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Biomedical subjects

G Weber

Publications and source records attributed to G Weber.

989 records · Page 55Linked to original sources
PubMedDate not supplied

Critical evaluation of limb salvage concept and indication for infrapopliteal reconstructive surgery.

A large number of surgical procedures aimed at revascularizing the popliteal and infrapopliteal arteries has been reported in patients affected by rest pain or gangrene of the extremities as well as intermittent claudication. In consideration of the high incidence of early and late unsuccessful results following this type of surgery as reported in the literature, we believe that peripheral reconstructions should be restricted to those patients presenting a clinical picture of such severity that major amputation is unavoidable in the short run. In these patients our choice of the appropriate surgical procedure is strictly related to the patency or not of the popliteal artery. The role of the above knee femoropopliteal bypass is discussed. A series of patients that we have operated upon according to these criteria is analyzed. The low number of cases in our group of patients and the high rate of postoperative failures reflect our policy on this matter.

Amputation, Surgical↗
PubMedDate not supplied

[Breast cancer in context - results of a prospective study and implications for therapy].

56 patients admitted to the surgical clinic for a breast biopsy were interviewed on the day of their admission. The interviewer recorded his impression of the conversation in eight rating scales. The assessments were repeated by an independent rater from edited tape recordings of the interviews. There was a statistical difference between breast cancer patients and patients with a benign node in all eight scales used and the diagnosis cancer was predicted by the interviewer and rater in 80-90% of all cases. A specific mode of therapeutic procedure is discussed in which the cancer is seen as the final link in a chain of similar occurrences, and in which inclusions of the surrounding field is more conclusive to success than working with the individual alone. The basic idea of this approach has for a long time played a part in the work with "difficult" patients: it very positively sanctions the behavior exhibited as a survival feat in an extremely difficult situation and it accepts that for the time being any other behavior is hardly possible. Thus, a paradoxical effect often ensues: the families begin to offer resistance to the doctor's one-sided representation and at the same time call their own behavior into the question.

Adult↗
PubMedDate not supplied

[Ultrasound imaging of the symphysis fissure for evaluating damage to the symphysis in pregnancy and postpartum].

In a cross-sectional study of 211 patients with a normal pregnancy the distance of the symphysis was sonographically measured during pregnancy and normal values were evaluated. Physiologically a continuous widening of the symphysis was shown up to 3 mm an average. The sonographical sign of the damage of the symphysis was a deviation in widening and also a difference in height. The value of the sonographic examination is shown in 2 cases with damage of the symphysis and compared to the x-ray picture results.

Adult↗
PubMedDate not supplied

Molecular mechanisms in the antiproliferative action of taxol and tiazofurin.

The molecular antiproliferative effects of taxol and tiazofurin were studied in human K562 leukemia, and in MCF-7 breast and OVCAR-5 ovarian carcinoma cell cultures. A single treatment with taxol (2 to 100 nM) or tiazofurin (5 to 20 microM) on K562 leukemia cells resulted in both a differentiation program and apoptosis in the same cell culture. Tiazofurin proved to be the most potent inducer of differentiation among the inducers, however, taxol had a major impact on induction of the alterations characteristic of apoptosis. The antiproliferative effect of tiazofurin was mediated by 37 to 85% inhibition of IMP dehydrogenase activity. Both the differentiation and apoptosis induced by tiazofurin were dependent on GTP supply. The induction of differentiation and/or apoptosis was mediated by downregulation of c-myc and Ki-ras oncogenes in all three cell lines treated with tiazofurin (by 2 hr) or taxol (by 24 hr). Combined treatments with tiazofurin and taxol exerted a schedule-dependent, antiproliferative interaction in the cell lines studied. Synergistic inhibition of cell proliferation was observed when cells were pretreated with tiazofurin (10 to 15 microM) for at least 12 hr, then taxol (5 to 15 nM) was added.

Antineoplastic Agents↗
PubMedDate not supplied

Increased signal transduction activity and down-regulation in human cancer cells.

The purpose of this study was to elucidate the behavior of signal transduction activity in rat and human carcinoma cells. Signal transduction activity was measured by the steady-state activity of the three enzymes involved in the conversion of 1-phosphatidylinositol (PI) to IP3, PI 4-kinase, PI 4-phosphate 5-kinase, and phospholipase C activities were measured by our methods. The results indicate that the steady-state activities of the three signal transduction enzymes and the end-product, IP3, were up-regulated in a transformation- and progression-linked fashion. In rat liver PI kinase, PIP kinase and PLC activities were 0.4, O.04, and 800 nmol/hour/mg protein, respectively. PI and PIP kinase and PLC activities were increased 2- to 8-fold in five rat hepatomas and 29-, 45-, and 4-fold, respectively, in rapidly growing hepatoma 3924A. PI and PIP kinase activities as compared to normal ovary were elevated in human ovarian epithelial carcinomas (4- and 3-fold) and in OVCAR-5 cells in culture (31- and 11-fold). Compared to normal breast parenchymal cells, PI and PIP kinase activities were increased in human breast carcinoma cells (96- and 16-fold). When breast carcinoma cells were plated and expressed their neoplastic proliferative program. IP3 concentration increased 20-fold in early log phase: PI and PIP kinase activities increased 11-fold in mid log phase: PLC activity did not change throughout. PI and PIP kinase activities in bone marrow had short half-lives (t1/2 = 8 minutes) but PLC had a long one (t1/2 > 6 hours). The elevated signal transduction activity was down-regulated by the anti-cancer drug, tiazofurin, and also by quercetin, an inhibitor of PI kinase. The addition of these drugs to cultured carcinoma cells reduced the IP3 concentration, and the cells were killed. These integrated studies are the first showing that signal transduction activity is stringently linked with transformation and progression in rat and human solid tumors and carcinoma cells. Down-regulation (by tiazofurin) or inhibition of PI and PIP kinase activities (by quercetin) in human carcinoma cells led to a marked reduction of IP3 concentration and to cell death. Tiazofurin and quercetin may be useful in the treatment of carcinomas with increased signal transduction capacity.

1-Phosphatidylinositol 4-Kinase↗
PubMedDate not supplied

Tiazofurin: molecular and clinical action.

UNLABELLED: The purpose is to provide an overview of the molecular and clinical impact of tiazofurin. METHOD: The biochemical and clinical techniques were reported (1, 2). RESULTS: IMP DH activity increased in various animal and human tumors and was particularly high in leukemic blast cells. The increased activity was due to an elevation in the mRNA concentration of type II isozyme. Tiazofurin, a C-nucleoside, was converted in sensitive cells to the active metabolite, TAD, which tightly bound at the NADH site inhibited IMP DH activity. The inhibition led to decreased GTP concentration, down-regulation of ras and myc oncogenes and induced maturation of blast cells. New evidence shows that tiazofurin injection downregulated signal transduction activity due to a reduction of the activities of PI and PIP kinases leading to a decrease in the concentration of the second messenger, IP3. In patients; tiazofurin infusion and allopurinol administration led to reduction of IMP DH activity and GTP concentration. Allopurinol inhibited xanthine oxidase activity leading to a marked rise in hypoxanthine concentration which inhibited the increased guanine salvage pathway. In the clinic, the increase in serum hypoxanthine concentration is essential for the success of tiazofurin treatment. Tiazofurin showed additivity or synergism with ribavirin, retinoic acid, taxol, quercetin, gemcitabin, dipyridamole and brefeldin. Ribavirin which inhibits IMP DH at the IMP site has been shown to prolong the IMP depressing action of tiazofurin in rat bone marrow cells. CONCLUSION: Tiazofurin and allopurinol achieve reduction of GTP concentration in leukemic blast cells through inhibition of IMP DH and GPRT activities. As a result, induced maturation occurs with down-regulation of ras and myc oncogenes and probably reduced signal transduction capacity. Tiazofurin in leukemic patients provides over 75% therapeutic responses and patients can be treated with this combination for many months with good quality of life. These clinical and biochemical results were recently confirmed independently (3).

Allopurinol↗
PubMedDate not supplied

Biochemically targeted therapy of refractory leukemia and myeloid blast crisis of chronic granulocytic leukemia with Tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.

Conventional antileukemic chemotherapy in relapsed or refractory acute leukemia or myeloid blast crisis of chronic granulocytic leukemia (CGL) is not curative and remissions, if attained, are usually of short duration. The primary goal of antileukemic therapy in these patients should be the identification of agents that are more selective and better targeted in their action. Tiazofurin is known to inhibit inosine 5'-phosphate dehydrogenase (IMPDH), the rate limiting enzyme of de novo guanine ribonucleotide synthesis. The activity of this enzyme is markedly increased in leukemic cells. To prevent de novo GTP synthesis, it is also necessary to block the guanine-salvaging activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This was achieved by increasing the plasma levels of hypoxanthine through the administration of allopurinol. Twenty-seven patients with end stage leukemia or myeloid blast crisis of CGL were treated with tiazofurin. Assays of IMPDH activity and GTP concentrations in leukemic cells, as well as hypoxanthine levels in the serum, provided a method to monitor the impact of tiazofurin/allopurinol therapy and to adjust drug doses. In these poor prognosis patients seven attained a complete response (CR), 3 had a hematologic improvement and an antileukemic effect was seen in 4. An excellent correlation was observed between biochemical and clinical activity of tiazofurin/allopurinol, with biochemical responses preceding clinical results. However, clinical responses were usually short-lived with IMPDH activity starting to increase soon after discontinuation of therapy, but patients responding again after reinstitution. Tiazofurin therapy was generally well tolerated in patients with less than 15 days of treatment and no other major medical complications. Although an antiproliferative effect was observed in some patients, bone marrows remained cellular in most cases with a marked shift from blasts to granulocytes. Severe neutropenia was absent in the majority of cases and patients could be discharged in good clinical condition immediately after completion of therapy. Tiazofurin/allopurinol therapy provided a rational, biochemically targeted and biochemically monitored approach to the treatment of poor prognosis leukemia and should serve as a paradigm in enzyme pattern-targeted chemotherapy.

Adult↗
PubMedDate not supplied

Increased thymidine kinase and thymidylate synthase activities in human epithelial ovarian carcinoma.

BACKGROUND: Thymidylate synthase (dTMP synthase, EC 2.1.1.45) is responsible for the de novo biosynthesis of thymidylate (dTMP) whereas thymidine kinase (TdR kinase, EC 2.7.1.21) is the salvage enzyme which leads to the production of dTMP even in presence of d TMP synthase inhibition. The current study was undertaken to compare the steady-state activities of d TMP synthase and TdR kinase in extracts of human epithelial ovarian carcinoma and normal ovaries. MATERIAL AND METHODS: Tissue extracts of epithelial ovarian carcinomas and normal ovaries were analyzed for activities of d TMP synthase (by a method that measures released 3H2O) and TdR kinase (by polyethyleneimine impregnated (PEI) cellulose plate radioassay), methods established in this laboratory. RESULTS: The dTMP synthase activity (mean +/- S.E.) in extracts of ovarian carcinomas (N = 11) was 0.198 +/- 0.069 and in extracts of normal ovaries (N = 12) it was 0.025 +/- 0.0004 nmol/hr/mg protein. By contrast, TdR kinase activity in extracts of ovarian carcinoma (N = 13) was 27.7 +/- 8.5 compared to 1.0 +/- 0.3 nmol/hr/mg protein in extracts of normal ovaries (N = 15). CONCLUSION: The observed 140-fold higher TdR kinase activity suggests that DNA synthesis may continue despite inhibition of dTMP synthase with current schedules of 5-fluorouracil (5-FU) and leucovorin. The addition of azidothymidine, a competitive inhibitor of TdR kinase, to 5-FU and leucovorin might be a rational biochemical strategy to employ in patients with refractory ovarian carcinoma.

Adult↗
PubMedDate not supplied

Intracellular signalling: phosphatidylinositol lipid metabolism in cancer cells.

Evidence for heightened capacity for signal transduction in rat hepatoma as well as in human breast and ovarian carcinoma cells as reflected by coordinate increases in PI kinase and PIP kinase in the PI phosphorylation sequence leading to the production of second messengers IP3 and DAG is shown. The linkage of signal transduction enzymes with malignant growth is also seen as MDA-MB- 435 human breast carcinoma or ovarian OVCAR-5 cells express their proliferative capacity in tissue culture in the log phase. In both cases, quercetin inhibit cell proliferation with a decline in PI kinase activity and IP3 levels preceding the growth inhibition seen with quercetin. The elevated steady state activities of PI and PIP kinase indicate a metabolic up-regulation in signal transduction capacity of cancer cells which is down-regulated by quercetin. Since the gain in function manifested in the over-expressed capacity for signal transduction confers selective growth advantage to cancer cells, increased activities of PI and PIP kinases may be considered as sensitive targets for cancer chemotherapy. The potential of quercetin as an interceptor of intracellular signal transduction mechanisms needs to be explored.

1-Phosphatidylinositol 4-Kinase↗
PubMedDate not supplied

Phospholipase C (EC 3.1.4.11): a malignancy linked signal transduction enzyme.

AIM: To elucidate the relationship between phospholipase C, phosphatidylinositol-4,5-bisphosphate (PIP2) phosphodiesterase, EC 3.1.4.11 (PLC) and transformation, progression and proliferation, steady-state activity was determined in a spectrum of transplantable solid rat hepatomas of different growth rates, and in a variety of normal rat organs. METHODS: To measure PLC activity in the plasma membrane fraction a standard isotopic method was developed using exogenous PIP2 as substrate. PLC activity was linear with time for 2.5 min and proportional with protein concentrations over a range of 5 to 29 micrograms per 50 microliters reaction mixture. RESULTS: The apparent K(m) for PIP2 was 0.3 mM in both normal liver and rapidly growing hepatoma 3924A. PLC activity in adult rat liver was 747 and 986 nmol/h/mg protein; it increased 1.7- to 2.1-fold in hepatomas of slow and intermediate growth rates and 3.7-fold in rapidly growing hepatoma 3924A. By contrast, no significant difference was observed between 24 hours regenerating and sham-operated livers. PLC activity was high in thymus, spleen, testis, bone marrow, lung, brain, heart and renal cortex, but in the same range in skeletal muscle and liver. PLC has a relatively long half-life as there were no significant changes in PLC specific activity in bone marrow during the 9 hour period after intraperitoneal injection of the protein biosynthetic inhibitor, cycloheximide. PLC was subject to nutritional regulation because at 3 days' starvation the specific activity in rat bone marrow decreased to 78% of control values and recovered after 1-day refeeding. CONCLUSION: The results indicate that PLC is a transformation- and progression-linked signal transduction enzyme. This work and recent studies showing increased 1-phosphatidylinositol 4-kinase (EC 2.7.1.67) and 1-phosphatidylinositol 4-phosphate-5-kinase (EC 2. 7. 1. 68) provide evidence of a gain in function for a markedly elevated capacity of signal transduction sequence in transplantable rat hepatomas of different growth rates. Inhibition of the activities of kinases and PLC may provide sensitive targets for selective cancer therapy by down-regulating the up-regulated signal transduction cascade.

Animals↗