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  • 1
    Electronic Resource
    Electronic Resource
    The bgI1 gene encoding extracellular β-glucosidase from Trichoderma reesei is required for rapid induction of the cellulase complex (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Molecular microbiology 6 (1992), S. 0 
    Details
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: We have used a targeted gene deletion event to remove the coding region for the bgli gene encoding an extracellular β-glucosidase from the genome of the cellulolytic fungus Trichoderma reesei. The bgli null mutants were used to investigate the role of [1-glucosidase in the hydrolysis of cellulose and induction of the other cellulolytic enzyme components. In the absence of extracellular βglucosidase, growth of bgl1 null strains on several carbon sources was the same as that of the parent (as measured by mycelial dry weight). However, levels of extracellular protein and total endoglucanase production were seen to lag relative to those levels observed in the control strain. The mRNA levels of the CBHI, CBHII, EGI, and EGII cellulase genes (cbh1, cbh2, egli and egl3) showed a corresponding lag in induction, suggesting that the absence of extracellular β-glucosidase has an effect on the co-ordinate regulation of the other cellulase genes at the level of transcription. The addition of a potent inducer of the cellulase complex (sophorose) resulted in normal rates of cellulase gene mRNA production and extracellular protein release. This indicates that the absence of β-glucosidase is not affecting some intrinsic cellular ability to produce mRNA or secrete protein. These data suggest that a functional β-glucosidase is at feast partially responsible for the efficient induction of the depolymerase enzymes of the cellulase complex. The observation that the cellulase complex is induced, albeit after a lag, suggests that other enzymes are present that can substitute for the function of β-glucosidase during induction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2958.1992.tb01777.x
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  • 2
    Electronic Resource
    Electronic Resource
    Enzyme-gold affinity labelling of cellulose (1988)
    New York, NY : Wiley-Blackwell
    Journal of Electron Microscopy Technique 8 (1988), S. 371-379 
    Details
    ISSN: 0741-0581
    Keywords: Casuarina ; Cellulase ; Cell walls ; Codium ; Colloidal gold ; Dictyostelium ; Udotea ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Natural Sciences in General
    Notes: The enzyme-linked colloidal gold affinity labelling technique was tested as a method to localize cellulose on thin sections of plant cell walls and slime mold spores. Commercially available cellulase from cultures of Trichoderma reesei, the main components being cellobiohydrolase I and II (CBH I, CBH II) and endoglucanase (EG), was linked to colloidal gold by using standard techniques and applied as a dilute, buffered suspension to thin sections. After brief exposure, e.g., 15-30 minutes, cellulose exposed on the surface of sections was labelled with the enzyme-gold complex. Poststaining did not appear to have a deleterious effect on the labelled sections. The specificity of labelling was demonstrated by its complete inhibition when carboxymethylcellulose was incorporated in the labelling mixture, by lack of labelling of 1,4-β-mannans or 1,3-β-xylans in noncellulosic walls of marine algae, by lack of labelling of 1,4-β-glucans in chitin, by much lower labelling density when done at 4°C, and by lack of labelling when sections were predigested with cellulase. Labelling with the crude commercial cellulase was compared to labelling with purified CBH I-, CBH II-, and EG-linked colloidal gold, and the labelling pattern was similar. This method was found useful on conventionally fixed material and required no special preparation other than the use of inert (Ni or Au) grids and 0.5% gelatin to reduce nonspecific binding of the gold complex. Labelling was similar in the several embedding resins tested: LR White, Lowicryl K4M, Epon 812, and Spurr's. The cellulase-gold probe remained active for at least 4 weeks at 4°C and much longer when frozen at -80°C in 20% glycerol. This technique should prove useful in studies of cellulose degradation and cellulose deposition and of the interaction of cellulose with other wall components.
    Additional Material: 17 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jemt.1060080406
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  • 3
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    Protective Cytotoxic Clonal T-Cells in Myeloma Have the Characteristics of Telomere-Independent Senescence Rather Than an Exhausted or Anergic Phenotype: Implications for Immunotherapy (2014)
    American Society of Hematology
    Details
    Publication Date: 2014-12-06
    Description: Dysfunctional T-cells associated with human tumors can be identified utilizing multi-parameter flow cytometry and studied for intracellular signalling checkpoints using phospho-flow or time-of-flight mass spectrometry. Whether tumor-induced hypo-responsive T-cells in patients with myeloma are anergic, exhausted or senescent has not yet been determined. Anergic T-cells are hypo-responsive with low cytokine production and induce tolerance to protect the host from autoimmune disease. T-cell exhaustion is usually associated with chronic viral infection such as CMV but also with some cancers. Both exhausted and anergic T-cells express PD-1, LAG-3, Tim-3, CD160 and CD28. Hypo-responsive T-cells associated with melanoma have the phenotype of exhausted T-cells which can be reactivated using targeted immune check point blockade, resulting in clinical benefit. Senescent T-cells accumulate in an oligoclonal manner with ageing and chronic antigen exposure. Senescence can be characterised by telomere shortening, the expression of CD57, KLRG-1, CD160 and the absence of CD28. However, not all senescent cells have shortened telomeres as telomere independent senescence involving the p21-p53 and p16-pRb pathways and senescence associated secretory phenotype (SASP) T-cells have been described. The aim of this study was to determine whether tumor-induced hypo-responsive T-cells in patients with myeloma are anergic, exhausted or senescent and to identify targetable checkpoints to restore T-cell function. Cytotoxic T-cell clones (CD57+ CD28- TCRVβ restricted) determined by BetaMark TCRVβ analysis were present in 51% of patients with myeloma (n=264), are protective (OS χ2=6.2; p
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    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 4
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    Clonal Expansions of Cytotoxic T Cells in the Blood of Patients with Waldenstrom's Macroglobulinaemia Are Anergic and Disappear After Nucleoside Analogue Therapy. (2009)
    American Society of Hematology
    Details
    Publication Date: 2009-11-20
    Description: Abstract 1820 Poster Board I-846 T cells contribute to the immunomodulatory control of the tumor in patients with monoclonal gammopathies. We previously found that CD3+CD8+CD57+TCRVβ+restricted cytotoxic T cell expansions were present in 48% of patients with multiple myeloma (n=221) and conferred a significant favorable prognosis. We now report the presence of these expansions in 70% of patients with Waldenstrom's Macroglobulinaemia (WM) (n=20) with a wide spectrum of the TCRVβ repertoire represented. Previous nucleoside analogue (NA) therapy, known to be associated with an increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVβ expansions (χ2=11.6; p
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  • 5
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    Gene Expression Profiling of the Clinical Significant CD57+CD8+ Cytotoxic T Cell Expansions in Patients with Waldenstrom’s Macroglobulinemia. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Previous studies have suggested that expanded T-cell clones are found in the blood of 59% of patients with multiple myeloma. These expanded T-cell clones are associated with prolonged overall survival and thus it has been suggested that they may have anti-tumor activity. We have previously reported similar T-cell clones exist in the peripheral blood of patients with Waldenstrom’s Macroglobulinemia (WM) by using flow cytometry to determine the T cell receptor (TCR) Vβ repertoire. Expanded T-cell clones were detected in 9 of 15 (60%) patient samples. Of the nine patients with TCR Vβ clones, four patients had multiple clones. The TCR Vβ clones were not identical, representing a variety of families across the TCR Vβ repertoire. We have previously found that while the TCRVβ+CD8+CD57 negative subset represents polyclonal populations, the CD57 positive subset represents either monoclonal or biclonal populations. By comparing the genetic profiling of these two subsets from a statistically significant gene list, two genes have been found to be highly upregulated in the CD57 negative polyclonal subset. These two genes are i.) SESN3, a member in the Sorting Nexin (SNX) protein family which is implicated in regulating membrane traffic capable of interaction with phosphatidylinositol-3-phosphate (10.4 fold, p=0.0241); ii.) Epstein-Barr virus induced gene 2 (lymphocyte-specific G protein-coupled receptor) EBI2 (7.4 fold, p=0.0207): This finding is in contrast to previous report that EBI2 is expressed in B-lymphocyte cell lines and in lymphoid tissues but not in T-lymphocyte cell lines or peripheral blood T lymphocytes. For the CD57 positive clonal T cell expansions, consistent with our previous reports, CD28 expression was found to be down regulated by 2.6 fold. There are two genes found to be highly upregulated. They are i.) Granzyme B (4.3 fold, p=0.0337) also called Cytotoxic T-lymphocyte proteinase 2. This enzyme is necessary for target cell lysis in cell-mediated immune responses through caspase-dependent apoptosis; ii.) Granzyme H, also called Cytotoxic T-lymphocyte proteinase and probably necessary for target cell lysis in cell-mediated immune responses. In summary, we have shown that CD57 positive clonal T cell populations exist in some patients with WM. Importantly, microarray results have indicated some genes and proteins that may related to better patients survival as previously demonstrated in patients with Multiple Myeloma.
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  • 6
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    Hypermethylation of E-cadherin in leukemia (2000)
    American Society of Hematology
    Details
    Publication Date: 2000-05-15
    Description: E-cadherin gene is often termed a “metastasis suppressor” gene because the E-cadherin protein can suppress tumor cell invasion and metastasis. Inactivation of the E-cadherin gene occurs in undifferentiated solid tumors by both genetic and epigenetic mechanisms; however, the role of E-cadherin in hematologic malignancies is only now being recognized. E-cadherin expression is essential for erythroblast and normoblast maturation, yet expression is reduced or absent in leukemic blast cells. This study examined the messenger RNA (mRNA) and protein expression of the E-cadherin gene in bone marrow and blood samples from normal donors and patients with leukemia. We found that all normal donor samples expressed E-cadherin mRNA, whereas both samples of acute myelogenous leukemia and chronic lymphocytic leukemia had a significant reduction or absence of expression. However, normal blast counterparts expressed only a low level of E-cadherin surface protein. Sodium bisulphite genomic sequencing was used to fully characterize the methylation patterns of the CpG island associated with the E-cadherin gene promoter in those samples with matched DNA. All of the normal control samples were essentially unmethylated; however, 14 of 18 (78%) of the leukemia samples had abnormal hypermethylation of the E-cadherin CpG island. In fact both alleles of the E-cadherin gene were often hypermethylated. We conclude the E-cadherin gene is a common target for hypermethylation in hematologic malignancies.
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    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 7
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    The Immunomodulatory Action of Thalidomide in Patients with Multiple Myeloma Involves a Clonal Expansion of Late-Differentiated Cytotoxic Effector Cells. (2005)
    American Society of Hematology
    Details
    Publication Date: 2005-11-16
    Description: Although thalidomide has been reported to increase T cell activity and NK cell cytotoxicity in the blood of patients with multiple myeloma (MM) it is not known whether thalidomide stimulates tumour-specific T cells or causes a general lymphocytosis. We investigated the immunodulatory effects of thalidomide by studying peripheral blood samples from 64 patients in the Australian ALLG MM6 trial, a multicentre randomised phase III study of low-dose thalidomide, prednisolone and Zometa versus prednisolone and Zometa used as post-autologous stem cell transplant (ASCT) maintenance therapy in patients with MM. We have previously demonstrated that TCR Vβ clonal expansions are present in approximately 50% of patients with MM and that their presence correlates with a good prognosis. Sequencing has confirmed that these cells are a clonal expansion of CD3+CD8+CD57+CD28−CD27− late-differentiated cytotoxic effector cells. Flow cytometric analysis of TCR Vβ expansions (24 families) was performed on blood samples from 64 patients enrolled in the MM6 trial both prior to and 12 months post transplant. Prior to transplant, 59% of the 64 patients had TCR Vβ expansions. After thalidomide, T cell expansions were found in a further 8/34 patients compared with 3/30 in the control, no thalidomide group. In the thalidomide group, 70% of the patients had an expansion of more than one T cell clone compared with 32% in the control group (chi2=28.8; p
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  • 8
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    Phospho-Flow Cytometry Quantitation of STAT Signalling Checkpoints in Malignant and Non-Malignant Cells Identifies Patients Suitable for pSTAT3 and 5 Targeted Inhibitors (2015)
    American Society of Hematology
    Details
    Publication Date: 2015-12-03
    Description: Background IL-6 receptor/JAK/STAT is a major signalling pathway associated with pleiotropic functions including cell transformation and proliferation. STAT3, one of a family of 7 STAT members, sits at the apex of the signalling cascade and is a potential target for cancer therapy. Small molecular weight inhibitors either prevent STAT3 phosphorylation or target high constitutive levels of phosphorylated pSTAT3 (pSTAT3). Increased constitutive expression of pSTAT3 is a hallmark of solid tumors and is associated with increased morbidity. However recent studies suggest that this may not apply to hematological malignancies. Phospho-flow cytometry offers a novel approach for the quantitation of constitutive and cytokine induced pSTAT3 expression in subsets of hemopoietic cells. Constitutive pSTAT3 expression is not a prognostic factor for patients with either multiple myeloma (MM) or acute myeloid leukemia (AML), though we recently demonstrated that IL-6 induced pSTAT3 was associated with better prognosis in MM (χ2 =13.06; p5% of normal lymphocytes) in the malignant plasma cells of 44% of patients with MM but by comparison was not increased in AML or B-CLL. Constitutive pSTAT5 was increased (〉5%) in 68% of MM plasma cells and 75% of AML cells and was either normal or decreased in CLL cells. Patients with increased pSTAT3 or 5 in MM cells also had high expression in autologous normal T cells. The level of constitutive pSTAT3 and 5 was not related to the disease status (relapse vs remission). In patients with MM, IL-6 induced an increased pSTAT3 expression (induced/constitutive ratio 〉1.5) in both MM cells and T cells in 88% of samples. IL-6 induced pSTAT3 expression in blasts of 89% of AML patients (median ratio = 79). There was no correlation between the level of pSTAT3 induced by IL-6 and IL-6 receptor expression. IL-6 did not increase pSTAT5 levels in MM, AML or CLL. SP cells in the MM cell line RPMI 8226 had lower constitutive pSTAT3 than the non-SP population and a lower IL-6 receptor expression, but had a greater response to cytokine stimulation, suggesting that SP cells may be more sensitive than non-SP cells to inhibitors of STAT phosphorylation. Addition of RPMI 8226 cells or supernatant to normal T cells caused an increase in pSTAT3, suggesting that the upregulation of pSTAT3 is at least partly due to a tumor-derived soluble agent in the microenvironment. Conclusions These results demonstrate the heterogeneity of constitutive and cytokine induced pSTAT3 and 5 expression in MM, AML and CLL. Elevated levels of constitutive pSTAT3 (approx 44% of MM) and pSTAT5 (88% of MM and AML) in the malignant clone were associated with high levels in autologous non-malignant T cells and are not of prognostic significance. Therefore elevated pSTAT3 and 5 may not be an exclusive hallmark of the malignant clone, as reported in solid tumors, but rather a result of the microenvironment and a high IL6-R expression. Phospho-flow cytometry enables precise quantitation of constitutive and cytokine-induced pSTAT3 and 5, and thus can identify the patients most likely to respond to direct STAT-3 or 5 inhibitor therapies. SP cells (putative MM stem cells) appear to be potentially targetable. Inhibitors targeting signalling pathways may be more efficacious if therapy is directed to patients with targetable checkpoints. Disclosures Hart: DendroCyte BioTech Pty Ltd: Equity Ownership.
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  • 9
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    Differentiation of Multiple Myeloma and MGUS by Cross Validated Differential Proteomic Analysis. (2006)
    American Society of Hematology
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    Publication Date: 2006-11-16
    Description: The recent development of a standardised proteomic microarray technique, DotScan, has allowed an innovative approach to the investigation of haematological disorders. In this study, mononuclear cells from 49 peripheral blood samples were studied to determine whether the technology could identify a differential consensus pattern of antigen expression for patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). An automated reader simultaneously determined the expression of 82 different cell surface antigens by binding cells to antibodies on microscopic dots on the nitrocellulose-coated region of a microscope slide. The figure illustrates the image from a typical slide. A consensus pattern of antigen expression was analysed in duplicate by cross-validated discriminant analysis and a pilot database of disease groups was accumulated. Cross validated discriminant analysis successfully predicted patients with monoclonal gammopathy (98% success) and a discrete mosaic pattern could differentiate patients with MM who were treated with thalidomide (n=9). As expected, no single antigen could be used to discriminate between multiple myeloma (n=24), MGUS (n=14) and normal controls (n=11). Antigens with the highest ranking for differentiating the monoclonal gammopathies were CD25 (reduced after thalidomide), CD8 and CD57 (high in MM), CD28 (reduced in MM) and CD95 (reduced in MGUS) reinforcing the importance of immunomodulatory mechanisms in both MM and MGUS. Traditional flow cytometry was used to confirm these specific observations but also to demonstrate that the reduced CD28 expression was specific for CD8+ cells and the reduced CD95 expression was on CD8+ CD57+ cells. Three patients with MGUS were misclassified as MM but on review these 3 patients could have been classified as smoldering myeloma. There was no significant difference in the mosaic of 5 long term survivors of MM (〉 10 years). This study has demonstrated the potential of using disease-specific databases to compare the mosaic of antigen expression for the diagnosis of monoclonal gammopathies. Long term studies will be required to accurately determine the prognostic significance at diagnosis and the ability of consensus patterns to identify which MGUS patients develop MM. Figure Figure Specificity and sensitivity of proteomic array for monoclonal gammopathies MGUS MM MM Thal Normal Sensitivity % Specificity % MGUS prediction 5 3 2 4 35 100 MM prediction 0 15 0 0 100 91 MM Thal prediction 0 0 9 0 100 95 Normal prediction 0 0 0 11 100 89
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  • 10
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    Ten Year Survival in Patients with Myeloma Is Characterized by the Persistence of Immunological Control Which Is Detected by Immunological Biomarkers (2012)
    American Society of Hematology
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    Publication Date: 2012-11-16
    Description: Abstract 1818 There is clinical evidence for the presence of a limited degree of host-tumor control in patients with multiple myeloma (MM) but the exact mechanisms involved are not known. Patients who survive for more than ten years are likely to have the most active immunological host-tumour control and are an ideal cohort to study. We now add to our preliminary observations using a range of immunological biomarkers in the 29 of these patients who attend our clinic. 51% of MM patients (n=264) had expanded CD3+CD8+ TCRVβ+ CD57+T cell clones detected by TCRVβ analysis (Beckman, BetaMark). Clonality was confirmed by IgH CDR3 sequencing. These clones accounted for 14.3% (median) of the CD3 cells (range 4–49%). CFSE tracking demonstrated the anergic nature of these clonal T cells (median 6% proliferation) compared with other CD8 cells (70% proliferation) while Geneset analysis of mRNA microarrays (Affymetrix U133) identified that anergy was caused by upregulated RAS, CSK, TOB and suppressed ERK pathways. Unlike recent reports for T-LGL, microarray analysis suggested that there was no evidence of STAT3 upregulation in the MM T cell clones. Functional studies suggested that these non-proliferating clones have split anergy as interferon-γ production was normal. In contrast, all ten year survivors had expanded T cell clones and serial studies demonstrated a 〉8 year persistence of the same clone in 8 out of 12 patients studied. More importantly, unlike the other MM patients, the T cell clones in 19 out of 21 of the ten year survivors studied were not anergic. The Treg/Th17 ratio in the ten year survivors was significantly lower than other MM patients (median 1.9 vs 12.0; p
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