Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autoimmune hemolytic anemia of NZB mice is pathogenetically mediated by a genetically prescribed anti-erythrocyte autoantibody response directed to the X erythrocyte autoantigen. The cellular locus of the immunoregulatory defect underlying the anti-X response was explored by adoptively transferring bone marrow cells (BMC) from NZB mice to lethally irradiated histocompatible recipients. Before adoptive transfer, BMC from donor mice were assayed for antigen-binding lymphocytes with receptors for the X autoantigen (X-ABL) by immunocytoadherence assays and for anti-X autoantibody-secreting cells (X-PFC) by plaque-forming cell assays. Twelve weeks after adoptive transfer, splenic lymphocytes from recipient mice were assayed for X-PFC and humoral anti-X autoantibody by Coombs' tests. Transfer of 15 to 30 x 10(6) BMC containing 6 to 12 x 10(3) X-ABL but no X-PFC from 6- to 8-week-old NZB mice to lethally irradiated BALB/c, B10.D2, C57BL/Ks, and DBA/2 mice produced X-PFC in 70% of the recipients. Development of X-PFC was not simply dependent upon available X-ABL since transfer of 15-30 x 10(6) BMC, containing comparable numbers of X-ABL, from BALB/c, B10.D2, C57BL/Ks, or DBA/2 mice to NZB or syngeneic recipients did not produce X-PFC. Transfer of BMC from NZB mice to BALB/c, B10.D2, and DBA/2 mice with weekly administrations of AKR anti-theta antiserum had no effect on the development of X-PFC; Tlymphocyte ablation was evidenced by the absence of theta+ spleen cells. These results suggest that the pathogenetic anti-X response is not genetically prescribed at the level of macrophages, humoral factors, or T cells, but rather appears to be a phenotypic expression of a primary B lymphocyte defect permitting or promoting differentiation of NZB X-ABL.
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PMID:Evidence for a B lymphocyte defect underlying the anti-X anti-erythrocyte autoantibody response of NZB mice. 32 60

The efficacy of glucan in combination with local radiation therapy was measured using three solid murine tumors of differing abilities to induce a host defense. Using the KHT fibrosarcoma which induces no measurable host defense, glucan did not improve tumor-free survival over radiation alone; the combination produced a marginal improvement in tumor-free survival in animals bearing the highly immunogenic EMT-6 tumor. The most marked improvement in tumor-free survival was found with the mildly immunogenic 6C3HED lymphosarcoma. The efficacy of glucan in combination with BCNU chemotherapy was measured using the disseminated AKR transplantable leukemia; the combination yielded a high level of cures compared to no survival for either agent alone. Using the AKR transplantable leukemia in an F1 model, the effect of amphotericin B (AmB) alone or in combination with BCNU was tested. AmB or BCNU alone had little or no curative effect when tested in (AKR X DBA)F1 mice, but 56% of mice were cured when combined therapy was employed. When tested in (AKR X C57BL)F1 or (AKR X A)F1 mice, a small fraction was cured with AmB alone while about 90% were cured with either BCNU alone or the combination.
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PMID:Preliminary observations on the effect of glucan in combination with radiation and chemotherapy in four murine tumors. 72 4

Activation of 202 and (2'-5')(A)n synthetase genes after injection of interferon (IFN)-inducing, double-stranded, poly rI:rC was compared in various mouse strains. The 202 mRNA level increased 4.5- to 10-fold in DBA/2, BALB/c, and C3H/HeJ mice, whereas in C57BL/6 mice it rose only to about that in untreated DBA/2, BALB/c, and C3H/HeJ mice. To determine whether this low level was due to a reduced transcription rate, a nuclear "run-on" assay was performed with NIH 3T3 cells or BLK cells derived from C57BL/6 mice. IFN-alpha increased the 202 mRNA transcription severalfold in NIH 3T3 cells only, and that of a (2'-5')(A)n synthetase gene in both cell lines. The possibility that an alteration in transacting factors could be responsible for this difference was examined. For this purpose the 5' terminal flanking region (called the b segment, about 0.8 kb) of the 202 gene was linked to a heterologous reporter gene--chloramphenicolacetyl-transferase (CAT) and transfected into normal or transformed NIH 3T3 cells and into various C57BL/6-derived cell lines. IFN-alpha induced strong CAT activity in transfected normal or transformed NIH 3T3 cells, but a much lower activity in those from C57BL/6 mice. The b segment contains an IFN-responsive element (ISRE) (35 bp) homologous to that present in several other IFN-inducible genes. Three tandem copies of the 202 ISRE were linked to an enhancerless SV40 early promoter driving an influenza virus hemagglutinin (HA) cDNA segment. No increase in HA mRNA expression was detected in the transfected BLK cell line derived from C57BL/6 mice following IFN treatment, whereas in the NIH 3T3 cell line, the IFN treatment resulted in a 2.5-fold increase. These and other results suggest that C57BL/6 mice and cell lines derived from them might carry defective transacting factors impairing the ability of IFN-alpha to activate the 202 gene without impairing its ability to activate a (2'-5')(A)n synthetase gene.
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PMID:Impaired transcription of the poly rI:rC- and interferon-activatable 202 gene in mice and cell lines from the C57BL/6 strain. 153 Dec 77

The vast majority of pediatric RBC hypoplastic anemias are accounted for by red blood cell aplasia associated with chronic hemolysis, Diamond-Blackfan anemia, and transient erythroblastopenia of childhood. However, other causes of hypoplastic anemia occur in children, and some of these are similar to what is seen in adult RBC aplasia. For example, it has been reported that a 5-year-old girl with an aregenerative anemia had a thymoma and later developed pancytopenia. RBC aplasia also has been seen in children receiving anticonvulsant drug therapy, children recovering from severe protein malnutrition, children with hepatitis, and in children with leukemia during maintenance therapy. In addition, it is not uncommon for pediatric hematologists to observe children with RBC aplasia where there is no obvious diagnosis, although many are considered to be variants of Diamond-Blackfan anemia. Several important questions about RBC hypoplastic anemias in children need to be resolved; it is hoped that this will be accomplished in the next decade. Do RBC hypoplastic crises associated with hemolytic anemia occur with viral infections other than HPV? What is the cellular pathophysiology in DBA and TEC? Does the apparent heterogeneity of these disorders reflect limitations of laboratory techniques or are we looking at several different diseases? Is acute leukemia a real complication of Diamond-Blackfan anemia? Is TEC a completely benign entity or will we see other long-term problems in these children? Is the incidence of TEC actually increasing? Will TEC-like problems be seen in other aged children? As a case in point, we recently observed a 16-year-old girl who presented with pure RBC aplasia that required RBC transfusion support for 5 months; she also received prednisone therapy. After 7 months, however, this young lady had a spontaneous remission, and now 4 years later she is normal and free of any hematologic abnormalities. This was a most unusual event in our experience and, in view of the apparent increasing incidence of TEC in young children, we queried whether we were observing an adolescent equivalent of this disorder. During the next several years the answer to this and the other questions posed herein should be available.
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PMID:Diagnosis and management of red cell aplasia in children. 312 94

With the aid of a specific rabbit antibody preparation to purified monoclonal murine IgE, two plaque-forming cell (PFC) assays have been developed for the detection and enumeration of mouse IgE-secreting cells. The first assay, utilizing protein A-coated sheep red cells (protein A-SRC), detected antibody-secreting cells on the basis of the class of the secreted Ig irrespective of antigen specificity. With this assay, 30% of the class of the viable cells of two distinct IgE-secreting hybridoma cell lines were scored as PFC. Under these conditions, plaques were not obtained with IgG1 or IgG2a-secreting hybridoma cells. The second PFC assay, which utilized SRC coated with ovalbumin (OA-SRC), enumerated cells secreting anti-OA IgE antibodies. Similar kinetic patterns were observed for the cellular (IgE PFC/spleen) and humoral (IgE serum levels) responses of (C57BL/6 x DBA/2)F1 mice following immunization with 10 micrograms of OA adsorbed to 1 mg of A1(OH)3. Thus, it is concluded that the reverse plaque assay detecting all IgE-secreting cells, as well as the antigen-specific IgE PFC assay, can be used for the quantitation of IgE responses at the cellular level.
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PMID:The enumeration of mouse IgE-secreting cells using plaque-forming cell assays. 616 50

This study was carried out on five types of experimental tumors maintained by serial subcutaneous transplants in isogeneic mouse hosts. These tumors involved three mammary carcinomas (dbrB, DBAH, MT2), a spindle-cell sarcoma (TEC) and a lymphoblastic type of lymphoma (DBA/3). Growth curves of these tumors are presented. Computed percent labeled mitoses curves for the five types of tumors, the derived cell cycle parameters (TG1, TG2, TS, Tc), and the volume-doubling time (VDT) in days are also presented. The histologic and morphologic appearance of each type of tumor is seen by light microscopy, and the ultrastructural morphology of each type of tumor is seen in electron micrographs. The variation in the kinetic parameters and the autoradiographic exposure time needed to obtain comparable labeling intensity for the five types of tumors is interpreted on the basis of the ultrastructural integrity of the cytoplasmic components of the individual tumor type. The response of these five tumor types to radiotherapy was investigated. The therapy consisted of administering combined treatments of three agents: X-rays, the radiosensitizing drug, misonidazole, and microwave hyperthermia. This treatment resulted in an enhancement factor of 3.9, compared with that of X-rays alone. Total tumor regressions were obtained with microwave hyperthermia alone. The required time of exposure to hyperthermic treatments differed, depending on the response of each type of tumor.
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PMID:Cell kinetics, cell structure, and radiotherapy. 696 41

Trisomy of chromosome 11 (Ts11) is the second most frequent nonrandom chromosomal change in murine plasmacytomas (PCTs). The frequency of Ts11 is significantly higher in PCTs induced in pristane-conditioned mice infected by Abelson-murine leukemia virus (52%) compared to those induced by pristane alone (8.1%). Although the significance of Ts11 in mouse plasmacytomagenesis is not clearly understood it is hypothesized that a gene or genes located on chromosome (Chr) 11 may specifically promote the development of PCTs in which both oncogenes, c-myc and v-abl, are abundantly expressed. To test this assumption we induced PCTs by three highly effective plasmacytomagenic retroviruses: ABL-MYC, J3V1, and RIM. Nearly 90% of PCTs that arose in BALB/c, (BALB/c x DBA/2N)F1, BALB/c-nu/nu, and 5-month-old SCID mice infected with ABL-MYC virus were trisomic for Chr 11. In contrast, < 10% of PCTs induced by J3V1 or RIM retroviral constructs encompassing either v-myc and v-raf or c-myc and v-Ha-ras oncogenes, respectively, contained Ts11. We have also investigated whether the entire Chr 11 or any particular subregion is preferentially duplicated in the process of ABL-MYC plasmacytomagenesis. By inducing PCTs in F1 heterozygous mice that are carriers of reciprocal translocations involving Chr 11 we found that the duplicated chromosomal region is located distal to the T4Dn breakpoint (11B5 band) on the telomeric segment of Chr 11. The regular duplication of this chromosomal segment strongly suggests the presence of a gene or genes whose amplification is of critical importance for v-abl associated murine plasmacytomagenesis.
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PMID:Nonrandom chromosomal change (trisomy 11) in murine plasmacytomas induced by an ABL-MYC retrovirus. 786 5

The immunodominant T cell determinant of type II collagen (CII) recognized by DBA/1 mice (I-Aq) is CII 260-267. The aims of this study were to determine the role of the amino acid residues within CII 245-270 in T cell signal transduction. To that end, we utilized I-Aq-restricted, CII-specific T cell hybridomas and examined tyrosine phosphorylation of TCR-zeta following stimulation with either wild-type CII 245-270 or a panel of analogue peptides. A variety of patterns occurred, ranging from increased phosphorylation of TCR-zeta to either partial or a complete abrogation of phosphorylation. Critical substitutions also completely abrogated the phosphorylation of ZAP70, a downstream molecule in TCR-zeta signaling. Evaluation of the supernatants of the T cell hybridomas for cytokine production in response to the peptides revealed a close correlation between the induction of phosphorylation of TCR-zeta and the amount of cytokine induced. Selected analogue peptides were tested as tolerogens in neonatal mice. Analogues that did not induce the phosphorylation of zeta chain, such as B3 (CII 251-270s263F-->N), were completely unable to induce tolerance, while analogues that caused a partial phosphorylation, such as B6 (CII 251-270s267Q-->T) and A3 (CII 245-270s269P-->A), induced partial tolerance judged by intermediate degrees of suppression of arthritis. We conclude that discrete alterations in specific amino acid residues of antigenic peptides had profound effects on T cell signaling and that the signaling correlated with T cell cytokine secretion and T cell function in the induction of tolerance and suppression of arthritis.
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PMID:Characterization of signal transduction through the TCR-zeta chain following T cell stimulation with analogue peptides of type II collagen 260-267. 953 Dec 68

The TEC-2 epitope is a carbohydrate located on the plasma membrane (oolemma) of the oocyte and appears to be involved in bovine sperm-oolemma fusion. The carbohydrates N-acetylgalactosamine (GalNAc) and galactose are part of the TEC-2 epitope and this study investigated the involvement of these carbohydrates during bovine fertilization. Gametes were exposed to the carbohydrates GalNAc, galactose, and fructose, and the lectins DBA and Con A to determine whether there was an effect on fertilization. The DBA lectin recognizes the carbohydrate GalNAc, whereas Con A recognizes the carbohydrates glucose and mannose. Oocytes pretreated with the DBA lectin prior to fertilization showed a reduction in cleavage corresponding to an increase in lectin concentrations. There was a significant increase in sperm-oolemma binding although fusion was inhibited. Oocytes exposed to GalNAc prior to sperm insemination had no effect on fertilization, however, sperm pretreatment with the carbohydrate caused inhibition of fertilization, with a reduction in cleavage rates as the GalNAc concentration increased. There was also a significant decrease in sperm-oolemma fusion and a significant increase in sperm-oolemma binding. When gametes were exposed to GalNAc at the time of fertilization a similar response to that seen with sperm pretreatment was observed. The carbohydrates galactose and fructose and the lectin Con A did not affect fertilization. In conclusion, the carbohydrate GalNAc, which is associated with the TEC-2 epitope, has a specific role during bovine sperm-oolemma fusion. This study also suggests that there is a carbohydrate-binding molecule on the sperm that binds GalNAc.
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PMID:Inhibition of bovine sperm-oocyte fusion by the carbohydrate GalNAc. 1047 78

This study investigated the possible role of nitric oxide (NO) in the development of neocortical spike-and-wave spindling episodes (S&W) of DBA/2J mice. The administration of distilled water did not modify either the number or duration of S&W in DBA/2J mice during the whole recording period (240 min). L-N(G)-nitro arginine methyl ester (L-NAME) (3-300 microg/mouse, i.c.v.) dose-dependently reduced the S&W of DBA/2J mice. This effect appeared 30 min after drug administration and lasted for the duration of the recording period (240 min). In addition, L-NAME treatment did not induce significant alterations of stereotyped behaviour such as licking, sniffing, chewing or tremors of the head and body and behavioural excitability, whereas the electroencephalogram desynchronized pattern was also significantly reduced. By contrast D-N(G)-nitro arginine methyl ester at the same doses did not affect S&W of mice. The inhibitory effect of L-NAME on S&W of mice was dose-dependently reversed by L-arginine (L-ARG, 3-300 microg/mouse, i.c.v.) but not by D-arginine. Finally, glyceryl trinitrate on its own (3-300 microg/mouse, i.c.v.) significantly increased the S&W of mice and it was also able to reverse the inhibition on S&W of mice operated by L-NAME. These results provide evidence that NO may play a significant role in the development of brain excitability.
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PMID:Nitric oxide is involved in the expression of neocortical spike-and-wave spindling episodes in DBA/2J mice. 1295 1


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