Biomedical subjects

Martin F Fey

Publications and source records attributed to Martin F Fey.

23 records · Page 2Linked to original sources

PubMed2003

Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials.

PURPOSE: To compare patients treated in or outside clinical protocols, using de novo acute myeloid leukemia (AML) as a model disorder. PATIENTS AND METHODS: We retrospectively compared the characteristics of all patients with de novo AML diagnosed in the referral area of our university hospital between 1985 and 1994. RESULTS: Of a total of 170 AML patients, 45% were included in a phase III trial for the treatment of AML and 55% were treated outside a protocol. Another 45 patients were registered only at diagnosis but were treated elsewhere. Nonstudy patients differed significantly from patients included in clinical trials with respect to age and performance status at clinical presentation, comorbidity, and type of AML. The great majority of patients excluded from trial participation showed distinct exclusion criteria, such as advanced age and severe comorbidity. Study patients were treated significantly more often with curative intent and achieved better response and survival. Patients treated in an equivalent manner but outside a protocol showed no significant difference in survival compared with patients enrolled onto a trial. CONCLUSION: Study patients were not representative for the entire population of patients with AML; many patients were excluded from phase III trial participation for failure to meet stringent entry criteria. Therefore, results of phase III studies may not be extrapolated to all AML patients but should only be applied to patients who do not differ in substantial characteristics from the study population.

Adolescent↗

PubMed2003

Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns.

We have cloned two novel, alternatively spliced messages of human cyclin D-binding Myb-like protein (hDMP1). The known, full-length protein has been named hDMP1alpha and the new isoforms, hDMP1beta and hDMP1gamma. The hDMP1alpha, -beta, and -gamma splice variants have unique expression patterns in normal hematopoietic cells; hDMP1beta mRNA transcripts are strongly expressed in quiescent CD34+ cells and freshly isolated peripheral blood leukocytes, as compared with hDMP1alpha. In contrast, activated T-cells and developing myeloid cells, macrophages, and granulocytes express low levels of hDMP1beta transcripts, and hDMP1gamma is ubiquitously and weakly expressed. Mouse Dmp1 has been shown to activate CD13/aminopeptidase N (APN) and p19ARF gene expression via binding to canonical DNA recognition sites in the respective promoters. Assessment of CD13/APN promoter responsiveness demonstrated that hDMP1alpha but not hDMP1beta and -gamma, is a transcriptional activator. Furthermore, hDMP1beta was found to inhibit the CD13/APN promoter transactivation ability of hDMP1alpha. Stable, ectopic expression of hDMP1beta and, to a lesser extent hDMP1gamma, reduced endogenous cell surface levels of CD13/APN in U937 cells. Moreover, stable, ectopic expression of hDMP1beta altered phorbol 12-myristate 13-acetate-induced terminal differentiation of U937 cells to macrophages and resulted in maintenance of proliferation. These results demonstrate that hDMP1beta antagonizes hDMP1alpha activity and suggest that cellular functions of hDMP1 may be regulated by cellular hDMP1 isoform levels.

Alternative Splicing↗

PubMed2003

Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL).

One fifth of B-cell chronic lymphocytic leukaemia (B-CLL) patients exhibit loss of heterozygosity (LOH) at 10q23.3, the site of the tumour suppressor PTEN. Microsatellite markers mapped complete LOH to 10q23.3 in 2/41 B-CLL (5%) and allelic imbalances in 6/41 (15%). No PTEN gene mutations were found. PTEN protein expression was not detected in 11 B-CLL (28%), and was reduced in eight patients (20%). LOH or allelic imbalances at 10q23.3 were fairly frequent in B-CLL, but did not encompass the PTEN gene. Nevertheless, PTEN protein may be absent in B-CLL with a normal PTEN genotype, suggesting a role of this phosphatase in the molecular pathology of B-CLL.

Allelic Imbalance↗

PubMed2002

A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL).

The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

Alleles↗

PubMed2002

Impact of the Human Genome Project on the clinical management of sporadic cancers.

The publication of the human genome sequence has provided a new basis for cancer research. Molecular analysis of single cancer genes in isolation may lead to an underestimation of the impact of networks of intertwined genes in molecular cancer pathology. However, new technologies such as DNA microarrays or microchips will enable the detection of global gene-expression profiles--already described for lymphomas, acute leukaemias, and various solid tumours--and may help to overcome some of the limitations of gene function analysis. In addition, DNA microchip data banks may uncover new genes that are relevant to the molecular pathology of specific cancers and trigger detailed analysis of their function. Clinically, microchips will enable us to identify new molecular cancer markers or marker profiles of prognostic and predictive value, since global gene-expression patterns can highlight molecular tumour characteristics that relate to clinically distinct entities within heterogeneous cancers, such as non-Hodgkin lymphomas or breast cancer. However, before its promise can be realised, all molecular information stemming from the Human Genome Project will need to be tested for its clinical relevance in appropriate cancer trials; this presents a formidable but important challenge.

Human Genome Project↗