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Biomedical subjects

B Zanke

Publications and source records attributed to B Zanke.

12 recordsLinked to original sources
PubMed2001

NKIATRE is a novel conserved cdc2-related kinase.

The mitogen-activated protein kinases (MAPKs) and the cyclin-dependent kinases (CDKs) are key mediators of cell proliferation in response to extracellular signals. Recent additions to each of these families and the identification of kinases with structural features of both have provided insights into fundamental processes, such as cell division and differentiation. To identify novel serine kinases with features of MAPKs or CDKs, a degenerate PCR-based amplification approach was undertaken. The 57- and 52-kDa isoforms of a novel protein kinase, termed NKIATRE, were molecularly cloned from rat brain and jejunum cDNA libraries. Like the MAPKs, NKIATRE has a Thr-Xaa-Tyr motif in kinase subdomain VIII. NKIATRE also shows close homology to the cyclin-dependent kinase class of protein kinases and the cdc2-related kinases NKIAMRE, KKIALRE, and KKIAMRE, containing both conserved inhibitory phosphorylation sites and a putative cyclin-binding domain. Two isoforms of NKIATRE that differ in their carboxy-terminal ends have been identified. A functional nuclear localization signal is specific to the longer 57-kDa alpha isoform. Sequence similarity to the putative human tumor suppressor gene NKIAMRE, which is lost in leukemic patients with chromosome 5q deletions, suggests that NKIATRE may have a role in restricting cell growth or maintaining differentiation.

Amino Acid Sequence↗
PubMed2001

Fludarabine in alkylator-resistant follicular non-Hodgkin's lymphoma.

Follicular small cell and follicular mixed small and large cell lymphoma (FL) are incurable with conventional chemotherapy, and generally follow a relapsing course, eventually becoming resistant to first-line therapy with alkylating agents. Fludarabine is a novel chemotherapeutic agent that is effective in FL, but its role in alkylator-resistant disease remains unclear. We conducted a retrospective review of all patients with alkylator-resistant FL treated with fludarabine. Patients were identified from pharmacy records and included if they fulfilled criteria for alkylator-resistant FL. Resistance was defined as failure to achieve a partial response, progression while on therapy, or relapse within six months of completing therapy. Seventeen patients met the criteria of alkylator-resistant FL and were included in the analysis. All patients received fludarabine 25 mg/m(2) for five days. A median of 2.5 courses of fludarabine was given. One patient had a complete remission and eight patients had partial remissions, for an overall response rate of 53%. Median progression-free survival was 5.4 months and median overall survival was 15.4 months for all patients. Four patients underwent subsequent autologous stem cell transplantation; all required additional salvage chemotherapy for post-fludarabine relapses. Three patients remain in remission more than 12 months post-transplantation. Fludarabine produces partial responses in patients with advanced refractory FL; however, the duration of the response limits its utility in alkylator-resistant disease.

Actuarial Analysis↗
PubMed1999

No association between hepatitis C and B-cell lymphoma.

Chronic viral infection has been implicated in the pathogenesis of B-cell lymphoma, and hepatitis C virus (HCV) infects lymphocytes. Chronic infection with HCV may result in B-cell proliferation. Individuals infected with hepatitis C are often co-infected with the RNA virus GB virus type C. Studies from Europe where hepatitis C infection is more common than in North America have shown a high prevalence of hepatitis C infection in patients with B-cell lymphoma. The aim of this study was to establish the prevalence of HCV and GBV-C infection in patients with B-cell lymphoma in an area of low HCV prevalence. One hundred patients with B-cell lymphoma (10 high grade, 46 intermediate grade, and 44 low grade) and 100 controls with nonhematological malignancies were studied. Serum was analyzed for HCV antibodies by third generation enzyme-linked immunosorbant assay, and HCV RNA and GBV-C RNA was analyzed by reverse transcriptase PCR. None of the controls or lymphoma patients had antibodies to HCV. HCV RNA was undetected in 60 out of 100 lymphoma patients tested. GBV-C RNA was detected in the serum of 5 out of 100 (5%) of lymphoma patients and in 3 out of 100 (3%) controls. Hepatitis C and GBV-C are, therefore, unlikely to play a major role in the pathogenesis of B-cell lymphoma in North America.

Antibodies, Viral↗
PubMed1998

Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance.

The extracellular microenvironment of tumors differs from most normal tissues. Many tumors have relatively acidic extracellular pH (pHe), although the intracellular pH (pHi) of tumor cells remains normal due to efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms which regulate pHi, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the anti-apoptotic gene bcl-2 and its pro-apoptotic binding partner bax, the Stress Activated Protein Kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. While expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its pro-apoptotic function. Inhibition of SAPK, through expression of a dominant negative mutant of its activator, SEK1 protected cells from acid-induced cell death. Caspase activation, as measured by poly (ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of ICE proteases by the peptide z-VAD.fmk did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.

Animals↗
PubMed1996

Reconstitution of novel signalling cascades responding to cellular stresses.

Mammalian cells respond to their immediate environment by inducing signal transduction cascades that regulate metabolism, secretion and gene expression. Several of these signalling pathways are structurally and organizationally related insofar as they require activation of a protein-serine kinase via it's phosphorylation on tyrosine and threonine; the archetype being mitogen-activated protein kinase (MAPK) which responds primarily to mitogenic stimuli via Ras. In contrast, two more recently identified cascades are responsive to cellular stresses such as heat, inflammatory cytokines, ischaemia and metabolic poisons. The recent identification of the components of these pathways has allowed manipulation of the stress-responsive pathways and evaluation of their physiological roles. These studies reveal a high degree of independence between the pathways not apparent from in vitro studies. Manipulation of the pathways in vivo will likely result in novel therapies for inflammatory disease and reperfusion injury.

Amino Acid Sequence↗
PubMed1995

Incidence of second cancers in patients treated for Hodgkin's disease.

BACKGROUND: Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. PURPOSE: We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. METHODS: We conducted a study within a cohort that included 10,472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. RESULTS: We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0; 95% CI = 1.1-3.6), procarbazine (RR = 4.9; 95% CI = 2.6-9.1), vinblastine (RR = 1.7; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8; 95% CI = 1.9-7.4). RRs were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4; 95% CI = 1.1-5.4). CONCLUSIONS: Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. IMPLICATIONS: Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors.

Adolescent↗
PubMed1994

A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1.

Tyrosine phosphorylation is an important regulator of cell growth and differentiation reflecting the interaction of protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP). Although excessive PTK activity can result in hematopoietic cell transformation, perturbation of either of these two modulators may result in uncontrolled cell growth. Myeloid cells are responsive to growth factors and cytokines that induce tyrosine phosphorylation and can become ligand independent when endogenous PTKs become dysregulated. Specific PTPs, through mutation or altered expression, may enhance PTK activities and also cause myeloid ligand independence, though this has not yet been demonstrated. We have previously reported the isolation of a hematopoietic specific cytoplasmic PTP (HePTP). We now report that this gene maps to chromosome 1q32.1 utilizing fluorescent in situ chromosomal hybridization (FISH). This site is frequently amplified in preleukemic myeloproliferative diseases. FISH analysis of a patient with myelodysplastic syndrome characterized by myeloid hypoplasia and monocytosis reveals triplication of the HePTP gene on one allele with elevated protein expression in neoplastic myelomonocytic cells. Elevated expression is also identified in blasts from some patients with acute leukemia. These observations prompted us to examine the experimental effects on cell growth of HePTP overexpression. Though normal myeloid cells show minimal HePTP expression, all hematopoietic cell lines tested show high expression of HePTP. Gene transfer of HePTP into NIH 3T3 cells was therefore performed, which caused altered cell morphology, disorganized growth, anchorage independent colony formation and subtle differences in the pattern of tyrosine phosphoproteins compared to control cell lines. We conclude that amplification and overexpression of HePTP may be an important cofactor contributing to abnormal myeloid cell growth.

Adult↗
PubMed1992

Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase).

Tyrosine phosphorylation and dephosphorylating events have been shown to be central to the process of growth regulation and signal transduction. We report here, the identification of a new gene with a tyrosine phosphatase domain (EC 3.1.3.48) which is expressed exclusively in thymus and spleen. A cDNA of 2760 bp encodes a 339-amino acid, intracellular, single-domain tyrosine phosphatase. When expressed as a glutathionine-S-transferase fusion protein, efficient lysis of p-nitrophenyl phosphate is noted, indicating in vitro enzymatic activity of the cloned gene product. Normal mouse lymphocytes increase mRNA expression 10-15-fold upon stimulation with phytohemagglutinin, concanavalin A, lipopolysaccharide or anti-CD3 monoclonal antibody. This new hematopoietic tyrosine phosphatase, (HePTP), may play a role in the regulation of T and B lymphocyte development and signal transduction.

Amino Acid Sequence↗
PubMed1990

Comparison of two APTT methods of monitoring heparin therapy. APTT ratio and heparin response of pooled normal plasma.

The sensitivity of the reagents for activated partial thromboplastin time (APTT) test varies greatly. Consequently the physicians who prescribe heparin based on certain APTT ratios may order different doses of heparin and produce different levels of anticoagulation in their patients, depending on the sensitivity of APTT reagent used by the laboratory. The authors have been recommending that physicians in their hospital use a therapeutic range for heparinization based on the sensitivity of the APTT reagent and keep the APTT of patients within the range of APTT of pooled normal plasma containing 0.2-0.4 units of heparin per milliliter. Because the patient's response to heparin in vivo may be different from that of pooled normal plasma, the authors planned to compare the effect of these two methods of heparin monitoring on heparin usage and complications of heparin therapy. In a retrospective study, the authors reviewed the hospital records of patients treated with continuous intravenous heparin for the management of thromboembolic disorders during two periods: one period in which the laboratory used an APTT reagent with low in vitro sensitivity to heparin (LSH) and another period in which the authors used an APTT reagent with high sensitivity to heparin (HSH). The authors found that there were no significant differences between the incidence of bleeding or thrombotic complication in the two periods. Furthermore, they found that in both periods, the patients had received similar total doses of heparin during the first 72 hours of therapy. However, as was expected from in vitro sensitivity, the APTT of patients during the LSH period was significantly lower than those during the HSH period. More heparin would have been used during the LSH period compared to the HSH period of physicians were to use the APTT ratio method for monitoring the therapy. The authors conclude that using the therapeutic range for monitoring heparin therapy based on the heparin response of pooled normal plasma will result in a more comparable level of heparinization from year to year and from center to center than by using the APTT ratio method.

Blood Coagulation Tests↗
PubMedDate not supplied

The potential role of HSP70 as an indicator of response to radiation and hyperthermia treatments for recurrent breast cancer.

Twenty-three patients with recurrent breast cancer participating in a Phase III trial evaluating radiotherapy (XRT) with or without hyperthermia (HT) were included in a parallel study of heat shock protein (hsp) expression. The patients had core biopsies and/or fine needle aspirates (FNA) performed on their tumours, before and after treatment. These were analysed for hsp content using immunohistochemical staining with a monoclonal antibody to the inducible form of hsp 70. The proportion of samples containing identifiable cancer cells was greater for the core biopsy specimens (80%) than with FNA (60%). Staining intensity was analysed using either the majority score, i.e. the staining intensity (on a relative scale from 0 to 3) for the largest proportion of tumour cells, or the arithmetic score, which is the sum of the product of percentage of tumour cells and their staining intensity. The staining intensity for hsp's after treatment correlated inversely with the probability of attaining a complete response (CR). Specifically, the median and maximum scores for the biopsy specimens were significantly inversely related to the probability of attaining CR. The results suggest that this technique may be useful in predicting for thermotolerance development, though more data is needed to confirm the utility of the technique. Results from this study corroborate data from other clinical studies which suggest that tumours with elevated hsp levels may demonstrate resistant biologic behaviour.

Biopsy↗