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Biomedical subjects

N Kaminski

Publications and source records attributed to N Kaminski.

At least 19 recordsLinked to original sources
PubMed2001

DNA microarray analysis of genes involved in p53 mediated apoptosis: activation of Apaf-1.

The transcription regulation activity of p53 controls cellular response to a variety of stress conditions, leading to growth arrest and apoptosis. Despite major progress in the understanding of the global effects of p53 on cellular function the pathways by which p53 activates apoptosis are not well defined. To study genes activated in the p53 induced apoptotic process, we used a mouse myeloid leukemic cell line (LTR6) expressing the temperature-sensitive p53 (val135) that undergoes apoptosis upon shifting the temperature to 32 degrees C. We analysed the gene expression profile at different time points after p53 activation using oligonucleotide microarray capable of detecting approximately 11,000 mRNA species. Cluster analysis of the p53-regulated genes indicate a pattern of early and late induced sets of genes. We show that 91 and 44 genes were substantially up and down regulated, respectively, by p53. Functional classification of these genes reveals that they are involved in many aspects of cell function, in addition to growth arrest and apoptosis. Comparison of p53 regulated gene expression profile in LTR6 cells to that of a human lung cancer cell line (H1299) that undergoes growth arrest but not apoptosis demonstrates that only 15% of the genes are common to both systems. This observation supports the presence of two distinct transcriptional programs in response to p53 signaling, one leading to growth arrest and the other to apoptosis. The proapoptotic genes induced only in LTR6 cells like Apaf-1, Sumo-1 and gelsolin among others may suggest a possible explanation for apoptosis in LTR6 cells.

Apoptosis↗
PubMed2001

DNA microarrays identification of primary and secondary target genes regulated by p53.

The transcriptional program regulated by the tumor suppressor p53 was analysed using oligonucleotide microarrays. A human lung cancer cell line that expresses the temperature sensitive murine p53 was utilized to quantitate mRNA levels of various genes at different time points after shifting the temperature to 32 degrees C. Inhibition of protein synthesis by cycloheximide (CHX) was used to distinguish between primary and secondary target genes regulated by p53. In the absence of CHX, 259 and 125 genes were up or down-regulated respectively; only 38 and 24 of these genes were up and down-regulated by p53 also in the presence of CHX and are considered primary targets in this cell line. Cluster analysis of these data using the super paramagnetic clustering (SPC) algorithm demonstrate that the primary genes can be distinguished as a single cluster among a large pool of p53 regulated genes. This procedure identified additional genes that co-cluster with the primary targets and can also be classified as such genes. In addition to cell cycle (e.g. p21, TGF-beta, Cyclin E) and apoptosis (e.g. Fas, Bak, IAP) related genes, the primary targets of p53 include genes involved in many aspects of cell function, including cell adhesion (e.g. Thymosin, Smoothelin), signaling (e.g. H-Ras, Diacylglycerol kinase), transcription (e.g. ATF3, LISCH7), neuronal growth (e.g. Ninjurin, NSCL2) and DNA repair (e.g. BTG2, DDB2). The results suggest that p53 activates concerted opposing signals and exerts its effect through a diverse network of transcriptional changes that collectively alter the cell phenotype in response to stress.

Animals↗
PubMed2001

Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types.

Interleukin (IL)-13, a cytokine released by T lymphocytes during immediate hypersensitivity responses, is a central mediator of asthma. Because IL-13 induces phenotypic features of asthma in mice deficient in T and B lymphocytes, it is likely that this cytokine contributes to the development of asthma by acting directly on resident airway cells. To analyze the global effects of IL-13 on gene expression in airway cells that could contribute to the phenotypic features of asthma, we used Genechip HuGene FL arrays (Affymetrix, Santa Clara, CA) that contain probes for approximately 6,500 human genes. Despite activating a common signaling pathway, IL-13 induced dramatically different patterns of gene expression in primary cultures of airway epithelial cells, airway smooth muscle cells, and lung fibroblasts, with little overlap among cell types. The most prominent effects of IL-13 were on airway smooth muscle, but several genes induced in airway epithelial cells and fibroblasts are also candidates that may contribute to phenotypic features of asthma. These results suggest that the in vivo response to IL-13 in the airways likely results from a combination of distinct effects on each of several resident airway cell types.

Cells, Cultured↗
PubMed2001

TGF-beta is a critical mediator of acute lung injury.

We have shown that the integrin alphavbeta6 activates latent TGF-beta in the lungs and skin. We show here that mice lacking this integrin are completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury (ALI). Pharmacologic inhibition of TGF-beta also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. TGF-beta directly increased alveolar epithelial permeability in vitro by a mechanism that involved depletion of intracellular glutathione. These data suggest that integrin-mediated local activation of TGF-beta is critical to the development of pulmonary edema in ALI and that blocking TGF-beta or its activation could be effective treatments for this currently untreatable disorder.

Animals↗
PubMed2000

Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin beta6 subunit (beta6(-/-)), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

Animals↗
PubMed2000

Use of oligonucleotide arrays to analyze drug toxicity.

The advent of oligonucleotide arrays allows the simultaneous analysis of the expression of thousands of genes. This powerful technology, highly dependent on advanced analysis tools, can transform the level of information currently available on the mechanisms underlying drug-related toxicity. It is now possible to analyze the global transcriptional response to a drug and determine the global pathways associated with the effects of this agent. This analysis can be performed on samples from patients that developed a toxic effect, on cells exposed to the toxic agent, and in animal models of toxicity. Especially useful is the comparison of transcriptional responses in animals susceptible to drug-induced disease with those of genetically modified animals that are resistant to this effect. This analytic strategy allows the delineation of specific mechanisms relevant and specific to drug-induced toxicity and thus might lead to novel therapeutic interventions in these toxic reactions.

Animals↗
PubMed2000

Bioinformatics. A user's perspective.

This review provides an overview of bioinformatics from the user's point of view. Bioinformatics, defined as the application of computers, databases, and computational methods to the management of biologic information, is essential for almost every aspect of data management in modern biology. The rapid accumulation of genomic sequence information together with the wide availability of new technologies that analyze global gene expression patterns have created an information overload. Molecular biology labs are increasingly dependent on computers, large-capacity databases, search and analysis tools, and high-quality Internet connections. Currently available bioinformatics tools are discussed and a general approach is outlined. Using the resources and approaches in this review, readers should be able to form their own view of bioinformatics and tailor the solutions to the information overload according to their needs.

Computational Biology↗
PubMed1999

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.

Transforming growth factor beta (TGF beta) family members are secreted in inactive complexes with a latency-associated peptide (LAP), a protein derived from the N-terminal region of the TGF beta gene product. Extracellular activation of these complexes is a critical but incompletely understood step in regulation of TGF beta function in vivo. We show that TGF beta 1 LAP is a ligand for the integrin alpha v beta 6 and that alpha v beta 6-expressing cells induce spatially restricted activation of TGF beta 1. This finding explains why mice lacking this integrin develop exaggerated inflammation and, as we show, are protected from pulmonary fibrosis. These data identify a novel mechanism for locally regulating TGF beta 1 function in vivo by regulating expression of the alpha v beta 6 integrin.

3T3 Cells↗
PubMed1994

Regression of Kaposi's sarcoma after intravenous immunoglobulin treatment for polymyositis.

The authors report on the case of a patient with polymyositis who was given immunosuppressive therapy and then developed Kaposi's sarcoma. Subsequently, the polymyositis was treated with high dose intravenous immunoglobulin, and the Kaposi's sarcoma regressed abruptly. The association between these two diseases and the beneficial effect of intravenous immunoglobulin on Kaposi's sarcoma are discussed.

Humans↗
PubMed1994

Acute bacterial diarrhoea in the emergency room: therapeutic implications of stool culture results.

Empiric treatment with ciprofloxacin and norfloxacin has been recommended recently for patients with acute diarrhoeal disease. In a retrospective 6-month study period the results of stool cultures from 209 patients with acute diarrhoea admitted to the emergency room were analysed. Seventy-eight cultures (37%) were positive for one or more bacteria. Shigella was the most commonly isolated pathogen (68%). Shigella sonnei comprised 72% and Shigella flexneri 19% of all the bacterial isolates. While no antimicrobial resistance to ciprofloxacin was found for both Shigella species, only 36 and 26% of the Shigella isolates were sensitive to ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ), respectively. These findings point out to the emergence of drug resistance to commonly used antimicrobial drugs. Shigella's high sensitivity to the newer quinolones should make this the treatment of choice for the very sick patient, although physicians should be cautioned to the fact that indiscriminate use of this drug could result in the emergence of resistance similar to that noted with ampicillin and TMP-SMZ.

Acute Disease↗
PubMed1993

Primary tumours of the duodenum.

Six primary duodenal tumours were diagnosed in our 300 bed institute during a period of 10 years. Two patients had benign tumours (leiomyoma and carcinoid) and four had malignant tumours (adenocarcinoma). The most common manifestation was severe iron deficiency anemia. Diagnosis was usually delayed (with a mean time of 7.7 months from initial complaints), endoscopy being the most common and useful diagnostic tool. A curative procedure was performed in two patients. Patients with unexplained chronic iron deficiency anaemia should undergo thorough gastrointestinal evaluation, including the small intestine, as a curable disease may be found to be the source of the complaint.

Adenocarcinoma↗