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Biomedical subjects

S Milutinovic

Publications and source records attributed to S Milutinovic.

9 recordsLinked to original sources
PubMed2002

[Primary CNS lymphomas. Morphology and diagnosis].

Diagnostically primary central nervous system lymphomas (PCNSL) have to be differentiated from glioblastoma and brain metastases. Histologically the overwhelming majority of PCNSL is represented by diffuse large B-cell lymphomas, in this series with a BCL6 expression in 80% of the cases detected by immunohistochemistry. Stereotactic biopsy is the method of choice in establishing the definite diagnosis and intraoperative smear cytology will detect the lymphoid blasts. To confirm the B-cell lineage, immunohistochemistry is needed (CD20, CD79a). Small reactive T-lymphocytes and monohistiocytic cells and activated "microglia" are found within and at the periphery of PCNSL foci. The infiltrated brain tissue shows partially pleomorphic reactive astrocytes that can be confused with neoplastic astrocytes, especially in small specimens. In contrast to high-grade gliomas, however, PCNSLs do not show endothelial proliferations. Subtypes or variants of diffuse large B-cell lymphomas can also be observed in cases of PCNSL: the anaplastic variant with large multinucleated tumour cells resembling Reed-Sternberg cells, T-cell rich B-cell lymphoma and intravascular B-cell lymphoma with primary manifestation within the brain or the spinal cord. HIV/AIDS-associated PCNSLs are characterised by large plasmoblastic or small Burkitt-like cells and tumour necrosis. Primary leptomeningeal large B-cell lymphomas do occur very rarely and are diagnosed by cerebrospinal fluid cytology.

Central Nervous System Neoplasms↗
PubMed2000

The DNMT1 target recognition domain resides in the N terminus.

DNA-cytosine-5-methyltransferase 1 (DNMT1) is the enzyme believed to be responsible for maintaining the epigenetic information encoded by DNA methylation patterns. The target recognition domain of DNMT1, the domain responsible for recognizing hemimethylated CGs, is unknown. However, based on homology with bacterial cytosine DNA methyltransferases it has been postulated that the entire catalytic domain, including the target recognition domain, is localized to 500 amino acids at the C terminus of the protein. The N-terminal domain has been postulated to have a regulatory role, and it has been suggested that the mammalian DNMT1 is a fusion of a prokaryotic methyltransferase and a mammalian DNA-binding protein. Using a combination of in vitro translation of different DNMT1 deletion mutant peptides and a solid-state hemimethylated substrate, we show that the target recognition domain of DNMT1 resides in the N terminus (amino acids 122-417) in proximity to the proliferating cell nuclear antigen binding site. Hemimethylated CGs were not recognized specifically by the postulated catalytic domain. We have previously shown that the hemimethylated substrates utilized here act as DNMT1 antagonists and inhibit DNA replication. Our results now indicate that the DNMT1-PCNA interaction can be disrupted by substrate binding to the DNMT1 N terminus. These results point toward new directions in our understanding of the structure-function of DNMT1.

Base Sequence↗
PubMed2000

DNA methyltransferase inhibition induces the transcription of the tumor suppressor p21(WAF1/CIP1/sdi1).

Previous lines of evidence have shown that inhibition of DNA methyltransferase (MeTase) can arrest tumor cell growth; however, the mechanisms involved were not clear. In this manuscript we show that out of 16 known tumor suppressors and cell cycle regulators, the cyclin-dependent kinase inhibitor p21 is the only tumor suppressor induced in the human lung cancer cell line, A549, following inhibition of DNA MeTase by a novel DNA MeTase antagonist or antisense oligonucleotides. The rapid induction of p21 expression points to a mechanism that does not involve demethylation of p21 promoter. Consistent with this hypothesis, we show that part of the CpG island upstream of the endogenous p21 gene is unmethylated and that the expression of unmethylated p21 promoter luciferase reporter constructs is induced following inhibition of DNA MeTase. These results are consistent with the hypothesis that the level of DNA MeTase in a cell can control the expression of a nodal tumor suppressor by a mechanism that does not involve DNA methylation.

Cell Division↗
PubMed2000

How does DNA methyltransferase cause oncogenic transformation?

Global hypomethylation of genes and repetitive sequences, as well as hypermethylation of certain genes known to be involved in tumor suppression, are observed concurrently in cancer cells. Aberrant expression of DNA methyltransferase 1 (dnmt1) is a downstream effector of multiple tumorigenic pathways, and several data suggest that dnmt1 plays a causal role in these pathways. These data raise two critical questions: Why does ectopic expression of dnmt1 transform cells? and How can global hypomethylation exist in a cell that bears high levels of DNMT1 activity? It is proposed that DNMT1 induces cellular transformation by a mechanism that does not involve DNA methylation and that the low level of methylation in cancer cells is a result of induction of a DNA demethylase in these cells. Both DNMT1 and the demethylase play a causal role in cellular transformation and are candidate anticancer targets.

Cell Transformation, Neoplastic↗
PubMed1997

Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration.

Amlodipine, 3-ethyl 5-methyl-2-[(2-aminoethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methy l-3,5-pyridinedicarboxylate, is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate. The pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration to healthy male human volunteers together with comparative administration of the racemic mixture of both enantiomers were studied. Plasma levels were studied as a function of time and assayed using an enantioselective chromatographic method (coupled chiral and achiral HPLC) with on-line solid-phase extraction and UV absorbance detection. The method was validated separately for the R-(+)- and S-(-)-enantiomer, respectively. Results of the study indicate that the pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration is comparable to that of each enantiomer after administration of the racemate. No racemization occurs in vivo in human plasma after single enantiomer administration.

Administration, Oral↗
PubMed1994

Oxalosis associated with aluminum bone disease: a new type of mixed renal osteodystrophy.

An 18-year-old man suffering from uremia was hospitalized because of severe skeletal pain and multiple exostoses. The patient had been treated for 5 years by regular hemodialysis; primary oxalosis was the suspected cause of uremia. Transiliac bone biopsy and subsequent histomorphometric analysis of undecalcified bone specimen as well as specific aluminum staining revealed a picture of oxalosis combined with osteomalacia and a marked accumulation of aluminum at the front of mineralization. This combination of histological features of oxalosis and aluminum bone disease suggests a new type of mixed renal osteodystrophy.

Adolescent↗
PubMed1991

Measurement of blood flow through AV-fistulae by means of Doppler sonography in regularly haemodialysed patients.

In regularly dialyzed patients a variety of pathological events can negatively influence haemodynamics and blood flow through arterio-venous fistula, leading to inadequate blood flow through the dialyzer or disturbances in hemodynamics of the whole body. It therefore appears important to quantify flow velocity and volume flow through the arteriovenous fistula in such cases. We used a Vasoview computer controlled system for noninvasive vascular diagnostics based on B-scan "real-time" ultrasound for imaging the structure of tissue, combined with pulsed Doppler ultrasound for determination of hemodynamics. Thirty patients (16 males and 14 females, aged 45 +/- 10 years; range 23 to 61 years), with different periods spent on hemodialysis (5.5 +/- 3.1 years, range 1 to 11 years) were included in this study. The average systolic, diastolic and mean blood volume flows were 2131.8 +/- 565.8, 972.0 +/- 309.6 and 728.4 +/- 287.4 ml/min, respectively. The mean blood volume flow was calculated by integration of the area under curve of blood flow in one heart cycle on the Doppler signal. It is calculated by the apparatus and displayed on the screen during measurement. The average blood vessel diameter was 9.1 +/- 1.3 mm (mu +/- omega). The results revealed a marked inter-individual variation in volume flow through arteriovenous fistulae of dialyzed uremics (range 240.0 to 1200.0 ml/min). Doppler ultrasound thus appears to be a valuable method for determination of blood flow through arteriovenous fistula of dialyzed uremics as well as for detection of hemodynamics disturbances of interest, such as turbulent blood flow.

Adult↗