PubMed Health⌕ Search

Biomedical subjects

A Rosenwald

Publications and source records attributed to A Rosenwald.

At least 19 recordsLinked to original sources
PubMed2007

[Extranodal diffuse large B-cell lymphoma--an organotypic disease?].

Roughly 30-40% of diffuse large B-cell lymphomas (DLBCL) arise primarily in extranodal sites. Most frequently, they occur in the gastrointestinal tract, especially in the gastric mucosa. They also occur in the central nervous system, as testicular lymphomas, in the lungs, or in the skin. Morphologically, they show the whole spectrum of peripheral B-blasts: centroblasts, immunoblasts, or plasmoblasts. Thus, there is no actual difference in their cytomorphological presentation compared to their nodal-and frequently systemic-counterparts. However, recent data point to profound differences in primary extranodal DLBCL compared to primary nodal tumors, as well as to each other, frequently relating to their molecular characteristics and especially implying organotypic features. These characteristics may relate to a particular organotypic site of origin, or the particular clinico-pathogenetic setting in which the tumors arise. This is exemplified in the description of the DLBCL subtypes as defined by the World Health Organization classification (mediastinal or intravascular B-cell lymphoma; primary effusion lymphoma). On the other hand, primary extranodal DLBCL are frequently characterized by a particular (cyto-)genetic constitution, often related to their site of origin. Finally, some preliminary data on gene expression profiling strongly argue in favor of particular gene signatures for primary extranodal DLBCL, and hence in favor of particular organotypic transformation pathways.

Central Nervous System Neoplasms↗
PubMed2006

[DNA-chips in the diagnosis of hematological malignancies].

In hematological malignancies, gene expression profiling using DNA-microarrays led to the discovery of novel lymphoma and leukemia subgroups. The heterogeneous entity of diffuse large B-cell lymphoma could be subdivided into the germinal center B-cell-like and the activated B-cell-like subtype which differ in pathogenesis and clinical behavior. In leukemia, existing entities defined by morphological, cytogenetic, molecular and immunophenotypic criteria were confirmed on the global gene expression level; in addition, new important molecular subgroups could be identified. In retrospective clinical lymphoma and leukemia studies, robust gene expression signatures were discovered that predict the clinical course at the time of diagnosis. Given the huge potential of the DNA-microarray technology, application in the routine diagnostic setting appears possible.

Biomarkers, Tumor↗
PubMed2006

Nematode infection of the liver mimicking metastasis of malignant melanoma.

BACKGROUND: The differential diagnoses of a circumscribed mass of the liver are varied. Especially if a malignant tumor, capable of setting metastases to the liver, is known in a patient's medical history, there might be difficulties in differentiating the tumor's entity. CASUISTRY: We report a case of a 40-year-old male with a history of malignant melanoma in whom follow-up investigations revealed a mass in the liver. RESULTS: The histopathological and microbiological results, however, showed an infestation of liver tissue with nematodes. Malignant tumor cells could not be detected. CONCLUSIONS: Roundworm-infections of the liver can present as lesions suspicious of being malignant. Therefore, along with e.g. microhamartoma, microabscesses and hepatocellular carcinoma, infestation with nematodes should be taken into consideration.

Adult↗
PubMed2006

Characterization of chromosomal aberrations in diffuse large B-cell lymphoma (DLBL) by G-banding and spectral karyotyping (SKY).

Cytogenetic chromosome analysis by classical G-banding was supplemented by spectral karyotyping (SKY) in 12 cases of diffuse large B-cell lymphoma (DLBL). SKY is a fluorescence in-situ-based, genome-wide screening technique allowing identification of genetic material even in highly condensed metaphase chromosomes of poor morphology. By simultaneous hybridization of whole chromosome painting probes onto tumor chromosome spreads genetic rearrangements are visualized permitting the clarification of even complex karyotype alterations and the identification of genetic material of previously unknown origin, so-called marker chromosomes. Taking the SKY results into account, we reevaluated the G-banding karyotypes initially carried out, thus generating a more precise karyotype in ten of twelve (83%) cases investigated. In particular, thirteen chromosomal rearrangements not correctly recognized by classical cytogenetics were identified, the genetic origin of seven marker chromosomes was elucidated and three structural genetic rearrangements were redefined. We found SKY to be a valuable technique to establish a definite karyotype in addition to classical cytogenetics.

Chromosome Aberrations↗
PubMed2005

Checkpoint kinase 1 (CHK1) protein and mRNA expression is downregulated in aggressive variants of human lymphoid neoplasms.

CHK1: gene encodes for a serine/threonine kinase involved in the regulation of cell cycle progression and DNA damage checkpoints. To determine the role of CHK1 in the pathogenesis of lymphoid neoplasms and its relationship to other DNA damage response genes, we have analyzed the gene status, protein, and mRNA expression in a series of tumors and nonneoplastic lymphoid tissues. CHK1 protein and mRNA expression levels were very low in both reactive tissues and resting lymphoid cells, whereas tumor samples showed a variable pattern of expression related to their proliferative activity. However, seven aggressive tumors showed a dissociate pattern of extremely low or negative protein expression in spite of a high proliferative activity. Four of these tumors were diffuse large B-cell lymphomas (DLCLs) with concordant reduced levels of mRNA, whereas one blastoid mantle cell lymphoma (B-MCL) and two DLCLs had relatively normal levels of mRNA. No gene mutations, deletions, or hypermethylation of the promoter region were detected in any of these cases. In all these tumors ATM, CHK2, and p53 genes were wild type. These findings suggest that CHK1 inactivation in NHLs occurs by loss of protein expression in a subset of aggressive variants alternatively to ATM, CHK2, and p53 alterations.

Blotting, Western↗
PubMed2003

Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis.

Autoimmune diseases such as multiple sclerosis are characterized by complex genetic traits and pathomechanisms that translate into clinical heterogeneity. This wide heterogeneity of multiple sclerosis as well as different biological responses to immunomodulatory drugs can be expected to contribute to differential treatment responses. Strategies that dissect the relationship between the treatment response and the biological characteristics in individual patients are valuable not only as a clinical tool, but also in leading to a better understanding of the disease. Here we address the in vitro and ex vivo RNA expression profile under one approved therapy of multiple sclerosis, interferon-beta (IFN-beta, Betaseron), by cDNA microarrays and demonstrate that non-responder and responder phenotypes to IFN-beta as assessed by longitudinal gadolinium-enhanced MRI scans and clinical disease activity differ in their ex vivo gene expression profile. These findings will help to better elucidate the mechanism of action of IFN-beta in relation to different disease patterns and eventually lead to optimized therapy.

Follow-Up Studies↗
PubMed2002

Identifying pre-post chemotherapy differences in gene expression in breast tumours: a statistical method appropriate for this aim.

Although widely used for the analysis of gene expression microarray data, cluster analysis may not be the most appropriate statistical technique for some study aims. We demonstrate this by considering a previous analysis of microarray data obtained on breast tumour specimens, many of which were paired specimens from the same patient before and after chemotherapy. Reanalysing the data using statistical methods that appropriately utilise the paired differences for identification of differentially expressed genes, we find 17 genes that we can confidently identify as more expressed after chemotherapy than before. These findings were not reported by the original investigators who analysed the data using cluster analysis techniques.

Antineoplastic Agents↗
PubMed2002

Tyrosine phosphorylation in human lymphomas.

In a previous study, we showed that the high level of protein tyrosine phosphorylation present in lymphomas containing an anaplastic lymphoma kinase (ALK) can be demonstrated in routinely processed paraffin tissue sections using immunolabelling techniques. In the present study we investigated whether oncogenic tyrosine kinase activation also occurs in other categories of lymphoma by staining 145 cases of lymphoma covering those tumours with a range of different subtypes including those with morphological similarity to ALK-positive anaplastic large cell lymphoma (ALCL). Twelve cases of the borderline malignant disorder lymphomatoid papulosis were also studied. Twenty seven of the 28 cases of ALK-positive ALCL showed the extensive cytoplasmic labelling for phosphotyrosine in the neoplastic cells. The remaining case containing moesin-ALK exhibited membrane-associated phosphotyrosine expression. There was no nuclear phosphotyrosine labelling in any of the ALK-positive ALCL, even though ALK was present within the cell nuclei in 23 of the tumours. Variable degrees of phosphotyrosine labelling, usually membrane-restricted, were observed in 7/40 cases of ALK-negative ALCL, 9/29 cases of diffuse large B-cell lymphoma, 3/6 cases of mediastinal B-cell lymphoma, 2/7 cases of Hodgkin's lymphoma, 3/6 cases of peripheral T-cell lymphomas unspecified, 4/6 cases of B-cell chronic lymphocytic leukaemia, 2/6 cases of follicular lymphomas and 2/12 cases of lymphomatoid papulosis studied. However none of these phosphotyrosine-positive cases showed the strong cytoplasmic labelling comparable to that seen in ALK-positive lymphoma. We conclude that activation of a tyrosine kinase is probably not a major oncogenic event in lymphomas other than ALK-positive ALCL.

Cell Nucleus↗
PubMed2001

Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

Gene Expression↗
PubMed2001

Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol.

BACKGROUND: Flavopiridol, a flavonoid currently in cancer clinical trials, inhibits cyclin-dependent kinases (CDKs) by competitively blocking their ATP-binding pocket. However, the mechanism of action of flavopiridol as an anti-cancer agent has not been fully elucidated. RESULTS: Using DNA microarrays, we found that flavopiridol inhibited gene expression broadly, in contrast to two other CDK inhibitors, roscovitine and 9-nitropaullone. The gene expression profile of flavopiridol closely resembled the profiles of two transcription inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), suggesting that flavopiridol inhibits transcription globally. We were therefore able to use flavopiridol to measure mRNA turnover rates comprehensively and we found that different functional classes of genes had distinct distributions of mRNA turnover rates. In particular, genes encoding apoptosis regulators frequently had very short half-lives, as did several genes encoding key cell-cycle regulators. Strikingly, genes that were transcriptionally inducible were disproportionately represented in the class of genes with rapid mRNA turnover. CONCLUSIONS: The present genomic-scale measurement of mRNA turnover uncovered a regulatory logic that links gene function with mRNA half-life. The observation that transcriptionally inducible genes often have short mRNA half-lives demonstrates that cells have a coordinated strategy to rapidly modulate the mRNA levels of these genes. In addition, the present results suggest that flavopiridol may be more effective against types of cancer that are highly dependent on genes with unstable mRNAs.

Antineoplastic Agents↗
PubMed2001

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study.

PURPOSE: Previously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome. METHODS AND MATERIALS: Eighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control. RESULTS: The overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients. CONCLUSION: Complete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.

Adult↗
PubMed2001

Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes.

Multiple sclerosis (MS) is considered an autoimmune disease that is mediated by proinflammatory T helper-1 lymphocytes. The putative mechanism of interferon-beta (IFN-beta), an approved treatment for MS, includes the inhibition of T-cell proliferation, blocking of blood-brain-barrier opening and T-cell transmigration into the brain via interference with cell adhesion, and the upregulation of anti-inflammatory cytokines. In the present study, a gene expression analysis of IFN-beta-treated peripheral blood mononuclear cells by cDNA microarray documents the broad effects of IFN-beta that are not purely anti-inflammatory. Specifically, we addressed the effect of IFN-beta on T helper-1 differentiation- or lineage markers such as the IL-12 receptor beta2 chain and the chemokine receptor CCR5 that have been implicated in the pathogenesis of MS. Both markers were significantly upregulated in vitro and in vivo under IFN-beta therapy, supporting that this cytokine exerts complex effects on the immune system. The combination of cDNA microarray and quantitative PCR will expand our knowledge of the immunological effects of such pleiotropic agents as IFN-beta, may provide a key to why certain patients fail to respond, and eventually may influence our view of the disease pathogenesis.

Adjuvants, Immunologic↗
PubMed2001

Signatures of the immune response.

A compendium of global gene expression measurements from DNA microarray analysis of immune cells identifies gene expression signatures defining various lineages, differentiation stages, and signaling pathways. Germinal center (GC) B cells represent a discrete stage of differentiation with a unique gene expression signature. This includes genes involved in proliferation, as evidenced by high expression of G2/M phase regulators and low expression of ribosomal and metabolic genes that are transcriptional targets of c-myc. GC B cells also lack expression of the NF-kappaB signature genes, which may favor apoptosis. Finally, the transcriptional repression signature of BCL-6 reveals how this factor can prevent terminal differentiation of B cells and cause B cell lymphomas.

Animals↗
PubMed2001

Molecular features of B-cell lymphoma.

Malignant transformation of B cells can occur at various steps of lymphocyte development, starting from early B-cell progenitors up to mature B cells, which reflects the heterogeneity of B-cell malignancies with regard to their biologic and clinical behavior. The genetic characterization of B-cell neoplasms during the past two decades has elucidated the mechanisms underlying B-cell lymphomagenesis and led to a more precise definition of lymphoma subgroups. This progress is reflected in the upcoming World Health Organization classification for hematologic neoplasms, which stresses the diagnostic importance of recurrent genetic alterations in leukemias and lymphomas. In the recent past, several genes deregulated by such recurrent chromosomal aberrations have been identified. In addition, the recent introduction of microarray technology has now allowed a more global assessment of gene dysregulation in B-cell oncogenesis and provided a new means for more exactly defining the molecular hallmarks of distinct lymphoma subtypes. This review will focus on recently described molecular features of B-cell lymphomas discovered by the application of new molecular cytogenetic techniques, advanced breakpoint cloning strategies, and microarray approaches.

Cell Transformation, Neoplastic↗
PubMed2000

Genetic aberrations common in gastric high-grade large B-cell lymphoma.

Genetic aberrations associated with the development of extranodal high-grade large B-cell lymphoma originating in the stomach have not been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261 and D6S310-D6S441, respectively, containing putative tumor suppressor genes (TSGs). These 6q aberrations were found to be the sole allelic imbalance in 1 patient only; they were mostly accompanied by additional abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and DCC genes, were found to suffer frequent LOH during lymphomagenesis. LOH was also detected in regions containing putative TSGs on 7q and 13q14. Frequent amplification of genomic material was found in the 2p, 3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL gene region with LOH at the p53 locus (P =.02). Only low frequency of microsatellite instability (MSI) was detected in these lymphomas and MSI incidence increased with age (P =.01). Karyotypic instability thus plays the main role in the development of gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and amplification of the 3q27 and the MLL gene regions. (Blood. 2000;95:1180-1187)

Age Factors↗