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J Hofmann

Publications and source records attributed to J Hofmann.

At least 73 records · Page 4Linked to original sources
PubMed1995

The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.

BACKGROUND: Streptococcus pneumoniae is a major cause of illness, and the emergence of drug-resistant strains threatens to complicate the management of pneumococcal infections. We conducted a laboratory-based surveillance for drug-resistant S. pneumoniae among patients with invasive pneumococcal infections in Atlanta. METHODS: From January through October 1994, pneumococcal isolates from 431 patients with invasive disease in metropolitan Atlanta were serotyped and tested to determine their susceptibility to various antimicrobial agents. Susceptibility to the antimicrobial agents was defined according to guidelines established by the National Committee for Clinical Laboratory Standards. RESULTS: The annual incidence of invasive pneumococcal infection was 30 cases per 100,000 population. Isolates from 25 percent of the patients were resistant to penicillin (7 percent were highly resistant), and isolates from 26 percent were resistant to trimethoprim-sulfamethoxazole (7 percent highly resistant). Fifteen percent of the isolates were resistant to erythromycin, 9 percent to cefotaxime (4 percent were highly resistant), and 25 percent to multiple drugs. Drug-resistant pneumococci were found in both children and adults. Children under six years of age were more likely than older children and adults to have isolates resistant to multiple drugs or cefotaxime. Whites were more likely than blacks to have invasive pneumococcal infections caused by drug-resistant organisms. Among white children younger than six years, 41 percent of the S. pneumoniae isolates were resistant to penicillin. CONCLUSIONS: Drug-resistant strains of S. pneumoniae are common among both children and adults in Atlanta. Although blacks had a higher incidence of invasive pneumococcal infections than whites, whites were more likely to be infected with a drug-resistant isolate. Control of drug-resistant pneumococci will require more judicious use of antimicrobial agents and wider use of the pneumococcal polysaccharide vaccine.

Adolescent↗
PubMed1995

Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance.

It has previously been shown that dexniguldipine-HCl (B8509-035) is a potent chemosensitizer in multidrug resistant cells [Hofmann et al., J Cancer Res Clin Oncol 118: 361-366, 1992]. It is shown here that dexniguldipine-HCl causes a dose-dependent reduction of the labeling of the P-glycoprotein by azidopine, indicating a competition of dexniguldipine-HCl with the photoaffinity label for the multidrug resistance gene 1 (MDR-1) product. Exposure to dexniguldipine-HCl results in a dose-dependent accumulation of rhodamine 123 in MDR-1 overexpressing cells. In the presence of 1 microM dexniguldipine-HCl, rhodamine 123 accumulated in multidrug resistant cells to similar levels as in the sensitive parental cell lines. At this concentration, dexniguldipine-HCl enhances the cytotoxicities of Adriamycin and vincristine. The resistance modulating factors (RMF), i.e. IC50 drug/IC50 drug + modulator, were found to be proportional to the expression of MDR-1, ranging from 8 to 42 for Adriamycin and from 16 to 63 for vincristine. Transfection with the MDR-1 gene was found to be sufficient to sensitize cells to the modulation by dexniguldipine-HCl. The compound does not affect the expression of the MDR-1 gene. Dexniguldipine-HCl has no effect on a multidrug resistant phenotype caused by a mutation of topoisomerase II. It is concluded that dexniguldipine-HCl modulates multidrug resistance by direct interaction with the P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Diabetes insipidus in Langerhans cell histiocytosis: results from the DAL-HX 83 study.

Diabetes insipidus (DI) in Langerhans cell histiocytosis (LCH) is a common complication of unclear etiology. The incidence varies among different publications from 15% to 50%. In the prospective DAL-HX 83 study, 19 out of 199 patients (9.5%) registered with newly diagnosed LCH were diagnosed to have DI. All patients were stratified according to uniform criteria. One hundred and six patients with disseminated disease were treated with standardized polychemotherapy promptly after diagnosis. At the time of diagnosis of LCH, DI was already established in 8 out of 199 patients (4%). After diagnosis, DI occurred in only one out of the remaining 91 patients with localized disease (1%) and in 10 out of 100 remaining patients with disseminated disease (10%). In 8 patients, the onset of DI was associated with other signs of active LCH. The cumulative risk to develop DI after a median observation time of 5 years 3 months was 11%. Retrospective analysis of clinical features revealed multisystem involvement, skull and orbital lesions, and in particular intracranial extension from osseous lesions to constitute risk factors for DI. Magnetic resonance imaging studies (MRI) were available in 12 patients and showed abnormalities of the pituitary region in 10 children. In none of the patients with established DI was it reversed or ameliorated by any treatment. However, the rapid institution of systemic chemotherapy for disseminated disease seems to prevent the occurrence of DI and may be responsible for the low frequency of DI in the DAL-HX83 study.

Adolescent↗
PubMed1995

Glucocorticoid receptors and growth inhibitory effects of dexamethasone in human lung cancer cell lines.

Expression of glucocorticoid receptors (GR) and growth effects of dexamethasone and the antiglucocorticoid RU-486 were investigated in six cell lines originating from small cell lung cancer (SCLC) and 13 cell lines from non-small cell lung cancer (NSCLC; four adenocarcinoma, four squamous cell carcinoma, four large cell carcinoma and one mesothelioma). All cell lines contained specific and saturable binding sites for the synthetic glucocorticoid dexamethasone, as determined by whole cell assays and by cytosolic receptor assays. The presence of GRs in the carcinoma cells was confirmed by immunocytochemistry. In NSCLC cell lines, GRs were present in large amounts (37-638 fmol/mg cytosolic protein). In SCLC cell lines, GRs were also detectable but in considerably lower concentrations. Growth inhibitory effects of dexamethasone were seen in the cultures of two squamous cell carcinoma lines (EPLC-32M1 and NCI-H157), one adenocarcinoma line (A-549), one large cell carcinoma cell line (LCLC-97TM1) and the cell line of a mesothelioma (MSTO-211H). All cell lines responsive to dexamethasone had high GR concentrations (> or = 164 fmol/mg cytosolic protein). The antiglucocorticoid RU-486 was virtually inactive when administered alone but was able to block the growth-inhibitory effect of dexamethasone. The results indicate that glucocorticoids may inhibit the progression of individual non-small cell lung carcinoma.

Antineoplastic Agents, Hormonal↗
PubMed1995

Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine.

Conjugation of pneumococcal polysaccharide antigens to a protein carrier may improve protective immunity after vaccination of young children, an age group with high incidence of Streptococcus pneumoniae infection and poor immune responses to polysaccharide vaccines. To identify serotypes most commonly associated with infection in young children, pneumococcal isolates were serotyped from 3884 children < 6 years old (including 3007 < 2 years old) with pneumococcal bacteremia (n = 3169), meningitis (n = 401), or otitis media (n = 314). The isolates were submitted as part of a national surveillance during 1978-1994. Seven serotypes (14, 6B, 19F, 18C, 23F, 4, and 9V) accounted for 3045 isolates (78%). A conjugate pneumococcal vaccine protecting against these seven serotypes and serologically cross-reactive serotypes could potentially prevent 86% of bacteremia and 83% of meningitis but only 65% of otitis media cases. The proportion of isolates covered by such a vaccine increased from 78% to 87% during 1978-1994. Surveillance for pneumococcal serotypes causing infection is needed to detect shifts in serotype distribution over time.

Bacterial Vaccines↗
PubMed1995

Decreased potency of MDR-modulators under serum conditions determined by a functional assay.

A variety of agents are capable of overcoming P-glycoprotein-mediated multidrug resistance (MDR) in vitro. However, the clinical potential of these compounds is often limited due to high plasma protein binding. We compared the efficacy of several MDR-reversing compounds in serum-free culture medium and under serum conditions by means of a functional assay. Using flow cytometry the efflux of the fluorescent dye rhodamine 123 (Rh123) was measured from normal peripheral blood CD8+ T-lymphocytes which express low levels of P-glycoprotein. Inhibition of Rh123 efflux by R-verapamil, dexnigludipine-HCl, cyclosporin A, SDZ PSC833 and the protein kinase C (PKC) inhibitor CGP 41251 was determined in serum-free medium and in serum at concentrations from 0.1 to 50 mumol/l. With the exception of SDZ PSC833 all MDR modulators showed an insufficient or suboptimal modulation of P-glycoprotein under serum conditions at concentrations achievable in vivo. The highest potency under serum conditions demonstrated SDZ PSC833: even at a concentration of 0.5 mumol/l a sufficient inhibitory effect was observed. Subsequently this approach was applied to patients suffering from B-cell chronic lymphocytic leukaemia (B-CLL; n = 3) and acute myeloid leukaemia (AML; n = 2) which were positive in the Rh123 efflux assay. As for normal CD8+ T-lymphocytes, much higher drug concentrations were required under serum conditions to effectively inhibit Rh123 efflux from the leukaemic cells. Thus the interpretation of results of clinical 'modulator' trials should consider the decreased bioavailability of MDR-reversing agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Low frequency of activity of P-glycoprotein (P-170) in acute lymphoblastic leukemia compared to acute myeloid leukemia.

The purpose of our investigations was to measure P-glycoprotein (P-170) activity in blast cells of 35 adults with acute myeloid leukemia (AML), and 24 children and adults with acute lymphoblastic leukemia (ALL) at time of diagnosis. Studies were based on a flow cytometric assay that detects efflux of the fluorescent dye rhodamine 123 (Rh123), which is transported from the cell by the P-170 pump. Dual-fluorescence staining with Rh123 and phycoerythrin-labeled monoclonal antibodies allowed selective measurement of Rh123 efflux in blast cells. Samples were scored positive when the fraction of blast cells showing Rh123 efflux exceeded 10% after a 120-min incubation. Activity of P-170 was observed in 19 (54%) of the 35 AML cases and was completely blocked in the presence of multidrug resistance inhibitors. Efflux activity was significantly higher in CD34-positive AML samples (p < 0.02). All AML patients with the FAB-subtype M5 (n = 5) lacked Rh123 pumping activity (p < 0.03). The complete remission rate in response to induction chemotherapy was significantly higher for Rh123-negative (11/13, 85%) than for Rh 123-positive AML patients (4/15, 27%) (p < 0.007). At a median follow-up of 9 months overall survival was significantly shorter for Rh123-positive than for Rh123-negative patients (p < 0.05). In contrast to AML, we could detect Rh123 efflux in only two (8%) out of 24 ALL cases. The immunological subtypes of these two positive cases was of B-ALL and pre-T-ALL. Bone marrow cryostat sections from 13 AML and five ALL patients were further analyzed for staining with monoclonal antibodies MM4.17 and JSB1. Ten of 13 AML and two of five ALL cases expressed the MDR protein. Our results indicate that there is a rather low frequency of P-170 pumping activity in ALL compared with AML. Further, functional activity of P-170 contributes to chemoresistance in de novo AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

The protein kinase C inhibitor CGP 41251, a staurosporine derivative with antitumor activity, reverses multidrug resistance.

Multidrug resistance (MDR) is frequently associated with overexpression of a 170-kDa P-glycoprotein (Pgp). Data suggest altered protein kinase C (PKC) activity in cells expressing the multidrug-resistant phenotype. The staurosporine derivative CGP 41251, an experimental anticancer drug, has been shown to exert selectivity for inhibition of protein kinase C activity and to exhibit antitumor activity in vitro and in vivo. Here we show that CGP 41251 is also able to reverse MDR. After treatment of the multidrug-resistant human lymphoblastoid cell line CCRF-VCR1000 with 500 nM Adriamycin, cell proliferation was reduced to 81% of untreated controls. A combination of 500 nM Adriamycin with a non-toxic concentration of 150 nM CGP 41251 (IC50 for inhibition of cell proliferation 420 nM CGP 41251) inhibits cell proliferation of CCRF-VCR1000 cells to 29% of untreated controls. In sensitive CCRF-CEM cells no enhancement of Adriamycin-induced cytotoxicity was observed upon addition of 150 nM CGP 41251. Strong synergism of the inhibition of cell proliferation was also observed after concomitant treatment of KB-8511 cells with CGP 41251 and Vinblastine or Adriamycin. Drug-sensitive KB-31 cells could not be further sensitized to Adriamycin or Vinblastine with CGP 41251 doses above 100 nM. Pretreatment with 50-1000 nM CGP 41251 for 30 min led to a dose-dependent increase in the intracellular accumulation of rhodamine 123, a substrate of P-glycoprotein. Treatment of multidrug-resistant CCRF-VCR1000 cells with CGP 41251 for 10 min was sufficient to inhibit the efflux of rhodamine 123. Preincubation with CGP 41251 for 12 or 24 hr did not alter multidrug resistance gene (mdrI)-mRNA levels. CGP 41251, a drug with antitumor efficacy in experimental systems, might offer an attractive combination partner for the treatment of tumors expressing the MDR phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

The protein kinase C inhibitor ilmofosine (BM 41 440) arrests cells in G2 phase and suppresses CDC2 kinase activation through a mechanism different from that of DNA damaging agents.

The thioether phospholipid derivative ilmofosine (BM41440), a selective inhibitor of protein kinase C, is a new anticancer drug presently undergoing Phase II clinical trials. We have examined the influence of the compound on cell cycle progression. Ilmofosine was found to induce a dose-dependent accumulation of CA46 cells in G2-phase of the cell cycle. G2-arrest correlated with suppression of cdc2 kinase activation. Ilmofosine did not affect cdc2 kinase activity in vitro, consistent with an indirect locus of action. Ilmofosine treated CA46 cells failed to accumulate hyperphosphorylated-cdc2/cyclin B1 complexes that are observed when G2-arrest is induced by either nitrogen mustard or ionizing radiation. Indeed, cdc2 became dephosphorylated and cyclin B1 protein levels decreased as ilmofosine treated cells became arrested in G2. Our findings suggest that ilmofosine down-regulates cdc2 kinase activation through a mechanism that affects the formation of cdc2/cyclin B1 complexes.

Alkaloids↗
PubMed1994

Production of insulin-like growth factor binding proteins by human ovarian carcinoma cells.

Cells of the human ovarian carcinoma lines EFO-21, EFO-27, MFO-35 and MFO-36 secrete binding proteins for insulin-like growth factors (IGFBPs) into their culture media. By sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ligand blotting, seven groups of IGFBPs with molecular masses of 25, 30 (doublet), 34, 37, 40, 45, and 50 kDa were observed, depending on the cell line under investigation. By Northern blot analyses using cDNAs or oligonucleotides specific for the six types of IGFBP (IGFBP-1 to IGFBP-6), mRNA for all IGFBPs tested except for IGFBP-1 could be detected in the ovarian carcinoma cell extracts. In detail, analysis of EFO-21 protein products by SDS-PAGE yielded IGFBPs of 25, 34, and 50 kDa; extracts of EFO-21 cells contained mRNAs for IGFBP-2, -3, -4, and -6. EFO-27 cells produced IGFBPs of 40 kDa and 45 kDa as determined by SDS-PAGE, and mRNAs for IGFBP-3, -4, and -6 were detected. In the conditioned medium of MFO-35 cells, IGFBPs of 25, 30 (doublet), 34, 37, 40, and 45 kDa were observed by SDS-PAGE, while mRNAs for the five proteins IGFBP-2 to IGFBP-6 were found. MFO-36 cells produced IGFBPs of 34 kDa and 50 kDa as determined by SDS-PAGE, and the cells expressed mRNAs for IGFBP-2, -3, -4, and -6. In relation to published molecular mass data of the known IGFBPs, the size of the secreted proteins could be correlated to the mRNA patterns expressed by the ovarian carcinoma cells. It is concluded that ovarian carcinoma cells frequently express IGFBP-3, -4, and -6 and, to a lesser extent, IGFBP-2; the expression of IGFBP-5 appears as a rather rare event, while IGFBP-1 was not found to be expressed in ovarian carcinoma cells.

Carrier Proteins↗
PubMed1994

Role of protein kinases in antitumor drug resistance.

The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.

Animals↗
PubMed1994

Malignant mesothelioma following radiation therapy.

BACKGROUND: Studies of the growing population of long-term survivors of cancer have led to increased recognition of the neoplastic complications of therapy. The causes of secondary malignancies are probably multifactorial, but radiation therapy and chemotherapy have certainly been implicated in the development of posttherapy neoplasia. PATIENTS AND METHODS: A case of pleural mesothelioma after successful radiation therapy for Hodgkin's disease is described with a review of radiation-associated mesotheliomas reported in the literature. In Hodgkin's disease, patients may receive radiation, chemotherapy, or combined treatment; the most common secondary malignancy is acute nonlymphocytic leukemia while sarcomas are the second most common solid tumors. CONCLUSIONS: Although mesothelioma is an uncommon sarcoma, its occurrence has been documented numerous times after exposure to diagnostic or therapeutic radiation.

Adolescent↗
PubMed1994

Internally located and oppositely oriented polymerase II promoters direct convergent transcription of a LINE-like retroelement, the Dictyostelium repetitive element, from Dictyostelium discoideum.

The Dictyostelium discoideum NC4 genome harbors approximately 150 individual copies of a retrotransposable element called the Dictyostelium repetitive element (DRE). This element contains nonidentical terminal repeats (TRs) consisting of conserved building blocks A and B in the left TR and B and C in the right TR. Seven different-sized classes of RNA transcripts from these elements were resolved by Northern (RNA) blot analysis, but their combined abundance was very low. When D. discoideum cells were grown in the presence of the respiratory chain blocker antimycin A, steady-state concentrations of these RNA species increased 10- to 20-fold. The D. discoideum genome contains two DRE subtypes, the full-length 5.7-kb DREa and the internally deleted 2.4-kb DREb. Both subtypes are transcribed, as confirmed by analysis of cloned cDNA. Primary transcripts from the sense strand originate at nucleotide +1 and terminate at two dominant sites, located 21 or 28 nucleotides upstream from the 3' end of the elements. The activity of a reasonably strong polymerase II promoter in the 5'-terminal A module is slightly upregulated by the tRNA gene located 50 +/- 4 nucleotides upstream and drastically reduced by the adjacent B module of the DRE. Transcripts from the opposite DNA strand (complementary-sense transcripts) were also detected, directed by an internally located polymerase II promoter residing within the C module. This latter transcription was initiated at multiple sites within the oligo(dA12) stretch which terminates DREs.

Animals↗
PubMed1994

[Functional detection of P-glycoprotein expressing cells with flow cytometry].

Classical multidrug resistance (MDR) is associated with the overexpression of a membrane glycoprotein termed P-glycoprotein (P-gp) that transports a variety of apparently unrelated anti-cancer drugs out of cells. Based on the fluorescent properties of the dye rhodamine 123 (Rh 123) we aimed to develop a functional flow cytometric assay for the detection of MDR-expressing cells. Using drug sensitive cell lines (KB-3-1) and MDR mutants (KB-8-5, KB-C1) experimental conditions were established enabling demonstration of significant differences in Rh 123 accumulation/efflux. Using two-colour flow cytometry we subsequently analysed 42 consecutive patients suffering from B-cell chronic lymphocytic leukemia (B-CLL). 34/42 (81%) cases showed a marked Rh 123 efflux which was completely abolished in the presence of the MDR inhibitor verapamil. The percentage of Rh 123 effluxing cells ranged from 10 to 70% with a median of 32%. In 26 cases extracted RNA was analysed by quantitative polymerase chain reaction to evaluate the expression of MDR 1 mRNA. In 25 of 26 (96%) cases MDR 1 mRNA was detectable. The levels of MDR 1 mRNA expression correlated well with the results of the Rh 123 efflux assay (r = 0.72; p < 0.0001). In addition, 37 cases of acute myeloid leukemia were analysed and demonstrated Rh 123 efflux in 18/37 (49%) cases. In this entity the percentage of Rh 123 effluxing cells ranged from 12 to 80% (median 45%). Additionally, we evaluated the Rh 123 efflux/retention in peripheral blood cells of healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

[Immunophenotyping of leukemia: overview].

Leukaemias that cannot be classified properly by morphological/cytochemical parameters may be diagnosed clearly by immunophenotyping. In this way, the neoplastic cells can be designated to either the myeloid or the lymphatic line of blood cells. Furthermore, myeloid leukaemias can be subtyped immunophenotypically in cases of type M0, M6, and M7, leukaemias, as well as in cases of mixed lineage or undifferentiated leukaemias. In patients with non-Hodgkin-lymphomas the cells can be characterized as being of B- or T-cell origin, and their activational or proliferative state can be assessed. Notably with acute lymphatic leukaemias, the prodigious therapeutical progress over the past years must be attributed to the refined definition of subtypes by immunophenotyping.

Antibodies, Monoclonal↗
PubMed1993

Activity of P-glycoprotein in B-cell chronic lymphocytic leukemia determined by a flow cytometric assay.

BACKGROUND: Chemoresistance in some hematologic malignancies has been associated with overexpression of P-glycoprotein, which is encoded by the MDR1 gene (also known as PGY1). However, inconsistencies in data on frequency and clinical relevance of multidrug resistance in B-cell chronic lymphocytic leukemia (B-CLL) may reflect a need for improved techniques to detect this overexpression. PURPOSE: Our purpose was to measure P-glycoprotein activity in peripheral blood cells of B-CLL patients and to analyze possible clinical correlations (disease duration, prior treatment, Rai disease stage, lymphocyte counts, and disease progression). METHODS: P-glycoprotein activity was assayed in peripheral blood cells of 42 consecutive B-CLL patients (22 treated and 20 untreated). We used dual fluorescence in a flow cytometric assay that detects efflux of the fluorescent dye rhodamine 123, which is transported from the cell by the P-glyprotein pump. Leukemia cells were costained with monoclonal antibody Leu12/CD19, and rhodamine 123 efflux was measured. Expression of MDR1 and MDR3 (also known as PGY3) messenger RNA (mRNA) was quantitatively evaluated by polymerase chain reaction (PCR) in 26 cases. RESULTS: Marked rhodamine 123 efflux was observed in 34 (81%) of the 42 cases and was abolished in the presence of multidrug resistance inhibitors. Rhodamine 123 efflux was not associated with Rai stage, lymphocyte counts, duration of disease, or disease progression. Although rhodamine 123-negative cases were about equally distributed among untreated and previously treated patients, the percentage of cells with rhodamine 123 efflux was significantly lower for untreated patients than for those treated with chemotherapy regimens including at least one multidrug resistance-associated drug. MDR1 mRNA was detected in 25 of 26 cases and MDR3 mRNA in all 26. MDR1 mRNA expression was significantly correlated with rhodamine 123 efflux, whereas MDR3 mRNA expression was not significantly correlated; MDR1 and MDR3 mRNA expression was not significantly associated with Rai stage, prior treatment, or disease progresssion. CONCLUSIONS: These findings suggest that P-glycoprotein overexpression in B-CLL is intrinsic rather than acquired and that P-glycoprotein activity is enhanced after exposure to multidrug resistance-associated drugs. This enhanced activity does not seem to be associated with more aggressive disease. Our results also indicate that an assay of P-glycoprotein function combined with PCR is suitable for clinical multidrug resistance screening. IMPLICATIONS: Additional studies are needed to determine whether functional activity of P-glycoprotein, measured by rhodamine 123 efflux, is directly related to clinical drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Different organization of the tRNA-gene-associated repetitive element, DRE, in NC4-derived strains and in other wild-type Dictyostelium discoideum strains.

The retrotransposon DRE (Dictyostelium repetitive element) was discovered in the course of an extensive study concerning the genomic organization of tRNA genes in the NC4-derived strains AX2 and AX3 of the cellular slime mold Dictyostelium discoideum. As a striking feature, DRE was found exclusively in a constant orientation and at a constant distance upstream from different tRNA genes. About 150-200 DRE with intact 5'-terminal-repeat structures are present in NC4-derived strains. These strains were termed high-copy DRE strains (HCD strains) as opposed to low-copy DRE strains (LCD strains) such as the wild-type D. discoideum isolates DD61, WS380B, OHIO and V12. LCD strains contain only 3-15 DRE with intact 5'-terminal-repeat-structures. However, in addition to these few intact elements, many 5'-truncated DRE elements are present in LCD strains. In HCD strains, most DRE show typical structural characteristics of retrotransposons containing terminal repeats at both ends, which seems to be one prerequisite for active transposition. In LCD strains, however, most DRE elements are 5'-truncated, which is a common feature of eukaryotic LINE elements. Despite their truncated 5'-ends, DRE in LCD strains retain unique integration specificities, i.e. they are always found position-specifically and orientation-specifically integrated in front of tRNA genes, flanked by a 12-16-bp target-site duplication.

Animals↗