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E Fritz

Publications and source records attributed to E Fritz.

At least 19 recordsLinked to original sources

Paxillus involutus mycorrhiza attenuate NaCl-stress responses in the salt-sensitive hybrid poplar Populusxcanescens.

In order to characterise the effect of ectomycorrhiza on Na+-responses of the salt-sensitive poplar hybrid Populus x canescens, growth and stress responses of Paxillus involutus (strain MAJ) were tested in liquid cultures in the presence of 20 to 500 mM NaCl, and the effects of mycorrhization on mineral nutrient accumulation and oxidative stress were characterised in mycorrhizal and non-mycorrhizal poplar seedlings exposed to 150 mM NaCl. Paxillus involutus was salt tolerant, showing biomass increases in media containing up to 500 mM NaCl after 4 weeks growth. Mycorrhizal mantle formation on poplar roots was not affected by 150 mM NaCl. Whole plant performance was positively affected by the fungus because total biomass was greater and leaves accumulated less Na+ than non-mycorrhizal plants. Energy dispersive X-ray microanalysis using transmission electron microscopy analysis of the influence of mycorrhization on the subcellular localisation of Na+ and Cl- in roots showed that the hyphal mantle did not diminish salt accumulation in root cell walls, indicating that mycorrhization did not provide a physical barrier against excess salinity. In the absence of salt stress, mycorrhizal poplar roots contained higher Na+ and Cl- concentrations than non-mycorrhizal poplar roots. Paxillus involutus hyphae produced H2O2 in the mantle but not in the Hartig net or in pure culture. Salt exposure resulted in H2O2 formation in cortical cells of both non-mycorrhizal and mycorrhizal poplar and stimulated peroxidase but not superoxide dismutase activities. This shows that mature ectomycorrhiza was unable to suppress salt-induced oxidative stress. Element analyses suggest that improved performance of mycorrhizal poplar under salt stress may result from diminished xylem loading of Na+ and increased supply with K+.

Antioxidants↗

Effects of lactulose and polyethylene glycol on colonic transit.

BACKGROUND: The effects of lactulose and polyethylene glycol on colonic transit are poorly established. AIM: To assess the effects of these laxatives on colonic transit in normal subjects. METHODS: Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3-day ingestion of 67-134 g/day lactulose, or 59 g/day polyethylene glycol. RESULTS: At similar stool weight (lactulose: 653 +/- 120 g/day; polyethylene glycol: 522 +/- 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose - 403 +/- 55 min; polyethylene glycol - 160 +/- 41.9 min). Short chain fatty acid concentration in 24-h stool correlated significantly with counts remaining in the distal colon at 12 h (r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = -0.56) and distal colon (r = -0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P < 0.001). CONCLUSION: Lactulose accelerates colonic transit. However, compared with polyethylene glycol, transit during lactulose is prolonged.

Adult↗

Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells.

CX+/CX- and Colo+/Colo- tumor sublines with stable heat shock protein 70 (Hsp70) high and low membrane expression were generated by fluorescence activated cell sorting of the parental human colon (CX2) and pancreas (Colo357) carcinoma cell lines, using an Hsp70-specific antibody. Two-parameter flow cytometry revealed that Hsp70 colocalizes with Bag-4, also termed silencer of death domain, not only in the cytosol but also on the plasma membrane. After nonlethal gamma-irradiation, the percentage of membrane-positive cells and the protein density of Hsp70 and Bag-4 were found to be strongly upregulated in carcinoma sublines with initially low expression levels (CX-, Colo-). Membrane expression of Hsp70 was also elevated in Bag-4 overexpressing HeLa cervix carcinoma cells when compared to neo-transfected cells. In response to gamma-irradiation, neo-transfected HeLa cells behaved like Hsp70/Bag-4 low-expressing CX- and Colo-, and Bag-4-transfected HeLa cells like Hsp70/Bag-4 high-expressing carcinoma sublines CX+ and Colo+. Immunoprecipitation studies further confirmed colocalization of Hsp70 and Bag-4 but also point to an association of Hsp70 and Hsp40 on the plasma membrane of CX+ and Colo+ cells; on CX- and Colo- tumor sublines, Hsp40 was detectable in the absence of Hsp70 and Bag-4. Other co-chaperones including Hsp60 and Hsp90 were neither found on the cell surface of CX+/CX-, Colo+/Colo- nor on HeLa neo-/HeLa Bag-4-transfected tumor cells. Functionally, Hsp70/Bag-4 and Hsp70/Hsp40 membrane-positive tumor cells appeared to be better protected against radiation-induced effects, including G2/M arrest and growth inhibition, on the one hand. On the other hand, membrane-bound Hsp70, but neither Bag-4 nor Hsp40, served as a recognition site for the cytolytic attack mediated by natural killer cells.

Adaptor Proteins, Signal Transducing↗

TEL1 from Saccharomyces cerevisiae suppresses chromosome aberrations induced by ionizing radiation in ataxia-telangiectasia cells without affecting cell cycle checkpoints.

The TEL1 gene from Saccharomyces cerevisiae has been shown to be the closest sequence homologue to ATM, the gene mutated in ataxia-telangiectasia (A-T) patients. Functional homology shared between the ATM and Tell proteins has recently been demonstrated based on heterologous expression of the TEL1 gene in human cells derived from A-T patients. TEL1 expression complemented specific cellular A-T deficiencies, i.e. increased radiation-induced apoptosis, telomere shortening and spontaneous hyperrecombination. The mechanism of cellular A-T complementation by TEL1 appears to be independent of p53-dependent signaling cascades, since the deficiency of A-T cells to properly induce p53 upon ionizing radiation was not corrected by TEL1. We now find that the basic number of chromosome aberrations is increased and the number of radiation-induced chromosome aberrations is suppressed in A-T cells upon TEL1 expression. In cell cycle analyses, we find no changes in basic cell cycle distribution or in radiation-induced cell cycle checkpoints following TEL1 expression. We conclude that the radioprotective function of the Tel1 protein includes suppression of apoptosis and suppression of chromosome aberrations, and that both cellular end-points can be uncoupled from ionizing radiation-induced cell cycle checkpoints.

Ataxia Telangiectasia↗

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.

Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P =.022), higher serum levels of beta(2)-microglobulin (P =.059), and a higher percentage of bone marrow plasma cells (P =.085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% +/- 6.9% compared with 15.6% +/- 8.2% in patients without the deletion; P =.0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1-deleted and rb-1-normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78. 6%; P =.009) and a shorter overall survival (24.2 months compared with > 60 months; P <.005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM. (Blood. 2000;95:1925-1930)

Adult↗

Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients.

BACKGROUND: After two decades of interferon (IFN) treatment in myeloma patients and many randomised clinical trials, no definite proof of its benefits exists. This meta-analysis of all available relevant published data tests the differences between IFN and control arms in a large patient population and addresses the issue of cost-effectiveness. PATIENTS AND METHODS: Meta-analysis was performed on 17 trials among 2333 patients who received IFN-chemotherapy induction treatment or chemotherapy alone and on 13 trials among 1615 patients on IFN maintenance therapy or without treatment. Response rates and parameters of published Kaplan Meier relapse-free and overall survival curves were analysed. RESULTS: Patients in IFN arms showed significantly better results in all investigated parameters: IFN-chemotherapy induction treatment yielded 6.6% higher response rates (2P < 0.002) as well as 4.8-month and 3.1-month prolongations of relapse-free (P < 0.01) and overall survival (P < 0.01), respectively. Interferon maintenance therapy lead to 4.4-month (P < 0.01) and 7.0-month (P < 0.01) prolongations of relapse-free and overall survival, respectively. Meta-analysis of all IFN trials combined resulted in 4.6-month and 3.7-month IFN-related gains in relapse-free and overall survival, respectively. As early as 6 and 12 months after the start of IFN treatment, percentages of cumulative relapse-free and overall survival were always significantly higher in IFN trial arms. IFN drug expenses for a one-year survival gain, as determined from AUCs of best-fitted Gompertz functions of IFN and control survival curves, were estimated to be US$42,482.28 for induction therapy and US$18,968.16 for maintenance treatment. CONCLUSIONS: Significantly superior outcomes were consistently found in IFN trial arms by meta-analysis of published data. These results are in accordance with a concomittantly conducted meta-analysis on individual patient data but were much easier to accrue. Taking all our results into account. i.e., the consistently significant, although limited, improvement of clinical outcomes and its acceptable cost-effectiveness, IFN treatment of patients with multiple myeloma seems worthwhile to be considered.

Cost-Benefit Analysis↗

Interferon in multiple myeloma--summary of treatment results and clinical implications.

Even though interferon (IFN) has been used in myeloma treatment for more than two decades, its efficacy is still controversial. Meta-analysis of randomized trials is based either on individual patient data or on published data. We performed meta-analyses on published and reported data using, in addition to the standard method, three independent methods of evaluating Kaplan-Meier curves. Thirty randomized trials on IFN induction or maintenance treatment were meta-analyzed. Combined IFN-chemotherapy induction treatment resulted in significant increases of repsonse rates (6.6%), as well as median relapse-free (4.8 months) and overall survival (3.1 months). IFN maintenance treatment prolonged median relapse-free survival by 4.4 months, median overall survival by 7.9 months. Drug costs of IFN per 1-year survival gain were US$ 42,236.19 for induction therapy and US$ 18,114.95 for maintenance treatment. To conclude, our results a are in accordance with those obtained from individual patient data by the Myeloma Trialists' Collaborative Group. Because of the consistent, though limited, improved trial outcomes, IFN treatment should be suggested to all myeloma patients who might benefit from it.

Antineoplastic Agents↗

The yeast TEL1 gene partially substitutes for human ATM in suppressing hyperrecombination, radiation-induced apoptosis and telomere shortening in A-T cells.

Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

Apoptosis↗

Predictive role of interphase cytogenetics for survival of patients with multiple myeloma.

PURPOSE: Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS: Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS: By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION: For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

Neurological function during long-term therapy with recombinant interferon alpha.

In 14 patients with myeloproliferative disorders associated with thrombocytosis, neurological and neuropsychological function were monitored prior to therapy with recombinant human interferon alpha (rIFN; dose 25 mU/week; range 10-35 mU/week) and after 3, 6, 9, and 12 months of treatment. No overt neurological side effects were observed except 1 case of cerebral insult, probably not treatment-related. Attention, memory function, and tapping improved significantly. The P2-N3 amplitudes of visually evoked potentials increased during normalization of platelet counts. Muscular strength and the amplitude of the compound muscle action potential of the median and peroneal nerves increased significantly in an inversely dose-related fashion. In patients with myeloproliferative disorders, long-term therapy with low to intermediate doses of rIFN does not seem to impair neurological function, but rather is associated with enhanced muscle power and the level of mental arousal.

Aged↗

Human fibroblasts transfected with an ATM antisense vector respond abnormally to ionizing radiation.

ATM, the gene mutated in ataxia-telangiectasia (A-T), mediates multiple cellular responses to DNA damage. A-T homozygotes have a high risk of cancer and exhibit spontaneous chromosomal instability, and cultured A-T cells react abnormally to ionizing radiation. We have developed an ATM antisense vector that confers an A-T phenotype on normal cells. An episomal antisense vector was created that contained a 1.3 kb segment of the ATM cDNA, and was transfected into normal human fibroblasts. Intracellular levels of ATM protein were typically reduced 10-fold in antisense-expressing (GM639-46alpha) clones. GM639-46alpha clones exhibited the low threshold for radiation-induced apoptosis, low clonogenic survival, and cell cycle defects normally seen in A-T cells. Transfection with the corresponding ATM sense strand vector had no effect on the behavior of normal cells, and neither vector affected the behavior of A-T cells. Our results demonstrate that interference with ATM gene expression recreates the A-T phenotype in normal cells, and provide functional evidence linking the ATM gene to cellular DNA damage responses. The ATM antisense vector should prove a useful tool for studying ATM function in a variety of normal, mutant, and malignant cell lines.

Apoptosis↗

Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy.

In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for the D17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9 v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy.

Adult↗

Gene for topoisomerase III maps within the Smith-Magenis syndrome critical region: analysis of cell-cycle distribution and radiation sensitivity.

Smith-Magenis syndrome (SMS) is caused by an interstitial deletion of chromosome band 17p11.2 averaging 4-5 Mb. This deletion is likely to contain a large number of genes, each of which could potentially contribute toward the clinical phenotype. We report that the gene for topoisomerase III (hTOP3) is commonly deleted in SMS patients and maps between D17S447 and D17S258 on the short arm of chromosome 17. Cellular studies of SMS patient lymphoblasts and their respective parental cell lines were undertaken to determine the consequences of haploinsufficiency of hTOP3. Our studies indicate that hemizygosity for hTOP3 does not appreciably affect cell-cycle kinetics or activation of ionizing radiation-sensitive cell-cycle checkpoints. Furthermore, the induction of apoptosis in response to ionizing radiation in SMS and parental cells was similar. Our studies suggest that haploinsufficiency of hTOP3 does not have a major impact on the behavior of cells from SMS patients and may not play a significant role in the SMS phenotype.

Abnormalities, Multiple↗

Anemia in cancer patients.

Chronic anemia in cancer patients is caused by several pathophysiologic mechanisms. Reduced numbers of erythroid progenitor cells in the bone marrow and increased levels of inflammatory cytokines, which suppress erythropoiesis, result in a lower proliferative response of the erythron to erythropoietin stimulation. Erythropoietin production by the kidney in response to tissue hypoxia is often blunted; as a result, serum erythropoietin levels may be inappropriately low with regard to the degree of anemia. Red blood cell survival may be shortened; impaired iron utilization is manifested by enhanced retention of iron in the reticuloendothelial system. Chronic anemia also may be induced by cancer treatment, such as nephrotoxic chemotherapy.

Anemia↗

Anemia of cancer patients: patient selection and patient stratification for epoetin treatment.

Epoetin alfa is being used to treat patients with symptomatic anemia of cancer and to prevent or postpone chemotherapy-induced anemia in cancer treatment. As only approximately 50% of unselected anemic cancer patients respond sufficiently to epoetin alfa treatment, careful patient selection according to reliable prediction criteria is of great importance. Predictions of response to epoetin alfa treatment are based either on the degree of blunted erythropoietin response to the anemic condition or on indicators of responsiveness during the early treatment phase. The most accurate predictions of responsiveness, however, are derived from combinations of predictive factors. Combinations of synergistically acting hematopoietic growth factors, particularly epoetin alfa and granulocyte colony-stimulating factor, are beneficial to selected patients with myelodysplastic syndrome and may prolong survival in certain cases. Correction of anemia in cancer patients is particularly important because highly significant correlations have been reported between hemoglobin levels and quality of life in these patients.

Anemia↗

Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype.

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.

Apoptosis↗

Patient preferences for interferon alfa in multiple myeloma.

PURPOSE: Interferon alfa treatment in multiple myeloma marginally improves relapse-free and overall survival. Often it does so at the expense of toxicity and financial cost. If patients are unwilling or unable to participate in the decision of whether to initiate such treatment, known patient preferences can serve as guidelines for the physician. We interviewed myeloma patients in the United States to obtain information that might facilitate medical decision-making. PATIENTS AND METHODS: Three hundred fifty-five myeloma patients throughout the United States were interviewed by telephone. Without identifying interferon alfa as the treatment agent, interviewers described potential adverse effects, financial cost, and self-injection procedures. The potential benefits of four treatment choices, derived from a meta-analysis of published data, were presented as gains in remission rate (+10%), remission duration (an additional 4 and 7 months, respectively, for induction and maintenance treatment), and overall survival (an additional 3 and 6 months, respectively, for induction and maintenance treatment). Patients' choices for or against use of the unidentified substance were recorded, and interferon was subsequently disclosed as the treatment. The profiles of patients making different choices were determined using multivariate regression techniques. RESULTS: Approximately half of the patients accepted the unidentified treatment if remission and/or survival improved by at least 6 months. Accepters were younger and more likely to have used interferon. Of patients who rejected the unidentified treatment, 25% to 50% would have been willing to accept it if the benefits were > or = 12 months. Test/retest reliability of all choices, determined in 36 cancer patients, was 0.896. CONCLUSION: In multiple myeloma, interferon therapy and, by inference, other treatments with comparable features are acceptable to approximately half of the patients if a 6-month gain in relapse-free or overall survival can be expected.

Adult↗