,MT only. In contrast to this, t(11;18)-negative MZBL,MT were characterized by frequent gains on chromosome 3 and DNA amplifications on 2p13-p15. Furthermore, we found a clonal lymphoma progression from the small to the large cell component with accumulation of gains and losses of chromosomal material in the large cell component in giMZBLplusLBCL. Aberrations overlapping with MZBL,MT and giMZBLplusLBCL included losses on chromosome 13, amplifications of the REL proto-oncogene, or gains on chromosome 12. In addition, the large cell component revealed gains on 8q24, including amplifications of the MYC proto-oncogene, and losses on 2q. The giLBCL had frequent gains on chromosomes 12 and 9, as well as on 11q, and losses on 6q. We conclude that, based on the distinctive and partly overlapping patterns of genetic aberrations, MALT lymphomas can be divided into different genetic subgroups.

Chromosome Aberrations↗

PubMed2001

Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1.

Cytogenetic information on chordomas is rudimentary and restricted to GTG-banding analysis of 26 cases worldwide. In this study, we present the chromosomal imbalances detected in a series of 16 chordomas (10 sacrococcyeal, five sphenooccipital, and one spinal) from 13 patients using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). On average, 3.2 losses and 4.2 gains were detected per tumor. The most common DNA copy number alterations were losses on chromosomal arms 3p (50%) and 1p (44%). Losses of 3p were detected in five of seven primary chordomas. Therefore, the loss of 3p might be an early event in chordoma genesis. The most common gains involved 7q (69%), 20 (50%), 5q (38%), and 12q (38%). Additionally, we raised the first human chordoma cell line, U-CH1, from a recurrence of a sacral chordoma. U-CH1 and its parent tumor had almost the same CGH profile. According to GTG-banding and multicolor FISH, U-CH1 has the following clonal chromosomal abnormalities: der(1)t(1;22), del(4), +del(5), +del(6), +7, del(9), del(10), +der(20)t(10;20), +21. Thus, the novel permanent human chordoma cell line U-CH1 has chordoma-typical cytogenetic aberrations. Our data suggest that tumor suppressor genes or mismatch repair genes (located at 1p31 and 3p14) and oncogenes (located in 7q36) might be involved in chordoma genesis.

Adult↗

PubMed2001

Low incidence of SV40-like sequences in ependymal tumours.

Between 1955 and 1963, millions of children and adults were exposed to SV40-contaminated poliovirus vaccines. The oncogenic potential of this polyomavirus was revealed when intracerebral inoculation of SV40 into newborn hamsters resulted in the development of ependymomas and choroid plexus papillomas. Subsequently, SV40-like sequences were repeatedly detected in human ependymomas with broadly ranging incidence rates of 7-90%. Most epidemiological studies, however, have not described an increased occurrence of ependymomas. To gain more data on this controversial issue, this study examined 62 archived ependymal tumours from 31 children and 31 adults who underwent surgery between 1990 and 1999. Only three (5%) of the tumours--including 24 classical, 20 anaplastic, and 12 myxopapillary ependymomas; one subependymoma; and five ependymoblastomas--revealed subgenomic SV40 sequences. None of the ependymomas in patients born between 1920 and 1960 demonstrated SV40-like sequences. The positive tumours represent 7% of grade II and III ependymomas (two paediatric and one adult tumour). DNA sequencing of the PCR product revealed identical sequences of SV40 in the positive ependymal tumours. Compared with the results from other countries, this incidence rate is relatively low. Therefore, it seems likely that significant differences between individual countries exist regarding the prevalence of SV40-positive ependymomas. These differences may reflect different degrees of exposure to SV40-contaminated polio vaccine.

Adolescent↗

PubMed2001

Mediastinal B-cell lymphoma, a lymphoma type with several characteristics unique among diffuse large B-cell lymphomas.

Mediastinal B-cell lymphoma is a locally highly aggressive tumor with a rather unique pattern of clinical, morphologic, imunologic, and genetic features distinct from other diffuse large B-cell lymphomas. Characterization of this disease has been hampered by the relatively low incidence of this lymphoma type. Although recent studies on larger numbers of cases have allowed new insights into biology and clinics of this lymphoma type, the histogenesis of mediastinal B-cell lymphoma is not yet fully understood. This review will list morphologic, immunlogic, and genetic properties of mediastinal B-cell lymphoma and discuss recent data regarding the biology of this lymphoma type.

B-Lymphocytes↗

PubMed2001

Serum tenascin-C is an indicator of inflammatory bowel disease activity.

Tenascin-C is a multifunctional matrix protein that is induced in inflammation and neoplasia. In the colonic mucosa of ulcerative colitis patients tenascin-C indicates tissue repair, and mucosal concentrations are correlated with local disease activity. We prospectively examined the relationship between serum concentrations of tenascin-C parameters of disease activity in surgically treated patients with ulcerative colitis and patients with inflammatory bowel disease (IBD). Perioperative serum concentrations were quantified by ELISA in 58 patients admitted for restorative proctocolectomy; controls were 37 patients with familial adenomatous polyposis receiving the same treatment. We also measured tenascin-C serum levels in 47 patients with ulcerative colitis and Crohn's disease who were receiving nonsurgical treatment. Preoperative serum tenascin-C levels were significantly higher in ulcerative colitis patients than in controls (17.2 +/- 14.6 microg/ml vs. 3.2 +/- 1.7 microg/ml) and were significantly correlated with clinical and histological parameters of disease activity; levels decreased significantly after restorative proctocolectomy. Serum tenascin-C levels were also correlated with the course of disease activity in conservatively treated IBD patients. Tenascin-C is thus not disease-specific. However, it does indicate the activity of IBD and may reflect the degree of tissue remodeling. The tenascin-C levels therefore offers a novel serum parameter for assessing disease activity and monitoring therapy in patients with IBD.

Adolescent↗

PubMed2001

In situ characterization of genetically targeted (green fluorescent) single cells and their microenvironment in an adoptive host.

Stable expression of transgene-encoded enhanced green fluorescence protein (eGFP) was used as a sensitive and specific marker to detect in situ donor cells engrafted into different tissues of adoptive hosts. eGFP(+) lymphoid or myeloid cells (eg, CD4(+) T cells or bone marrow-derived dendritic cells) from eGFP-transgenic C57BL/6 donor mice were injected into congenic, immunodeficient RAG1(-/-) C57/BL6 hosts. eGFP(+) cells were detected in the adoptive host from 2 days to 4 weeks after transfer using an optimized method of fixed cryopreservation to process the tissue. This allowed the simple, sensitive, and specific detection of eGFP(+) donor cells in histological sections of transplanted hosts. We further demonstrate that this technique can be combined with other established labeling methods such as 1) immunofluorescent labeling to characterize the host cells interacting with engrafted cells and to determine the phenotype of the engrafted cells in situ; 2) terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining to detect apoptotic death of engrafted and autochthonous cell populations; and 3) fluorescent antibody labeling of incorporated bromodeoxyuridine to measure the fraction of proliferating cells in the graft.

Adoptive Transfer↗

PubMed2001

Is a preoperative multidiagnostic approach to predict surgical resectability of periampullary tumors still effective?

BACKGROUND: Multimodality staging is recommended in patients with periampullary tumors to optimize preoperative determination of resectability. We investigated the potency of currently used diagnostic procedures in order to determine resectability. METHODS: Ninety-five consecutive patients with periampullary tumors prehospitally staged resectable underwent preoperative diagnostic tests: helical-computed tomography (CT) with maximum intensity projection of arterial vessels (MIP), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreaticography (MRCP), endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreaticography (ERCP), digital subtraction angiography (DSA), and positron emission tomography (PET). Diagnoses were verified by surgery and histopathology. RESULTS: In 45 patients with benign and 50 patients with malignant periampullary tumors sensitivity for tumor diagnosis was 89% to 96% in CT, MRI, EUS, and PET. Small tumors were best diagnosed by EUS (100%). Diagnosis of malignancy was made with 85% (EUS), 83% (CT), 82% (PET), and 72% (MRI) accuracy. Arterial vessel infiltration was best predicted by CT/MIP with an accuracy of 85%. For venous vessel infiltration MRI reached 85% accuracy. Accuracy rates for local nonresectability were 93% (EUS), 92% (MRI), and 90% (CT). Two and 4 of 8 patients with distant metastases were identified by CT and PET, respectively. The correct diagnosis of malignancy and determination of resectability was made by CT in 71% and by MRI in 70%. Biliary stenting reduced accuracy of CT diagnosis of malignancy from 88% to 73%. CONCLUSIONS: CT obtained before stenting was the single most useful test, providing correct diagnosis in 88% and resectability in 71% of patients. If no tumor is depicted in CT, EUS should be added. Uncertain venous vessel infiltration can be verified by MRI or EUS. Angiography should no longer be a routine diagnostic procedure. Equivocal tumors or possible metastasis may be further examined with PET.

Ampulla of Vater↗

PubMed2001

Differential and mutually exclusive expression of CD95 and CD95 ligand in epithelia of normal pancreas and chronic pancreatitis.

Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4+Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95-/CD95L+, ducts were CD95-/CD95L-, and islets were CD95-/CD95L+. In areas of lymphohistiocytic infiltration, mainly consisting of CD3+CD4+ T cells and CD11c+, CD4+/-, S100p+ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR+, acini CD95+/CD95L-, and ducts CD95+/CD95L-. Islet cells were CD95-/CD95L+ in both conditions. IFNgamma levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p < 0.0003). In vitro, IFNgamma down-modulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95-/CD95L+ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFNgamma, CD4-Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack.

Antibodies, Monoclonal↗

PubMed2001

Differential effects of caspase-1/interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis.

There is recent experimental evidence that inhibition of caspase-1/interleukin-1beta converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1beta mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1beta protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-alpha mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1beta-mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-alpha.

Acute Disease↗

PubMed2001

Clustering of colonic lamina propria CD4(+) T cells to subepithelial dendritic cell aggregates precedes the development of colitis in a murine adoptive transfer model.

Initial lesions in inflammatory bowel disease induced during the repopulation of immunodeficient RAG1(-/-) mice with immunocompetent CD4(+) T cells have not been previously described. In this transfer colitis model, we followed CD4(+) T cell repopulation in the host by injecting autofluorescent CD4(+) T cells from congenic, enhanced green fluorescent protein (eGFP)-transgenic mice. This allowed the direct, sensitive, and unambiguous histological detection of the repopulation of the intestinal tract, mesenteric lymph nodes, and spleen of the host with donor eGFP(+) CD4(+) T cells. We identified in RAG1(-/-) mice intestinal dendritic cell (DC) aggregates under the basal crypt epithelium at the mucosa/submucosa junction from which F4/80(+) macrophages were excluded. At Days 8 to 11 posttransfer (before colitis was manifest), CD4(+) T cells clustered and proliferated in CD11c(+) DC aggregates. T cell clustering was most pronounced in the cecum where histologically overt colitis became manifest 5 to 10 days later. Junctional DC aggregates were thus prevalent in the triggering phase of the disease. The data suggest that pathogenic T cell responses inducing inflammatory bowel disease are primed or restimulated in situ in junctional CD4(+) T cell/DC aggregates.

Animals↗

PubMed2001

CD95 ligand (CD95L) immunohistochemistry: a critical study on 12 antibodies.

In recent years, some studies on the expression of CD95(Fas/APO-1) ligand (CD95L) in tissues or cells raised concerns about the specificity of the antibodies used. We therefore tested 12 CD95L antibodies for their reliability in immunocyto/histochemistry by (i) staining CD95L-transfected and control CV-1/EBNA cells and (ii) comparing staining patterns in immunohistochemically labeled tissue sections with the localization of CD95L+ cells in in situ hybridization. While G247-4, NOK-1, NOK-2, 4H9, and MIKE-1 stained CD95L-transfected cells and did not significantly bind to controls, G247-4 was the only antibody giving satisfying signals in tissue sections perfectly matching the distribution of CD95L+ cells by in situ hybridization. MAb 33, C-20, and N-20 comparably stained both transfected and control cells and showed considerable background or falsely positive staining in sections. MIKE-2, 8B8, A11, and 4A5 did not or only very faintly bind to either cells and, thus, were not tested on sections. We conclude that G247-4 is the only tested antibody that is recommendable for immunohistochemistry.

Antibodies, Monoclonal↗

PubMed2001

Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation.

OBJECTIVE: To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro. METHODS: Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson-Golabi-Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 microM cortisol and 2 microM BRL 49653, a PPAR gamma agonist. RESULTS: During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-specific mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required. CONCLUSION: The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8-15

Adipocytes↗

PubMed2001

Anti-ICAM-1 antibody modulates late onset of acinar cell apoptosis and early necrosis in taurocholate-induced experimental acute pancreatitis.

The hallmark of severe acute pancreatitis (SAP) is massive acinar cell death by necrosis. However, programmed, apoptotic acinar cell death has also been observed. Little is known about the dynamics, localization, and inductive factors of acinar cell apoptosis in SAP. We therefore induced SAP in rats by retrograde infusion of 3% sodium taurocholate. Starting as early as 5 minutes after taurocholate administration, small scattered groups of acinar cells showed zymogen degranulation, loss of cell polarity, cytoplasmic microvacuolization, and nuclear shrinkage, but no DNA degradation, thus featuring necrosis. The areas of necrotic acini extended at later time points giving rise to larger areas of complete parenchymal breakdown after 6 hours. Parenchymal degradation was paralleled by neutrophil infiltration and significant tumor necrosis factor (TNF)-alpha mRNA up-regulation. Up to the 12-hour interval, apoptotic acinar cells detected by TUNEL were as rare as in healthy pancreata. At 24 hours, however, the acinar apoptotic rate in nonnecrotic parenchyma had dramatically increased. Pretreatment of rats with anti-ICAM-1 antibody prior to pancreatitis induction led to a significant reduction of neutrophil infiltration along with decreased TNF-alpha mRNA expression throughout the 24-hour observation period without affecting the presence and dynamics of necrosis. However, anti-ICAM-1 pretreatment decreased the extent of acinar cell damage by necrosis and extensively suppressed acinar cell apoptosis. We conclude that taurocholate induces two sequential patterns of acinar cell death in terms of very early necrosis followed by late apoptosis during the postacute phase of SAP. The progression of necrosis and the late apoptotic acinar cell death seem to be influenced by the local presence of neutrophils via a TNF-alpha-dependent mechanism. In addition to augmenting necrosis, neutrophils might have an apoptosis-inducing potential in SAP.

Acute Disease↗

PubMed2001

Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization.

We screened 26 ependymomas in 22 patients (7 WHO grade I, myxopapillary, myE; 6 WHO grade II, E; 13 WHO grade III, anaplastic, aE) using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). 25 out of 26 tumors showed chromosomal imbalances on CGH analysis. The chromosomal region most frequently affected by losses of genomic material clustered on 13q (9/26). 6/7 myE showed a loss on 13q14-q31. Other chromosomes affected by genomic losses were 6q (5/26), 4q (5/26), 10 (5/26), and 2q (4/26). The most consistent chromosomal abnormality in ependymomas so far reported, is monosomy 22 or structural abnormality 22q, identified in approximately one third of Giemsa-banded cases with abnormal karyotypes. Using FISH, loss or monosomy 22q was detected in small subpopulations of tumor cells in 36% of cases. The most frequent gains involved chromosome arms 17 (8/26), 9q (7/26), 20q (7/26), and 22q (6/26). Gains on 1q were found exclusively in pediatric ependymomas (5/10). Using FISH, MYCN proto-oncogene DNA amplifications mapped to 2p23-p24 were found in 2 spinal ependymomas of adults. On average, myE demonstrated 9.14, E 5.33, and aE 1.77 gains and/or losses on different chromosomes per tumor using CGH. Thus, and quite paradoxically, in ependymomas, a high frequency of imbalanced chromosomal regions as revealed by CGH does not indicate a high WHO grade of the tumor but is more frequent in grade I tumors.

Adolescent↗