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A Kohlmann

Publications and source records attributed to A Kohlmann.

13 recordsLinked to original sources
PubMed2006

Gene expression profiling for the diagnosis of acute leukaemia.

An optimised diagnostic setting in acute leukaemias combines cytomorphology and cytochemistry, multiparameter immunophenotyping, cytogenetics, fluorescence in situ hybridisation, and polymerase chain reaction (PCR)-based assays. This allows classification and definition of biologically defined and prognostically relevant subtypes, and allows directed treatment in some sub-entities. Over the last years the microarray technology has helped to quantify simultaneously the expression status of ten thousands of genes in single experiments. This novel approach will hopefully become an essential tool for the molecular classification of acute leukaemias in the near future. It can be anticipated that new biologically defined and clinically relevant subtypes of leukaemia will be identified based on their unique gene expression profiles. This method may therefore guide therapeutic decisions and should be investigated in a diagnostic setting in parallel to established standard methods.

Acute Disease↗
PubMed2006

Parkin modulates gene expression in control and ceramide-treated PC12 cells.

Mutations in the parkin gene cause autosomal-recessive early-onset parkinsonism as a result of the degeneration of mesencephalic dopaminergic neurons. In cell culture models, parkin expression has been shown to protect against cell death mediated by the sphingolipid ceramide. To determine whether the antiapoptotic effect of parkin involves changes in gene expression, we used Affymetrix oligonucleotide microarrays to analyse gene expression in stably transfected PC12 cells which conditionally overexpress parkin, that were treated or not with C2-ceramide. Overexpression of parkin and ceramide treatment both modulated gene expression. A number of the genes upregulated in the presence of ceramide, and modulated by parkin, were associated with apoptosis or cellular stress reactions. We validated the upregulation of four such genes (CHK, EIF4EBP1, GADD45A and PTPN-5) by real-time PCR after 3, 6, 9 and 12 h of ceramide treatment in cells that overexpressed parkin or not. All were upregulated 2 to 11-fold, 3 and 6 h after application of ceramide. Parkin overexpression reduced the upregulation of EIF4EBP1, GADD45A and PTPN-5, but only at 6 h. These results suggest that, in this assay, the cytoprotective effect of parkin might result not only from its E3-ligase activity, but also from direct or indirect modulation of gene expression in a time-dependent manner.

Animals↗
PubMed2006

A generic concept for large-scale microarray analysis dedicated to medical diagnostics.

BACKGROUND: The development of diagnostic procedures based on microarray analysis confronts the bioinformatician and the biomedical researcher with a variety of challenges. Microarrays generate a huge amount of data. There are many, not yet clearly defined, data processing steps and many clinical response variables which may not match gene expression patterns. OBJECTIVES: To design a generic concept for largescale microarray experiments dedicated to medical diagnostics; to create a system capable of handling several 1000 microarrays per analysis and more than 100 clinical response variables; to design a standardized workflow for quality control, data calibration, identification of differentially expressed genes and estimation of classification accuracy; and to provide a user-friendly interface for clinical researchers with respect to biomedical interpretation. METHODS: We designed a database structure suitable for the storage of microarray data and analysis results. We applied statistical procedures to identify differential genes and developed a technique to estimate classification accuracy of gene patterns with confidence intervals. RESULTS: We implemented a Gene Analysis Management System (GAMS) based on this concept, using MySQL for data storage, R/Bioconductor for analysis and PHP for a web-based front-end for the exploration of microarray data and analysis results. This system was utilized with large data sets from several medical disciplines, mainly from oncology (approximately 2000 microarrays). CONCLUSIONS: A systematic approach is necessary for the analysis of microarray experiments in a medical diagnostics setting to get comprehensible results. Due to the complexity of the analysis, data processing (by bioinformaticians) and interactive exploration of results (by biomedical experts) should be separated.

Adult↗
PubMed2005

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes.

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias.

Acute Disease↗
PubMed2005

Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q.

We performed microarray analyses in AML with trisomies 8 (n=12), 11 (n=7), 13 (n=7), monosomy 7 (n=9), and deletion 5q (n=7) as sole changes to investigate whether genomic gains and losses translate into altered expression levels of genes located in the affected chromosomal regions. Controls were 104 AML with normal karyotype. In subgroups with trisomy, the median expression of genes located on gained chromosomes was higher, while in AML with monosomy 7 and deletion 5q the median expression of genes located in deleted regions was lower. The 50 most differentially expressed genes, as compared to all other subtypes, were equally distributed over the genome in AML subgroups with trisomies. In contrast, 30 and 86% of the most differentially expressed genes characteristic for AML with 5q deletion and monosomy 7 are located on chromosomes 5 or 7. In conclusion, gain of whole chromosomes leads to overexpression of genes located on the respective chromosomes. Losses of larger regions of the genome translate into lower expression of the majority of genes represented by only one allele. The reduced expression of these genes is the most characteristic difference in gene expression profiles between AML with monosomy 7 and AML with deletion 5q, respectively, and other AML subtypes. Therefore, these data provide evidence that gene dosage effects gene expression in AML with unbalanced karyotype abnormalities. Losses of specific regions of the genome determine the gene expression profile more strongly than the gain of whole chromosomes.

Chromosome Aberrations↗
PubMed2004

Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients.

Recent reports support a possible future application of gene expression profiling for the diagnosis of leukemias. However, the robustness of subtype-specific gene expression signatures has to be proven on independent patient samples. Here, we present gene expression data of 34 adult acute lymphoblastic leukemia (ALL) patients (Affymetrix U133A microarrays). Support Vector Machines (SVMs) were applied to stratify our samples based on given gene lists reported to predict MLL, BCR-ABL, and T-ALL, as well as MLL and non-MLL gene rearrangement positive pediatric ALL. In addition, seven other B-precursor ALL cases not bearing t(9;22) or t(11q23)/MLL chromosomal aberrations were analyzed. Using top differentially expressed genes, hierarchical cluster and principal component analyses demonstrate that the genetically more heterogeneous B-precursor ALL samples intercalate with BCR-ABL-positive cases, but were clearly distinct from T-ALL and MLL profiles. Similar expression signatures were observed for both heterogeneous B-precursor ALL and for BCR-ABL-positive cases. As an unrelated laboratory, we demonstrate that gene signatures defined for childhood ALL were also capable of stratifying distinct subtypes in our cohort of adult ALL patients. As such, previously reported gene expression patterns identified by microarray technology are validated and confirmed on truly independent leukemia patient samples.

Adult↗
PubMed2003

New insights into the biology of acute myeloid leukemia and their impact on treatment.

Acute myeloid leukemia (AML) is a heterogeneous group of disorders that can be discriminated by morphology, immunophenotyping or more recently by cytogenetic and molecular techniques. By cytogenetics two major groups of AML can be discriminated: One group with detectable chromosomal aberrations accounting for approximately 52 % of all de novo AML and the second group without cytogenetically detectable karyotype abnormalities. In the first group two major subtypes can be further distinguished. The first group comprises AML with balanced aberrations mainly consisting in t(8;21), t(15;17) and inv(16). The second group comprizes cases with unbalanced aberrations including particularly 5q-, 17q- -5 and AML with complex karyotypes. AMLs with balanced aberrations have a good prognosis with long term survival being achieved in approximately 60 %-80 % of cases. AMLs with non-balanced aberrations on the other hand have a poor prognosis with only 10 %-15 % long-term survivors. AMLs with no detectable abnormalities or other cytogenetic aberrations comprise a group with an intermediate prognosis in which long term survival is achieved in approximately 25 %-30 % of cases. Biologically, AMLs with balanced aberrations regularly involve the deregulation of transcription factors resulting in an impairment of cell differentiation and proliferation. AMLs with unbalanced aberrations are mostly characterized by a loss of genetic material resulting in an alteration of cell cycle control and DNA repair. A new view on the biology of AML has recently been made possible through the analysis of gene expression profiles. This technique is still under investigation. First results, however, already show that gene expression patterns have a high diagnostic potential and allow to detect biology subgroups with a high accuracy. Furthermore, by this technique pathways can be identified that are altered in the leukemic process. Gene expression profiling therefore opens a new and exciting perspective in leukemia biology and therapy that may have substantial impact on the improvement of diagnosis and more importantly may guide therapeutic strategies.

Acute Disease↗
PubMed2000

Nitric acid trihydrate (NAT) in polar stratospheric clouds.

A comprehensive investigation of polar stratospheric clouds was performed on 25 January 2000 with instruments onboard a balloon gondola flown from Kiruna, Sweden. Cloud layers were repeatedly encountered at altitudes between 20 and 24 kilometers over a wide range of atmospheric temperatures (185 to 197 kelvin). Particle composition analysis showed that a large fraction of the cloud layers was composed of nitric acid trihydrate (NAT) particles, containing water and nitric acid at a molar ratio of 3:1; this confirmed that these long-sought solid crystals exist well above ice formation temperatures. The presence of NAT particles enhances the potential for chlorine activation with subsequent ozone destruction in polar regions, particularly in early and late winter.

Journal Article↗
PubMed1999

Chemical analysis of polar stratospheric cloud particles

A balloon-borne gondola carrying a particle analysis system, a backscatter sonde, and pressure and temperature sensors was launched from Kiruna, Sweden, on 25 January 1998. Measurements within polar stratospheric cloud layers inside the Arctic polar vortex show a close correlation between large backscatter ratios and enhanced particle-related water and nitric acid signals at low temperatures. Periodic structures in the data indicate the presence of lee waves. The H2O/HNO3 molar ratios are consistently found to be above 10 at atmospheric temperatures between 189 and 192 kelvin. Such high ratios indicate ternary solution particles of H2O, HNO3, and H2SO4 rather than the presence of solid hydrates.

Journal Article↗
PubMed1976

The coupling effects of some thiol and other sulfur-containing compounds on the circadian rhythm of cell division in photosynthetic mutants of Euglena.

Previous work has demonstrated a persisting, free-running, circadian rhythm of cell division in the P4ZUL photosynthetic mutant of the alga Euglena gracilis Klebs (Strain Z) Pringsheim grown organotrophically in continuous light or darkness at 19 degrees C following prior synchronization by a repetitive LD:10,14 light cycle. A similar circadian rhythmicity has been recently discovered in the W6ZHL heat-bleached and the Y9ZNalL naladixic acid-induced mutants of Euglena grown under comparable conditions. Over extended timespans, however, these mutants appear to gradually lose first their ability to display persisting overt rhythms, and then even their capability of being entrained by imposed LD cycles. These properties can be restored by the addition of certain sulfur-containing compounds to the medium including cysteine, methionine, dithiothreital, sodium monosulfide, sodium sulfite, and sodium thiosulfate, as well as thioglycolic [mercaptoacetic] acid. The implications of these findings toward biological clock mechanisms are discussed: It appears that some sort of coupling process is operating as opposed to the initiation of an underlying oscillation.

Amino Acids, Sulfur↗