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991.
992.
Bergthorsson JT Johannesdottir G Arason A Benediktsdottir KR Agnarsson BA Bailey-Wilson JE Gillanders E Smith J Trent J Barkardottir RB 《Human genetics》2000,107(4):372-375
Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers. 相似文献
993.
Anti-CD20 monoclonal antibodies have been successfully employed in the clinical treatment of non-Hodgkin's lymphomas in both
unmodified and radiolabeled forms. Previous publications have demonstrated that the antitumor effects of unmodified anti-CD20
mAb are mediated by several mechanisms including antibody-dependent cellular cytotoxicity, complement-mediated cell lysis,
and induction of apoptosis by CD20 cross-linking. In this report, we demonstrate induction of apoptosis by three anti-CD20
monoclonal antibodies [1F5, anti-B1, and C2B8 (Rituximab)]. The magnitude of apoptosis induction was greater with the chimeric
Rituximab antibody than with the murine 1F5 and anti-B1 antibodies. Apoptosis could be enhanced with any of the antibodies
by cross-linking with secondary antibodies (or Fc-receptor-bearing accessory cells). The signaling events involved in anti-CD20-induced
apoptosis were investigated, including activation of protein tyrosine kinases, increases in intracellular Ca2+ concentrations, caspase activation, and cleavage of caspase substrates. Our results indicate that anti-CD20-induced apoptosis
can be attenuated by PP1, an inhibitor of protein tyrosine kinases Lck and Fyn, chelators of extracellular or intracellular
Ca2+, and inhibitors of caspases, suggesting that anti-CD20-induced apoptosis may involve modulation of these signaling molecules.
We also demonstrated that varying the expression of Bcl-2 did not affect the magnitude of anti-B1-induced apoptosis, possibly
because of the sequestering effects of other Bcl-2 family members, such as Bad. These studies identify several of the signal-transduction
events involved in the apoptosis of malignant B cells that transpire following ligation of CD20 by anti-CD20 antibodies in
the presence of Fc-receptor-expressing cells or secondary goat anti-(mouse Ig) antibodies and which may contribute to the
tumor regressions observed in mouse models and clinical trials.
Received: 27 May 1999 / Accepted: 1 October 1999 相似文献
994.
Hörig H Lee DS Conkright W Divito J Hasson H LaMare M Rivera A Park D Tine J Guito K Tsang KW Schlom J Kaufman HL 《Cancer immunology, immunotherapy : CII》2000,49(9):504-514
The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope
and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC)
constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study
in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses.
Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an
ALVAC-CEA-B7.1 vaccine (4.5 × 106, 4.5 × 107, and 4.5 × 108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored
for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA- B7.1 at doses up to 4.5 × 108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable
disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-γ enzyme-linked immunoassay
spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses.
This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted
in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific
T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1
to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with
tolerable toxicity.
Received: 6 May 2000 / Accepted: 13 July 2000 相似文献
995.
Summary Skeletal muscle hypertrophy is promoted in vivo by administration of β-adrenergic receptor (βAR) agonists. Chicken skeletal
muscle cells were treated with 1 μM isoproterenol, a strong βAR agonist, between days 7 and 10 in culture. βAR population increased by approximately 40% during
this treatment; however, the ability of the cells to synthesize cyclic adenosine monophosphate (cAMP) was diminished by twofold.
Neither the basal concentration of cAMP nor the quantity of myosin heavy chain (MHC) was affected by the 3-d exposure to isoproterenol.
To understand further the relationship between intracellular cAMP levels, βAR population, and muscle protein accumulation,
intracellular cAMP levels were artificially elevated by treatment with 0–10 μM forskolin for 3 d. The basal concentration of cAMP in forskolintreated cells increased up to sevenfold in a dose-dependent
manner. Increasing concentrations of forskolin also led to an increase in βAR population, with a maximum increase of approximately
40–60% at 10 μM forskolin. A maximum increase of 40–50% in the quantity of MHC was observed at 0.2 μM forskolin, but higher concentrations of forskolin reduced the quanity of MHC back to control levels. At 0.2 μM forskolin, intracellular levels of cAMP were higher by approximately 35%, and the βAR population was higher by approximately
30%. Neither the number of muscle nuclei fused into myotubes nor the percentage of nuclei in myotubes was affected by forskolin
at any of the concentrations studied. 相似文献
996.
YC-1, a benzyl indazole derivative, stimulates vascular cGMP and inhibits neointima formation 总被引:2,自引:0,他引:2
Tulis DA Durante W Peyton KJ Chapman GB Evans AJ Schafer AI 《Biochemical and biophysical research communications》2000,279(2):646-652
The pathobiologic process of arterial stenosis following balloon angioplasty continues to be an enigmatic problem in clinical settings. This research project investigates the ability of YC-1, a benzyl indazole derivative that sensitizes sGC/cGMP, to stimulate endogenous cGMP and attenuate balloon injury-induced neointima (NI) formation in the rat carotid artery. Northern and Western blot analyses revealed enhanced acute expression of iNOS and inducible heme oxygenase (HO-1) mRNA and protein in the injured artery. The contralateral uninjured artery also demonstrated acute HO-1 mRNA and protein induction without detectable iNOS expression. Perivascular application of YC-1 immediately following injury significantly stimulated acute vessel wall cGMP compared to untreated controls. YC-1 treated sections demonstrated significant reduction in NI area (-74%), NI area/medial wall area (-72%), and NI thickness (-76%) 2 weeks post-injury. These results directly implicate YC-1 as a potent new therapeutic agent capable of reducing post-angioplasty stenosis through endogenous CO- and/or NO-mediated, cGMP-dependent processes. 相似文献
997.
Previously we have reported that induction of apoptosis in Jurkat cells results in an inhibition of overall protein synthesis with the selective and rapid cleavage of eukaryotic initiation factor (eIF) 4GI. For the cleavage of eIF4GI, caspase-3 activity is both necessary and sufficient in vivo, in a process which does not require signaling through the p38 MAP kinase pathway. We now show that activation of the Fas/CD95 receptor promotes an early, transient increase in the level of eIF2alpha phosphorylation, which is temporally correlated with the onset of the inhibition of translation. This is associated with a modest increase in the autophosphorylation of the protein kinase activated by double-stranded RNA. Using a Jurkat cell line that is deficient in caspase-8 and resistant to anti-Fas-induced apoptosis, we show that whilst the cleavage of eIF4GI is caspase-8-dependent, the enhancement of eIF2alpha phosphorylation does not require caspase-8 activity and occurs prior to the cleavage of eIF4GI. In addition, activation of the Fas/CD95 receptor results in the caspase-8-dependent dephosphorylation and degradation of p70(S6K), the enhanced binding of 4E-BP1 to eIF4E, and, at later times, the cleavage of eIF2alpha. These data suggest that apoptosis impinges upon the activity of several polypeptides which are central to the regulation of protein synthesis and that multiple signaling pathways are involved in vivo. 相似文献
998.
An arabinogalactan-protein (AGP) was purified from differentiating xylem of loblolly pine (Pinus taeda L.) and the N-terminal sequence used to identify a cDNA clone. The protein, PtaAGP3, was not coded for by any previously identified AGP-like genes. Moreover, PtaAGP3 was abundantly and preferentially expressed in differentiating xylem. The encoded protein contains four domains, a signal
peptide, a cleaved hydrophilic region, a region rich in serine, alanine, and proline/hydroxyproline, and a hydrophobic C-terminus.
It is postulated to contain a GPI (glycosylphosphatidylinositol) anchor site. If the protein is cleaved at the putative GPI
anchor site, as has been observed in other classical AGPs, all but the Ser-Ala-Pro/Hyp-rich domain may be missing from the
mature protein. Xylem-specific AGPs are hypothesized to be involved in xylem development.
Received: 29 July 1999 / Accepted: 19 August 1999 相似文献
999.
1000.
Increase in Endogenous and Exogenous Cyclic AMP Levels Inhibits Sclerotial Development in Sclerotinia sclerotiorum 总被引:3,自引:0,他引:3
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Growth and development of a wild-type Sclerotinia sclerotiorum isolate were examined in the presence of various pharmacological compounds to investigate signal transduction pathways that influence the development of sclerotia. Compounds known to increase endogenous cyclic AMP (cAMP) levels in other organisms by inhibiting phosphodiesterase activity (caffeine and 3-isobutyl-1-methyl xanthine) or by activating adenylate cyclase (NaF) reduced or eliminated sclerotial development in S. sclerotiorum. Growth in the presence of 5 mM caffeine correlated with increased levels of endogenous cAMP in mycelia. In addition, incorporation of cAMP into the growth medium decreased or eliminated the production of sclerotia in a concentration-dependent manner and increased the accumulation of oxalic acid. Inhibition of sclerotial development was cAMP specific, as exogenous cyclic GMP, AMP, and ATP did not influence sclerotial development. Transfer of developing cultures to cAMP-containing medium at successive time points demonstrated that cAMP inhibits development prior to or during sclerotial initiation. Together, these results indicate that cAMP plays a role in the early transition between mycelial growth and sclerotial development. 相似文献