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Biomedical subjects

M Hummel

Publications and source records attributed to M Hummel.

At least 217 records · Page 12Linked to original sources
PubMed1995

[Primary brain lymphoma in acquired immunodeficiency syndrome. Immunophenotype and molecular pathologic characterization in stereotactic biopsy, autopsy and cerebrospinal fluid cytology].

In this study we present morphological, cytological, immunophenotypical, and molecular genetic features of ten cases of AIDS-related primary brain lymphomas obtained as sterotactic biopsies, autopsy specimens, or cerebrospinal fluid samples. Histologically, a very characteristic perivascular and diffuse lymphomatous spread in the brain parenchyma was observed. By applying a highly sensitive in situ hybridization technique (ISH) using digoxigenin-labeled antisense riboprobes, abundant Epstein-Barr virus (EBV)-encoded small nuclear RNAs (EBER) transcripts could be demonstrated in each case studied. A combination of ISH with immunohistochemical staining for latent membrane protein (LMP-1) and EBV nuclear antigen-2 (EBNA-2) showed different patterns of EBV latency with a predominance of the broad spectrum (EBER+/EBNA-2+/LMP-1+). Clonal rearrangements of immunoglobulin heavy chain (IgH) genes were demonstrated in four cases using a sensitive polymerase chain reaction. In one patient the rearrangement pattern suggested biclonal lymphoproliferation. Our observations confirm the implication of the EBV in the etiology of AIDS-related primary malignant lymphomas of the brain. The demonstration of EBV gene products and clonal IgH rearrangements even in small biopsy samples is a useful tool for distinguishing between reactive and neoplastic lymphocytic infiltrates, which are frequently observed in brain and cerebrospinal fluid specimens obtained from AIDS patients.

Adult↗
PubMed1995

Human papillomavirus type 31b late gene expression is regulated through protein kinase C-mediated changes in RNA processing.

Expression of the human papillomavirus (HPV) capsid genes, L1 and L2, as well as amplification of viral DNA and virion assembly occur in the terminally differentiated layers of infected stratified squamous epithelium in vivo. These processes can be duplicated in the laboratory through the use of organotypic or raft cultures. When CIN612 cells, which contain episomal copies of the high-risk HPV type 31b, are allowed to differentiate in raft cultures, the expression of transcripts encoding the early genes E1--E4 and E5 is induced. These transcripts are initiated at the differentiation-dependent P742 promoter located in the middle of the E7 open reading frame. Exposure of raft cultures to activators of protein kinase C, such as phorbol esters, results in the further induction of late gene expression as well as virion assembly. In this study, we have investigated the mechanism by which activators of protein kinase C induce late gene expression. The major L1 transcript was found to be encoded by a bicistronic E1--E4, L1 RNA which initiated at the differentiation-dependent promoter P742. Additional low-level expression of L1-containing RNAs was also observed from the early-region promoter, P97. The major L2 transcripts were found to be encoded by E1--E4, E5, L2, L1 RNAs which were also initiated in the early region, probably at the differentiation-specific promoter P742. While early and late RNAs were found to be expressed from the same promoter, they differed in utilization of splicing and polyadenylation sites. Raft cultures treated with activators of protein kinase C induced expression of late genes, but no change in the abundance of early RNAs initiated at the P742 promoter was observed. Thus, the increase in late gene expression was likely due to changes in RNA processing or stabilization rather than an increase in the rate of transcription from P742. Regulation of HPV late gene expression therefore occurs at two levels: differentiation-dependent induction of the P742 promoter, which can be mimicked in vitro by growth in raft cultures, and posttranscriptional changes that can be induced by activation of protein kinase C. These posttranscriptional changes may occur through inactivation or down-regulation of splicing factors which inhibit use of the late region polyadenylation site, resulting in increased stability of late region transcripts.

Cells, Cultured↗
PubMed1995

Frequent presence of latent Epstein-Barr virus infection in peripheral T cell lymphomas. A review.

Two-hundred and four cases of peripheral T cell lymphoma (PTCL) occurring in Europeans without any sign of HIV-infection were investigated for their association with an Epstein-Barr virus (EBV) infection. Polymerase chain reaction (PCR) was applied for EBV-DNA detection, in situ hybridisation (ISH) for the cellular localization of EBV-encoded small nuclear RNA (EBER) and immediate early gene expression (BHLF) and immunohistology (IH) for the detection of EBV-encoded latent membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2) expression. PCR and EBER-ISH produced congruent results in almost all cases with amplifiable DNA, leading to the finding of an overall frequency of EBV presence in 87/204 (42.6%) of the PTCL cases. Through EBER-ISH, the virus was identified to be exclusively present in small and blastic bystander lymphocytes in 29 cases, whilst an additional infection of neoplastic T cells was observed in the remaining 58 EBV-positive cases. The entity presenting with the most frequent EBV infection of tumour cells was that of angioimmunoblastic type PTCL, whilst the primary cutaneous PTCLs only seldom harbored the virus. Forty-eight of the EBV-positive TCLs showed an infection of a small proportion (1-20%) of the tumour cell population, whilst another ten cases, belonging to the pleomorphic TCL (PMTCL) group, displayed an infection of several to almost all neoplastic T cells (20-100%). Additional lytic EBV-infected cells could be detected in four cases by BHLF-ISH. LMP1 expression was present in a small proportion of the neoplastic T cells in 24 of the 58 cases with tumour cell infection, whilst an EBNA2 expression was detectable only in one case. Some non-malignant EBV-infected B-immunoblasts and Hodgkin/Reed Sternberg-like cells also expressed LMP1 in several cases. Our data imply a role of EBV in the pathogenesis of only a few PMTCL cases with predominant tumour cell infection, whilst the pathogenic significance of an EBV infection in the other PTCLs remains unclear due to the usually partial infection of the neoplastic cell component.

Antibodies, Monoclonal↗
PubMed1995

Burkitt's lymphomas express VH genes with a moderate number of antigen-selected somatic mutations.

The normal counterpart of the neoplastic B cells occurring in Burkitt's lymphomas (BL) is an issue of controversial debate. To clarify this matter, a semi-nested primer polymerase chain reaction was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (VH) gene of DNA extracts from 10 (8 sporadic and 2 endemic) BL cases. The resulting amplificates were sequenced for comparison with known germ line VH segments. The control cases comprised six cases of B cell chronic lymphocytic leukemia and six cases of mantle cell lymphoma known to display naive nonmutated, ie, pre-germinal center VH configurations; and eight cases of follicular center lymphoma known to display mutated VH genes with signs of a still-ongoing mutation reaction, characteristic for germinal center cells and lymphomas that derive therefrom. The results of this approach revealed that both sporadic and endemic BL express mutated VH genes with a mutation frequency considerably lower (4.9% and 5.4%, respectively) than that observed in follicular center lymphoma (11.8%). In addition, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations. These results led us to conclude that the derivation of neoplastic B cells in BL is definitely not from naive, nonmutated pre-germinal center B cells. Instead, our findings support the view that BL cells stem either from early centroblasts that are arrested after an initial hypermutation reaction, or from germinal center B cells that have differentiated in terms of surface immunoglobulin profile and mutation pattern but not in terms of morphology and proliferation toward SIgM+ IgD- memory B cells because of the deregulated c-myc gene expression.

Burkitt Lymphoma↗
PubMed1995

Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease.

Interleukin-7 (IL-7) is a pleiotropic cytokine acting mainly on cells of the hematolymphoid system. In vitro studies have shown enhanced proliferation of acute lymphoblastic leukemia cells in response to IL-7. On the other hand, tumor cell lines transfected with a functioning IL-7 gene and subsequently transplanted into mice resulted in a prominent inflammatory infiltrate and reduced tumorigeneicity. These data suggest an important role of this cytokine in the pathophysiology of lymphoid neoplasms. Because little is known about the in vivo expression of this cytokine in various neoplastic and nonneoplastic lesions of the lymphoid system, we examined frozen and paraffin-embedded tissue samples of normal, reactive, and malignant lymphoid lesions using in situ hybridization with a 35S-labeled RNA probe specific for IL-7. Tumor cells of nodular sclerosing and mixed cellularity type of Hodgkin's disease displayed IL-7-specific signals in 24 of 31 cases. Among reactive lesions, only thymic tissue showed labeling within both cortex and medulla (4 of 7 cases), whereas in tonsils clear-cut IL-7-specific signals could not be found. Tissues infiltrated by B-type chronic lymphocytic leukemia or T- or B-type lymphoblastic lymphoma showed cytokine-specific signals in only one case of lymphoblastic lymphoma in rare reactive cells. In conjunction with the finding of elevated levels of IL-7 in the serum of many patients with Hodgkin's disease, our data suggest an important role of this cytokine in the pathogenesis of Hodgkin's disease. The prominent reactive infiltrate observed in most cases of Hodgkin's disease could be a consequence of elevated local levels of this cytokine as similar infiltrates are also observed in tumors in mice resulting from injection of tumor cell lines transfected with a functioning IL-7 gene.

Child↗
PubMed1994

[Primary cutaneous Nocardia farcinica infection following heart transplantation].

A 57-year-old man, treated with immunosuppressive drugs for 3 months after a heart transplantation, developed a painful swelling of the left upper leg and fever. Needle biopsy of the lesion obtained pus from which Nocardia farcinica was cultured. Azathioprine treatment was discontinued and the dosage of cyclosporine reduced. Following antibiotic sensitivity tests, imipenem (4 g/d intravenously) and amikacin (1 g/d intravenously) were administered and the abscess split open. Although the fever responded and dissemination of the infection was excluded the response to treatment was not satisfactory. The drug dosages were repeatedly reduced in response to a rise in serum creatinine concentration to 3.4 mg/dl, deafness, double vision and generalized seizures: the local lesion got worse, but further surgical intervention then brought improvement. After 7 weeks of administration of the above antibiotics, treatment was changed to doxycycline (100 mg/d by mouth). 3 months later computed tomography could no longer demonstrate the lesion.

Abscess↗
PubMed1994

Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes.

The nature of Hodgkin and Reed-Sternberg (HRS) cells remains in question. Immunophenotypic studies favor a relation to the lymphoid lineage with the existence of B- and T-cell types. However, studies on the detection of antigen (Ag) receptor gene rearrangements provided inconsistent results. They concur in that rearranged Ig and T-cell receptor (TCR) genes are not demonstrable in most Hodgkin's disease (HD) cases. To clarify whether this is because of the insensitivity of the method of detection or a real absence of clonal Ig heavy chain (IgH) rearrangements, a polymerase chain reaction (PCR) method with high sensitivity was applied, allowing the detection of less than 50 cells with clonally rearranged IgH genes in a mixture of 100,000 germline or individually rearranged cells. In 67 cases of HD, most of those (67%) with B-Ag+ HRS cells express clonal VDJ rearrangements of the IgH gene. No cases with T-cell Ag+ HRS cells harbored detectable clonal VDJ rearrangements. Of 10 sequenced rearranged IgH genes, the VH segment of six contained considerable somatic mutations. These results suggest that the demonstrated VDJ rearrangements stem from the HRS cells themselves and that the HRS cells of cases with rearranged IgH genes are B-cell related and correspond in their differentiation stage either to naive pregerminal center B cells or (more commonly) to germinal center/postgerminal center-derived memory B cells.

Amino Acid Sequence↗
PubMed1994

Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle.

To clarify whether mantle cell lymphomas (MCLs) are related to naive pre-germinal center B cells (expressing nonmutated rearranged VH genes) or to germinal center-derived memory B cells (expressing mutated rearranged VH genes), clonal IgH gene rearrangements using DNA from six MCLs were polymerase chain reaction (PCR)-amplified and analyzed for the presence of somatic mutations. For comparison, six cases of B-chronic lymphocytic leukemia (B-CLL) known to display nonmutated rearranged VH genes and six cases of follicle center lymphomas (FCLs) known to display mutated rearranged VH genes were included in our study. The VH region sequences of the six MCLs showed, like those of the six B-CLL cases, no or very little somatic mutations, in contrast to the VH sequences of the six FCL cases, all of which were highly mutated. This is indicative of MCL, like B-CLL, being derived from naive pre-germinal center B cells and furthermore underscores the postulated relationship of MCLs with the B cells of the normal follicular mantle zone because it has recently been shown that this mantle zone is solely or at least largely composed of naive (nonmutated) B cells.

Gene Rearrangement↗
PubMed1994

Nucleophosmin (NPM) gene rearrangements in Ki-1-positive lymphomas.

The (2;5)(p23;q35) translocation which results in the fusion of the NPM (nucleophosmin) gene on chromosome 5q35 with the novel ALK (anaplastic lymphoma kinase) gene on chromosome 2p23 [S.W. Morris et al., Science (Washington DC), 263: 1281-1284, 1994] is associated with Ki-1 (CD30)-positive anaplastic large cell lymphomas (ALCL); a group of morphologically and immunophenotypically heterogenous high grade large cell lymphomas (LCL), which share many characteristics with Hodgkin's disease (HD), including the presence of variable numbers of Reed-Sternberg-like cells and the expression of CD30 antigen. Using a DNA probe immediately 5' to the NPM coding sequences, we have examined NPM gene rearrangements by Southern blotting in 5 Ki-1-positive lymphoma cell lines carrying a translocation involving the 5q35 breakpoint and in 25 Ki-positive lymphoma tumors, including 9 HD. Using this method, we detected rearrangements in all cell lines with apparent clustering of the breakpoints. Analysis of 25 Ki-1-positive lymphomas indicated that only 4 neoplasms, including two HD, had NPM gene rearrangements. Thus, our findings suggest that only a subset of ALCL has detectable involvement of the NPM gene. In addition, the presence of NPM gene rearrangements in HD indicates the involvement of this gene in a fraction of HD. Thus, NPM gene rearrangements may identify a certain subtype in ALCL and HD which may be closely related.

Chromosomes, Human, Pair 2↗
PubMed1994

Patterns of cytokine gene expression in infectious mononucleosis.

Primary infection with Epstein-Barr virus (EBV) may arise as infectious mononucleosis (IM) in adolescents and young adults. Morphologically, IM-affected lymphoid tissue is characterized by expanded interfollicular areas with formation of atypical lymphoid blasts. It is assumed that morphology and clinical presentation of IM are related to characteristic patterns of cytokine production by EBV-infected and reactive cells. We studied IM tonsils of eight patients and six normal tonsils with a double in situ hybridization procedure using [35S]-labeled RNA probes specific for various cytokines and digoxigenin-labeled probes for the detection of the nuclear EBV encoded RNA transcripts, EBER 1 and 2. All of the IM cases displayed the same distinct cytokine gene expression pattern. When compared with interfollicular areas of normal tonsils, expression of lymphotoxin (LT), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, but not IL-8 or IL-1 alpha was strongly enhanced in interfollicular areas in IM tonsils. LT was expressed predominantly by EBV-infected cells. TNF-alpha transcripts were also present in EBV-infected cells, although in smaller proportions. IL-6 specific signals were only found in few EBV-infected cells. IL-1 alpha-, IL-1 beta-, and IL-8-specific signals were not observed in EBV-infected cells, but were present at high signal intensity in many cells within and around foci of EBV-infected cells (IL-1 beta), next to areas of necrosis (IL-8, IL-1 beta), or in epithelial cells (IL-1 alpha). These data suggest that EBV infection in form of IM results in induction of specific sets of cytokine genes in EBV-infected and in neighboring EBV-negative cells contributing to the characteristic morphology and cellular arrangement of the lesion as well as the clinical presentation.

Cytokines↗
PubMed1994

The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen.

Tissue distribution and expression on mitogen and virally stimulated lymphocytes render the ACT35 molecule a human lymphocyte activation antigen which as yet could not be clustered. Expression cloning of the ACT35 antigen from a pCDM8 library of the HUT-102 cell line revealed strong homology of the cDNA and its encoded protein sequence with the formerly described rat OX40 antigen. The 1.4-kb nucleotide sequence and the deduced 277-amino acid sequence of the single transmembrane protein were 65% and 63% identical, in human and in rat, respectively. Conservation included one N-linked glycosylation site and one protein kinase C phosphorylation site. When expressed in COS-1 cells, the cDNA presented properties comparable to the native ACT35 antigen and the rat OX40 molecule (relative molecular mass 48,000). Thus, the ACT35 protein corresponds to the hitherto unknown human OX40 antigen and is, therefore, another member of the tumor necrosis factor/nerve growth factor receptor (TNFR/NGFR) family. After applying fluorescence in situ hybridization, the human ACT35/OX40 gene could be mapped to chromosome band 1p36 and is, thus, linked to the genes for TNFR II and CD30.

Amino Acid Sequence↗
PubMed1994

[Arteria lusoria--a rare cause of dysphagia].

A rare case of a 29-year old woman with aberrant right subclavian artery (A. lusoria) causing dysphagia is presented. This abnormality is generally silent and often an incidental x-ray finding. By means of a median thoracotomy the anomalous vessel was divided at its point of origin and an anastomosis to the ascending aorta with a graft was performed.

Adult↗
PubMed1994

Disseminated growth of Hodgkin's-derived cell lines L540 and L540cy in immune-deficient SCID mice.

Local tumor growth has been reported after subcutaneous and intraperitoneal injection of Hodgkin's disease (HD) derived cell lines into different immunodeficient mouse strains. An animal model with disseminated growth of tumor cells would be useful for studying the in vivo biology of HD cells as well as for preclinical testing of new therapeutic regimens. For this purpose the HD-derived cell lines L540, L540cy, L428, and KM-H2 were injected intravenously into SCID mice. In contrast to L428 and KM-H2, widespread neoplasia occurred after a period of four to six weeks following injection of L540 and the subline L540cy. Lymph nodes were found to be the preferred site of tumor growth. CD30 surface antigen expression on Hodgkin cells and the karyotype of the tumor cells were preserved in the animal host. Thus, to a large extent, the SCID mouse model mimics the dissemination pattern of Hodgkin's disease in man. To evaluate the role of adhesion molecule expression in the dissemination of HD-derived cell lines, CD44 and members of the immunoglobulin, integrin, selectin, and Fc receptor families were quantified by flow cytometry. CD30 expression was also measured. Although CD44 expression has been correlated with dissemination in non-Hodgkin's lymphoma (NHL), this was not the case in the Hodgkin's SCID mouse model. CD44 was not expressed on the disseminating cell lines L540 and L540cy but was expressed in the nondisseminating lines L428 and KM-H2.

Animals↗
PubMed1994

Interleukin-6 and interleukin-8 concentrations as predictors of outcome in ventricular assist device patients before heart transplantation.

OBJECTIVE: To determine whether the serum concentrations of some circulating cytokines (as highly sensitive markers of inflammation) are of value in predicting the outcome of patients with cardiogenic shock and end-stage heart disease, who undergo ventricular assist device implantation until heart transplantation. DESIGN: Cohort study. SETTING: University teaching hospitals. PATIENTS: Twenty patients with cardiogenic shock or end-stage heart disease were consecutively selected for this study, if assist device implantation was performed as a bridge to heart transplantation. MEASUREMENTS AND MAIN RESULTS: The circulating concentrations of the cytokines interleukin (IL)-1 beta, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha were monitored from the beginning to the end of assist device support two to three times a week, using commercial enzyme-linked immunosorbent assays (ELISA). In all patients, circulating IL-6 and IL-8 values were increased shortly after assist device implantation. In patients with uncomplicated courses, IL-6 and IL-8 concentrations decreased after an initial increase and were low at the time of transplantation, whereas serum cytokine concentrations increased and remained increased in the nonsurvivors (survivors vs. nonsurvivors, p < .001). Circulating IL-1 beta and TNF-alpha concentrations were rarely detectable. CONCLUSIONS: Monitoring of IL-6 and IL-8 values during ventricular assist device support provides a means of early identification of high-risk patients that may allow optimization of antimicrobial therapy and selection of the appropriate time for transplantation.

Adolescent↗
PubMed1994

Human resident peritoneal macrophages: phenotype and biology.

Macrophages represent the primary line of host defences in the peritoneal cavity. In order to study the metabolic activity and maturation stage of human resident peritoneal macrophages (PM phi). peritoneal fluid (PF) was taken by Douglas puncture from healthy hyperstimulated infertile women undergoing oocyte retrieval for in vitro fertilization. Peritoneal fluid and macrophage culture fluids were studied for different inflammatory mediators such as interleukin-1 (IL-1), tumour necrosis factor (TNF) and interleukin-6 (IL-6). The level of macrophage colony-stimulating factor (M-CSF), which represents a macrophage proliferation and differentiation factor, was determined in the PF and in the serum. Furthermore, the macrophage phenotypic profile was analysed, in particular the expression of sex steroid hormone receptors. IL-1. IL-6 and TNF were detectable in the PF and in the culture supernatants of PM phi whether stimulated or not by IFN-gamma and LPS. The mean level of M-CSF in the PF was 6.37 +/- 2.02 ng/ml as measured by RIA; this level did not correlate with the concentration of PM phi. The mean PF-M-CSF level was 1.4-fold higher than in the sera as measured by a EIA. Oestrogen and progesterone receptors could not be demonstrated on the PM phi analysed, so that a direct relationship between the ovarian steroid concentration in these women and the function of PM phi was unlikely. As compared to peripheral blood monocytes (Mo). PM phi showed a phenotypic profile, with some more mature features, e.g. increased expression of CD14, CD68, FcRII, FcRIII, CR3, CR4 and MHC class II determinants. These results indicate that resident PM phi have acquired in vivo a certain differentiation and/or activation state under micro-environmental factors where cytokines secreted by the M phi themselves or by other cells such as the mesothelium may play important roles.

Antibodies, Monoclonal↗
PubMed1994

Frequent presence of latent Epstein-Barr virus infection in lymphoepithelioid cell lymphoma (Lennert's lymphoma).

This study deals with the investigation of the biological significance of an Epstein-Barr virus (EBV) infection in lymphoepithelioid cell lymphoma. A selection of EBV-detection techniques was applied to 15 cases, including polymerase chain reaction (PCR) for the detection of EBV-DNA, in situ hybridization (ISH) for the cellular localization of EBV-encoded small nuclear (EBER 1 and EBER 2) and immediate-early (BHLF) RNAs, and immunohistology for the detection of EBV-encoded latent membrane protein (LMP) expression. PCR and EBER-ISH produced congruent results in those cases with amplifiable DNA, leading to an EBV presence in 11/15 lymphoepithelioid cell lymphoma cases (73%). EBER-ISH combined with immunohistology localized the virus predominantly in several B immunoblasts and small B lymphocytes in eight of the EBV-positive cases, five of which also contained single infected lymphocytes expressing T-cell characteristic antigens. LMP was detected using immunohistology in only a proportion of immunoblasts in four of these cases. The remaining three EBV-positive lymphoepithelioid cell lymphoma cases contained only single EBER-positive small B lymphocytes without LMP expression. No case contained BHLF-RNA expressing cells. These data imply that, although latently EBV-infected cells are frequently present in lymphoepithelioid cell lymphoma cases, the virus is probably not directly involved in the pathogenesis of this entity.

Antibodies, Monoclonal↗
PubMed1994

[Criteria for molecular biological diagnosis in pathology].

Since its initial description in 1985 (Saiki et al., 1985), the polymerase chain reaction (PCR) has become one of the leading techniques. This approach is not only able to clarify many questions in basic research, but also diagnostical issues. The application of PCR in the field of tissue diagnosis is still at its infant stage, although it has already proved to be of great value. However, the slow introduction of PCR in the field of Pathology is the cause of much misunderstandings for many clinician. Of the possible reasons for this, one could be the fact that the tissue diagnosis is carried out by the investigation of formalin-fixed material. One solution to this situation would be to propose a frame-work of conditions for the introduction of PCR as a diagnostically valuable method of investigation.

Chromosome Aberrations↗