Bone modeling alteration in premature infants.
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Bone Density↗
Biomedical subjects
G Weber
Publications and source records attributed to G Weber.
Antimetabolites reduce the activities of enzymes with short half-lives in addition to inhibiting their specific targets.
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Animals↗
The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45.8-kilobase open reading frame.
Cyclosporin A, a potent and clinically-important immunosuppressive drug (SandimmunR), is synthesized from its precursor amino acids by cyclosporin synthetase, a single multi-functional enzyme. In this study we report the cloning of the corresponding coding region of this synthetase. It contains an open reading frame of 45.8 kb which encodes a peptide with a calculated M(r) of 1,689,243. The predicted gene product contains 11 amino-acid-activating domains that are very similar to one another and to the domains of other peptide synthetases. Seven of these domains harbour N-methyltransferase functions. This is the largest genomic ORF described so far.
Amino Acid Sequence↗
Coordinated increase in activities of the signal transduction enzymes PI kinase and PIP kinase in human cancer cells.
The steady-state activities of the first two enzymes of the phosphatidylinositol (PI) phosphorylation pathway, PI 4-kinase, EC 2.7.1.67 (PI kinase) and PI 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) as compared to human normal ovary are elevated in human ovarian carcinomas (4.1- and 2.7-fold) and in human OVCAR-5 cells in tissue culture (31.2- and 8.9-fold). Compared to normal human breast parenchymal cells. PI kinase and PIP kinase activities were increased in breast carcinoma MDA-MB-435 cells grown in nude mice as solid tumors (7.3- and 2.3-fold, respectively) and in MDA-MB-435 cells grown in tissue culture (95.8- and 15.5-fold, respectively). When the human carcinoma cells were plated and expressed their neoplastic proliferative program in the log phase, in the MDA-MB-435 breast carcinoma cells the PI and PIP kinase activities coordinately increased 11-fold; in ovarian carcinoma OVCAR-5 cells 5.8- and 4.5-fold, respectively. These studies provide the first evidence in human cancer cells of an increased capacity for the operation of signal transduction. This is indicated by the markedly elevated activities of PI and PIP kinases in the phosphatidylinositol phosphorylation sequence which leads to production of second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
1-Phosphatidylinositol 4-Kinase↗
Synergistic action of taxol with tiazofurin and methotrexate in human breast cancer cells: schedule-dependence.
Taxol (paclitaxel, (NSC 125973)) is an active agent in the treatment of metastatic carcinoma of the breast; however, positive responses were observed in only about 60% of cases. Therefore, drug combinations which might improve the effectiveness are required. Since tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), methotrexate (MTX) and taxol exert their anticancer action in different phases of the cell cycle and have different biochemical targets, we tested the hypothesis that tiazofurin and methotrexate might by synergistic with taxol. MDA-MB-435 human breast cancer cells were grown in monolayer in flasks. In the growth inhibition assay for tiazofurin, methotrexate and taxol the IC50s were 12.5, 0.5 and 0.016 microM, respectively, and in the clonogenic assay 4.5, 0.065 and 0.004 microM. When taxol was given 6 hr before tiazofurin, antagonism was observed and summation was seen when drugs were given simultaneously. Synergism was obtained in both growth inhibitory and clonogenic assays when tiazofurin was followed 12 hr later by taxol. Methotrexate and taxol had an antagonistic effect when they were added simultaneously or when taxol was given 6 hr before methotrexate; summation was observed when taxol was followed 12 hr later by methotrexate. Synergistic action was obtained in the clonogenic assay when methotrexate was followed 12 hr later by taxol. The protocols yielding synergism should be of value in the design of taxol-based clinical trials for breast cancer.
Cell Division↗
Targeted and non-targeted actions of anti-cancer drugs.
(1) The currently used clinical anti-metabolites are targeted against-key enzymes of de novo purine and pyrimidine biosynthesis. However, the activities of salvage enzymes in each of the biosynthetic segments are markedly higher than those of the rate-limiting enzymes of de novo biosynthesis. Enzyme-pattern-targeted chemotherapy has been suggested to overcome the circumvention activity of salvage. Combination of inhibition of de novo and salvage pathways does provide a synergistic impact. Examples that enzyme-pattern-targeted drug treatment yields synergism include the following: tiazofurin (against IMP DH) and allopurinol (by raising serum hypoxanthine levels it inhibits GPRT); methotrexate or 5-FU lead to inhibition of the dTMP synthase reaction and AZT (a competitive inhibitor of thymidine kinase) or dipyridamole (a nucleoside transport inhibitor); acivicin, an inhibitor and inactivator of glutamine-utilizing enzymes in the de novo pathways of purine and pyrimidine biosynthesis, and dipyridamole. (2) Administration of MTX, 5-FU, tiazofurin or acivicin causes inhibition and/or inactivation of target enzymes. That these drugs are effective in spite of the presence of highly active salvage enzymes is now accounted for, at least in part, by new observations showing that these drugs markedly reduce (but do not eliminate) the activities (amounts) of CdR and TdR kinases, dTMP synthase and GPRT. This action is attributed to the rapid decay rate of these enzymes. (3) Studies on the bone marrow enzymic programs indicate that there is a window of opportunity for strengthening therapy and for the protection of bone marrow by administering salvage metabolites when the salvage enzymes are still present in high enough activities, i.e., 2-6 hr after administration of the blockers of de novo enzyme activities. (4) These results are a strong argument for discovering and utilizing inhibitors of purine and pyrimidine salvage enzymes to achieve more successful enzyme-pattern-targeted chemotherapy and to avoid development of resistant clones of cancer cells. (5) These approaches provide greater explanatory coherence than the previous accounts because recognition of (a) the importance of salvage and (b) rapid decay of key and salvage enzymes reveals a paradigm shift. The problem-solving process in chemotherapy should now be not only data-driven but also explanation-driven.
Animals↗
Molecular characterization of a recurring complex chromosomal translocation in two human extragonadal germ cell tumors.
The molecular characterization of a recurring complex chromosomal translocation involving 6p21, 6p22, 6q23, and 11q13 in two independent but similar extragonadal human germ cell tumors was initiated using fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) techniques. By using a series of specific probes from the 11q13 region, the translocation breakpoint in this chromosomal band could be located within a long-range restriction enzyme map in between the markers D11S457 and D11S546. In addition, aberrantly hybridizing restriction fragments were revealed by PFGE in both tumors, indicating that the breakpoint region must be located within a distance of at maximum 200 kilobase pairs (kbp) from the nearest DNA marker (D11S546).
Blotting, Southern↗
[Rupture of a splenic artery aneurysm intra partum].
The rupture of a splenic artery aneurysm in pregnancy and during labour is a rare event with a high maternal and fetal mortality rate. This report is, in view of previously reported cases, on the thirteenth case of a ruptured splenic artery aneurysm reporting survival of both mother and fetus. The etiology, clinical signs, diagnosis and therapy are discussed with reference to consideration of the literature. The necessity of an early differential diagnostic consideration of this rare occurrence is discussed, because this is the only way to achieve survival of mother and fetus.
Adult↗
[Minimally invasive therapy of peritoneal leiomyomatosis. A case report of diagnostic and therapeutic problems].
Leiomyomatosis peritonealis disseminata (LPD) is a rare benign disease characterised by the presence of multiple intraabdominal nodules, consisting of benign smooth muscle. LPD has only been found in women, predominantly in their late reproductive age. There is a very high association with excess exogenous and endogenous female gonadal steroids, specifically oestrogen and progesterone. Since it is grossly indistinguishable from diffuse carcinomatosis of the peritoneum, several unnecessary radical procedures have resulted. We describe the 44th documented case and the first case of minimal invasive surgery in a 42-year-old women with peritoneal leiomyoma on the right pelvic wall and uterine subserous and submucous leiomyoma.
Biopsy↗
The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumours.
Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction.
Blotting, Northern↗
Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s.
Since germline mutations in the RET proto-oncogene (RET) predisposing to tumor development in Familial Medullary Thyroid Carcinoma (FMTC), Multiple endocrine neoplasia type 2A (MEN 2A), and Multiple endocrine neoplasia type 2B (MEN 2B) were reported, it has become possible to identify gene carriers with a very high degree of accuracy. Mutations in FMTC and MEN 2A exclusively affect cysteine residues in exon 10 and 11 of RET, whereas in MEN 2B codon 918 in exon 16 is involved. This latter mutation has also been described in a subset of apparently sporadic medullary thyroid carcinomas (MTC). Mutations in MEN 2B often occur as de novo germline mutations, whereas de novo mutations have not yet been described in FMTC or MEN 2A. We analyzed ten MTC:s and ten pheochromocytomas, all clinically judged to be sporadically occurring, by direct DNA sequencing of exons 10, 11, and 16 of RET. This analysis revealed a de novo germline mutation of codon 634 in exon 11 in a patient with MTC. In addition, somatic mutations of codon 918 in exon 16 in six of the remaining MTC:s were found. Interestingly, the presence of this somatic mutation was associated with a significantly less favorable clinical outcome.
Adult↗
In vitro and in vivo effect of glucocorticoids on IgE and IgG subclass secretion.
Hydrocortisone (HC) as well as its synthetic derivatives have been shown to strongly enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. To investigate possible effects on IgG subclasses, peripheral blood mononuclear cells (PBMC) were incubated with different glucocorticosteroids in the absence or presence of IL-4. The glucocorticoids alone led to a strongly enhanced secretion of IgG1, IgG2 and IgG3, but not IgG4. The addition of IL-4 induced marked increases in IgG1 and IgG4, no changes in IgG3, but a consistent decrease in IgG2 synthesis. In order to find out whether these profound in vitro effects of corticosteroids are also reflected by changes in antibody serum levels during steroid treatment, 10 healthy volunteers took 25 mg prednisone for 7 consecutive days. We could not observe any significant changes of IgE or IgG subclass serum levels during or after this period. However, cell cultures performed after the glucocorticoid treatment revealed a marked decrease in the ability to produce IgG4 and a significantly lower potential to produce IgE in response to IL-4 alone or IL-4 and HC. We conclude that, although strongly implicated by the in vitro results, glucocorticosteroid treatment does not result in an increased allergy risk.
Adult↗
Synthetic glucocorticoids potentiate IgE synthesis. Influence of steroid and nonsteroid hormones on human in vitro IgE secretion.
Recently, hydrocortisone (HC) has been shown significantly to enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. For investigation of possible effects of synthetic corticosteroids but also of effects of other important human hormones, peripheral blood mononuclear cells (PBMC) were incubated with IL-4 and various concentrations of the hormones. IgE secreted in the supernatant was determined after a 14-d culture period. Like HC, all synthetic corticosteroids potentiated IgE secretion. A minor effect was noted for the mineralocorticoid aldosterone. No modulating effect on IL-4-induced IgE formation was observed for adrenocorticotropic hormone (ACTH), somatotropin (STH), thyroid-stimulating hormone (TSH), triiodothyronine, thyroxine, epinephrine, noradrenaline, insulin, and glucagon.
Aldosterone↗
Papillary thyroid carcinoma after total body irradiation.
Two children developed papillary thyroid carcinoma after allogeneic bone marrow transplantation (BMT) probably due to radiotherapy during remission and pretransplantation conditioning. Establishing a relationship between the cellular thyroid stimulating hormone (TSH) effect and development of carcinoma in cases with high serum TSH concentrations is difficult. After BMT, patients should be regularly followed up with thyroid ultrasound and, when nodularity is found, fine needle aspiration and/or open biopsy are recommended.
Bone Marrow Transplantation↗
Prevalence of thyroid autoantibodies and thyroid autoimmune disease in diabetic children and adolescents.
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Adolescent↗
[Thyroid autoimmunity and congenital hypothyroidism].
The involvement of thyroid autoimmunity in the pathogenesis of sporadic congenital hypothyroidism is still incompletely understood. While antithyroglobulin and anti-thyroperoxidase antibodies are harmless, the transplacental passage of TSH receptor antibodies with blocking activity from a mother with autoimmune thyroiditis to the fetus is responsible of transient neonatal hypothyroidism in the baby. This is however a rare condition. Thyroid growth blocking antibodies have been described in healthy mothers of children with permanent congenital hypothyroidism due to thyroid dysgenesis, but this observation was not confirmed in other studies including our own. Antibodies producing cell mediated cytotoxicity (ADCC), either transferred from the mother or due to an autoimmune thyroiditis developing in utero, might be involved in the pathogenesis of permanent congenital hypothyroidism. However, this hypothesis requires confirmation in more extensive studies.
Autoimmune Diseases↗
Synergism of taxol and gallium nitrate in human breast carcinoma cells: schedule dependency.
Since Taxol (paclitaxel, NSC-125973) arrests cells in mitosis and gallium nitrate (NSC-15200) inhibits cell replication in the S phase, and the two drugs have different biochemical targets, we tested the hypothesis that the combination of these drugs may be synergistic in human breast carcinoma cells. MDA-MB-435 human breast carcinoma cells were grown in monolayer in culture. Taxol and gallium inhibited cell proliferation with IC50 = 13 nM and 180 microM, respectively. In clonogenic assays, Taxol and gallium yielded IC50 = 2 nM and 25 microM, respectively. Synergism was observed in both cell proliferation and colony formation assays depending on the treatment schedule. Gallium (300 microM) 24 h prior to Taxol (10 nM) synergistically decreased cell proliferation to 6.5% of untreated cells, which was 50% of the predicted value. In clonogenic assay, gallium (40 microM) given 16 h prior to Taxol (2 nM) yielded 8.7% colony formation of the untreated cells, which was 44% of the predicted value. Combination chemotherapy with Taxol and gallium with this protocol schedule may be useful in the treatment of human breast carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
The laser microbeam trap as an optical tool for living cells.
Pulsed ultraviolet lasers coupled into a microscope can be used for micromanipulation of cells and subcellular structures. In addition, continuous infrared lasers can be used as ultrafine optical tweezers (or synonymously: optical trap). The pulsed UV lasers (for example excimer lasers or nitrogen lasers) can be used as optical scalpels for the preparation of protoplasts from plant root hairs. The precise microdissection of chromosomes with the laser microbeam provides access to chromosome segments where a specific gene is supported to be localized. From such segments, specific DNA libraries can be prepared for the search after such genes or markers in their environment. With the optical trap contact between effector cells of the immune system and their target cells can be established in a very simple and gentle way. The kinetics of the attack of a natural killer on an erythroleukemia cell can be studied from the first seconds after contact. Isolated plant cells as well as cells in a plant embryo tissue can be perforated and DNA or fluorescent molecules can be injected. From the temperature dependence of laser induced membrane lesions one can obtain predictions on laser induced cell fusion, which can be performed at slightly modified irradiation conditions under total microscopic control. Since focusing into the depth of a cell with an accuracy of better than a micrometer is possible, one can work on subcellular structures in the interior of a cell without opening it. For example, in rapeseed protoplasts subcellular structures such as mitochondria or chloroplasts can be perforated or moved out of their original position. Interestingly, such structures find their way back into the original position after the laser is switched off. From their speed one can obtain estimates on intracellular viscoelasticity.
Animals↗