Vancomycin-induced thrombocytopenia.
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Aged↗
Biomedical subjects
C Zent
Publications and source records attributed to C Zent.
Rearrangements of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: in vitro and in vivo studies.
AML1 is involved at the breakpoint of chromosome 21 band q22 in several recurring chromosomal translocations associated with myeloid and lymphoid leukemias. AML1 corresponds to CBFA2, and encodes one of the DNA-binding subunits of the enhancer core binding factor CBF. Other members of this family of DNA-binding proteins are CBFA1 and CBFA3, also known as AML3 and AML2. The three proteins are characterized by a highly conserved domain (runt domain, > 90% homology) at the amino end that is necessary for DNA-binding and protein dimerization, and by a unique domain at the carboxyl end that is necessary for transactivation. Two recurring chromosomal translocations involving AML1 associated with myeloid leukemias are the t(8;21)(q22;q22), seen in 20% of patients with acute myeloid leukemia (AML) M2, and the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. In five patients with a t(3;21) whom we studied, AML1 is interrupted by the translocation breakpoint between the runt domain and the transactivation domain, and is fused to two genes on chromosome band 3q26: EAP, which encodes the ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of the five patients we studied, a fusion with a third gene EVI1 also occurs. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric junction AML1/MDS1/EVII has been detected in cells from one of our patients with the 3;21 translocation. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. We have compared the normal AML1 to AML1/MDS1 and AML1/EAP as transcriptional regulators of the CSF1R promoter which contains the CBF target sequence. Our results indicate that whereas the normal AML1 can activate the promoter, the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. To determine the role of the chimeric proteins in cell growth, we expressed their cDNA in rat fibroblasts. When either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. However, only cells expressing AML1/MDS1 grow as large tumors in nude mice. Thus, although both chimeric genes have similar effects in transactivation of the CSF1R promoter, they affect cell growth as tumor promoters differently in vivo.
Acute Disease↗
Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties.
Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
Animals↗
Study of the effect of concomitant food on the bioavailability of rifampicin, isoniazid and pyrazinamide.
SETTING: Concomitant feeding and administration of antituberculosis medication has been proposed to increase compliance (by decreasing pyrazinamide associated nausea) and improve nutritional status. Food may however decrease the oral bioavailability of rifampicin and isoniazid. OBJECTIVE AND METHODS: A triple-crossover pharmacokinetic study in 27 patients with tuberculosis (15 males and 12 females) compared the bioavailability of rifampicin, isoniazid and pyrazinamide without food (control) with that when taken with a high carbohydrate (CHO) or high lipid (LIPID) diet. RESULTS: the CHO diet decreased isoniazid bioavailability. The maximum measured drug concentration (Cm) was decreased by 20% (P = 0.0002) and the area under the concentration-time curve to 8 h (AUC8) by 19% (P = 0.01). The CHO diet increased the time to maximum measured drug concentration (Tmax) for rifampicin by 21% (P = 0.03). The LIPID diet decreased the Cm of isoniazid by 9% (P = 0.03). Individual patient bioavailability on each meal was compared to the no-food control. A decrease of Cm or AUC8 of greater than 20% was considered significant. The bioavailability of isoniazid and rifampicin was decreased by food in a high percentage (33-56%) of patients. CONCLUSION: Concomitant feeding may thus have an important adverse effect on the therapy of tuberculosis and the desirability of this practice is called into question.
Adolescent↗
Drug allergy.
Drug allergy is an important complication in the use of agents such as penicillins, cephalosporins, sulphonamides, insulin and streptokinase. The allergenic properties of drugs are a function of molecular size and chemical reactivity. Factors determining an individual's risk of an allergic response are not fully understood but include genetic predisposition, prior exposure, route of administration, drug dosage, age and concomitant disease. The most dangerous but least common form of drug allergy is generalised anaphylaxis. The majority of reactions are non-anaphylactic and involve the skin, with a lesser incidence of haematological, renal, musculoskeletal, cardiorespiratory and other systemic manifestations. The only definitive test for allergy in a patient with a history of previous allergic reaction is rechallenge, a dangerous and seldom indicated procedure. An alternative is skin testing, but this requires an experienced practitioner and has intrinsic risk. In vitro testing may be of value in predicting the risk of rechallenge. Safe use of a suspect drug requires a careful assessment of risk and a cautious approach. Use of an offending drug in a high-risk patient is rarely indicated, but if it is considered essential, initial therapy or desensitisation in an intensive care environment is recommended.
Drug Hypersensitivity↗