bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer
Authors: Attar Ricardo M. , Jure-Kunkel Maria , Balog Aaron , Cvijic Mary Ellen , Dell-John Janet , Rizzo Cheryl A. , Schweizer Liang , Spires Thomas E. , Platero J. Suso , Obermeier Mary , Shan Weifang , Salvati Mark E. , Foster William R. , Dinchuk Joseph , Chen Shen-Jue , Vite Gregory , Kramer Robert , Gottardis Marco M.
Published: August 2009

Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the ∼30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer. [Cancer Res 2009;69(16):6522–30]
Zerumbone Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors in Human Colon Cancer Cells: Evidence for an Essential Role of Reactive Oxygen Species
Authors: Yodkeeree Supachai , Sung Bokyung , Limtrakul Pornngarm , Aggarwal Bharat B.
Published: August 2009

Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this correlated with the up-regulation of TRAIL death receptor (DR) 4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell-type specific, as its expression was also up-regulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species. Inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase but not of Jun NH2-terminal kinase abolished the effect of zerumbone on DR induction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DR induction or for enhancement of TRAIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results show that zerumbone can potentiate TRAIL-induced apoptosis through the reactive oxygen species–mediated activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL. [Cancer Res 2009;69(16):6581–9]
Parental Divorce and Adolescent Drunkenness: Role of Socioeconomic Position, Psychological Well-Being and Social Support
Authors: Tomcikova Z. , Madarasova Geckova A. , Orosova O. , van Dijk J.P. , Reijneveld S.A.
Published: August 2009

Background: The aim of this cross-sectional study was to explore the association between parental divorce and adolescent drunkenness in the last 4 weeks and the contribution of socioeconomic position, family structure, social support from family and well-being to this association. Methods: We obtained data on 3,694 elementary school students from several cities in Slovakia (mean age 14.3, 49.0% males; response rate 93%). Respondents completed questionnaires on how often they had been drunk in the last 4 weeks, whether their parents were divorced, their socioeconomic position (education of parents, family affluence), the composition of the household (one or two parents/step-parents), social support from the family and their own well-being. Results: Parental divorce was found to have an effect on adolescent drunkenness in the last 4 weeks, as well as high socioeconomic position, low social support from the family and high depression/anxiety. The effect of divorce on drunkenness decreased only slightly after adding social support into the model. Conclusion: Our findings indicate that parental divorce has a persistent influence on risk behavior independent of the influence of socioeconomic position and well-being. Parental divorce may increase the likelihood of drunkenness more than other factors such as low parental support and poor socioeconomic position.
Parental Factors in Association with Adolescent Smoking Relapse
Authors: van Zundert Rinka M.P. , Engels Rutger C.M.E.
Published: August 2009

The present study examined the role of parents in smoking relapse among adolescents who embarked on a serious attempt to quit. Participants were 135 adolescents aged 15–20 years who smoked daily and participated in an ecological momentary assessment study. Daily questions about their quitting experiences were administered during 4 weeks. Longitudinal logistic regression analyses were applied to test whether parental smoking, expected parental support, parental norms about cessation, and smoking cessation-specific parenting at baseline predicted the first lapse into smoking as well as mild and heavy relapse during the 4-week period, and abstinence at follow-up 2 months later. Neither parental smoking nor hardly any of the parenting variables explained successful smoking cessation among adolescents, except for expected parental support. Although parents have been found to be influential in the development of adolescent smoking, our findings suggest that parents’ influence is limited when it concerns actual smoking cessation and relapse.
Leukocytes from Patients Allergic to Chromium and Nickel Examined by the Sealed Capillary Migration Technique
Authors: Nordlind K. , Sandberg G.
Published: August 2009

Leukocytes from patients allergic to chromium and nickel were studied by a sealed capillary migration test. The migration indices were determined at 2, 5 and 24 h. The chromium-allergic group could be differentiated from the control group at all investigated times, and especially at 2 and 5 h, by using a potassium dichromate concentration of 1.7 × 10––5M in the capillaries. The migration indices in the nickel-allergic group could not be used for discrimination from the controls. The highest chromate (1.1 × 10––4M) and nickel sulfate (3.8 × 10––4M) concentrations inhibited the migration of leukocytes from both patients and controls, indicating toxic effects.
Immunopotentiation of Cell-Mediated Hypersensitivity by Corynebacterium parvum (Propionibacterium acnes)
Authors: Maguire, Jr. Henry C. , Cipriano Deborah
Published: August 2009

We have investigated the activity of local Corynebacterium parvum(Propionibacterium acnes) as an immunopotentiator of allergic contact dermatitis (ACD) and photo-ACD in rodents. C. parvum given into the sensitization site, but not at a distance, increased the delayed-type hypersensitivity to the chemical allergen. An immunoadjuvant effect could be realized even when C. parvum was given several days after allergen; it was readily obtained in B cell-deficient mice. Cyclophosphamide pretreatment heightened the immunopotentiation seen with local C. parvum. It is unlikely that the specific immunopotentiation by C. parvum is mediated by enhanced macrophage processing of antigen, as proposed by others, since C. parvum immunostimulation occurs just as well 2 days after allergen as on the same day as allergen. We hypothesize that a major mechanism of C. parvum immunopotentiation is the inhibition by stimulated macrophages of the generation of specific T suppressor cells.
Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals
Authors: Stewart Alan J. , Katz Arieh A. , Millar Robert P. , Morgan Kevin
Published: August 2009

The decapeptide hypothalamic-pituitary gonadotrophin-releasing hormone (GnRH)-I and the type I GnRH receptor drive the reproductive hormonal cascade in mammals by stimulating synthesis and secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH). Mammals possess a second GnRH system composed of a related hormone, GnRH-II (differing from GnRH-I by three amino acid residues), and the type II GnRH receptor. In many mammalian species, one or both of the GnRH-II system genes are disrupted or deleted, rendering their products non-functional. This includes humans who possess a gene encoding GnRH-II but lack a functional type II GnRH receptor. Here we examined the genes encoding prepro-GnRH-II (GnRH2) and the type II GnRH receptor (GnRHR2) in more than 20 mammalian species, encompassing 10 orders, to determine whether they encode functional proteins. The structural organisation of both genes in most mammalian genome sequence assemblies was poorly annotated or incompletely described. Our findings show significant variation in the DNA sequence conservation and functional status of each gene, even between closely related species. Prepro-GnRH-II was functionally compromised in 12/22 species and the type II GnRH receptor gene was disrupted in 14/22 species. Retention of large sections of each gene in most mammalian genomes suggests that mammalian ancestors had a functional GnRH-II system. Gene disruptions were due to a spectrum of mutations which must have occurred independently after the evolutionary divergence of mammals from ancestral animals. The genetic information will be useful for understanding the physiological role of the GnRH-II system and establishing animal models for functional studies.
Lymphocyte Receptors for Human Erythrocytes in Newborn Infants and Adults
Authors: Hallberg Anita , Hallberg Torgny
Published: August 2009

Lymphocyte receptors for human erythrocytes (HRBC) have been demonstrated by an optimized technique using neuraminidase-treated HRBC and high-protein diluent. Mean values of 55 and 50% reactive lymphocytes were found in the peripheral blood of newborn infants and adult donors, respectively. The HRBC receptor was labile under tissue culture conditions in vitro, in contrast to the receptors for sheep erythrocytes, Fc of IgG, and complement. Short-term culturing of lymphocytes with T cell mitogens (phytohemagglutinin, concanavalin A) increased the proportion of HRBC-receptor-bearing lymphocytes. Pokeweed mitogen, being mainly a B cell stimulator, was less effective in activating lymphocytes to resynthesize the receptor. It is concluded that the HRBC receptor is probably not a stable marker for a single subpopulation of human T lymphocytes. During the first week of life, the HRBC receptor is expressed on at least the same proportion of peripheral blood lymphocytes as in adults.
Kinetics and Drug Sensitivity of the Anti-Hapten and Anti-Carrier IgG1 and IgG2 Antibody Production in Guinea Pigs
Authors: DrÖssler K. , Klima F. , Ambrosius H.
Published: August 2009

The influence of the hapten-protein ratio on the induction and kinetics of specific IgG1 and IgG2 anti-hapten and anti-carrier antibody synthesis, and the sensitivity of these reactions to cyclophosphamide (CY) and 6-mercaptopurine (6-MP), were studied following immunization with two different dinitrophenylated bovine gamma-globulin (DNP20-BGG and DNP47-BGG) conjugates in Freund’s complete adjuvant (FCA) and drug treatment over the first 7 days after antigen injection. The DNP- and BGG-specific IgG1 and IgG2 serum antibody concentrations were determined weekly. Treatment by CY resulted in a complete suppression of the primary IgG1 and IgG2 anti-BGG antibody response, both in the DNP20-BGG and DNP47-BGG immunized guinea pigs. The anti-DNP reponse was completely suppressed only up to day 14 (DNP20-BGG immunized group) or day 21. This was followed by an increase that was significantly greater in the DNP20-BGG than in the DNP47-BGG immunized animals. The secondary IgG1 anti-BGG immune response induced by an injection of 1 mg BGG on day 86, was uninfluenced in animals immunized with DNP20-BGG but stimulated in the other group treated with DNP47-BGG. The IgG2 was completely suppressed in both groups. 6-MP, known to be less immunosuppressive in guinea pigs, led to very similar results. The finding that in animals immunized with DNP47-BGG the primary anti-BGG IgG2 antibody synthesis was uninfluenced by 6-MP, but the development of a memory was suppressed, would suggest that the primary antibody response and immunological memory are either separate mechanisms or have different sensitivities to 6-MP.
Production of Two Lymphocyte Chemotactic Factors by Antigen-Stimulated Guinea Pig Lymphocytes
Authors: Harita Shingo , Shimokawa Yasuo , Hayashi Hideo
Published: August 2009

Lymph node cells from guinea pigs sensitized by BCG elaborated two chemotactic factors for lymphocytes when stimulated with purified protein derivative in vitro 4 weeks after immunization. Production of the factors occurred within 24 h of incubation. The two factors were termed α- and β-lymphocyte chemotactic factors (α-LCF, β-LCF), relative to their elution order on gel chromatography. The molecular weights were about 160,000 and 27,000, respectively. α-LCF was labile to heating at 56 °C for 30 min. Both factors were sensitive to digestion by trypsin, and were effective for T cells but not for B cells.
HLA-Related Lymphocyte Responsiveness in Psoriasis
Authors: Gross W.L. , Vorwerk I. , Westphal E. , Christophers E. , Hahn G. , Schlaak M.
Published: August 2009

In order to find associations among the genetic, immunological and environmental factors that might be important in the pathogenesis of psoriasis, the relationship between streptococcal antigen- or mitogen-induced lymphocyte responses in vitro and HLA phenotypes was studied in 23 patients with psoriasis. Patients showed an elevated lymphocyte response to somatic A-streptococcal antigens when compared with healthy controls. In contrast, the response to mitogens (PHA, Con A, PWM) was impaired in patients with psoriasis. The impaired mitogen-induced lymphocyte transformation was found mostly in psoriatics with HLA-B13/B17. The elevated cellular immune response to somatic A-streptococcal antigens, on the other hand, was observed mainly in psoriatics without HLA-B13/B17. The results indicate that gene products of the HLA region known to be associated with psoriasis are involved in the cellular immune response, as expected from clinical trials. These findings also provide further evidence of at least two different subtypes of psoriasis, characterized by genetically and immunologically defined markers.
Peroral Immunization of Healthy Adults with Live Escherichia coli O4K12 Bacteria
Authors: Kaijser B.
Published: August 2009

6 healthy adult volunteers were immunized perorally with live Escherichia coli O4K12 bacteria. The bacteria could thereafter be identified in the stools of all individuals for different periods of time. No adverse reactions were noted. 04 antibodies of the IgG class appeared in the serum of all individuals and IgM antibodies in 2 of then. The corresponding figures for K12 antibodies were 2 and 1, respectively. In saliva from the glandula parotis, secretory IgA antibodies to 04 were seen in 3, and against K12 in 1 individual. It is concluded that peroral immunization might be an alternative for induction of antibodies. Nothing is known, however, about any protective effect of these antibodies. Only a low percentage of the individuals showed K12 antibody formation. Therefore, optimal prophylactic immunization against acute pyelonephritis could be achieved by giving immunogenic K antigen, that is conjugated to a carrier, which might induce antibody formation in most individuals.
The Activity of a New, Novel Inhibitor of Leukotriene Synthesis in Rhesus Monkey Ascaris Reactors
Authors: Johnson Herbert G. , McNee Martha L. , Bach Michael K. , Smith Herman W.
Published: August 2009

The IgE-mediated hypersensitivity to Ascaris antigen in reactor rhesus primates was used to assess the pharmacologic profile of U-60,257, a pyrrole analog of prostacyclin. Whether the compound was given by aerosol or intravenously, it effectively inhibited the bronchopulmonary effects of antigen challenge. Dose responses by the aerosol route showed a dose-dependent inhibition of resistance (RL) and compliance (Cdyn) changes (100% ± 0 to 10.2% ± 14.5 for RL and 79.9% ± 20 to 0% for Cdyn after 15 breaths of 1.0–0.01 % solutions delivered into the lungs; n = 16). When administered at 1.0% by aerosol the duration of the inhibitory effect was 6 h (n = 3). Dose-dependent inhibition in both RL (93.3% ± 5.6 to 69.4% ± 34.8) and Cdyn (51.4 ± 40.4 to 47.0% ± 28.5) was also seen when the compound was given intravenously (5.0–0.01 mg/kg; n = 16). U-60,257 is a selective inhibitor of leukotriene synthesis in in vitro systems. Therefore, the finding of synergism in the inhibition of response of primates to Ascaris between this compound and the H1 histamine blocker diphenhydramine suggests that the leukotrienes may play an etiologic role in this response.
Naturally Developing Antibodies to Wheat Gliadin Fractions and to Other Cereal Antigens in Rabbits, Rats and Guinea Pigs on Normal Laboratory Diets
Authors: Coombs R.R.A. , Kieffer Marianne , Fraser D.R. , Frazier P.J.
Published: August 2009

Rabbits, rats and guinea pigs on normal laboratory diets were examined for gliadin and other cereal antibodies comparable to those found in the sera of human coeliac patients. Many of the rabbits had very high levels of gliadin antibodies. Rats showed much lower titres more comparable to the findings in normal human sera. In both these species the reactivity was directed principally against the α-gliadins. The spectrum of reactivity against the prolamines of other cereals was again comparable to that of human coeliac sera. A difference, however, was the high reactivity with maize prolamine; this was decidedly lower in sera of coeliac patients. Guinea pigs were distinctive in having relatively no serum antibodies to wheat gliadin and also minimal reactivity to the albumins, globulins and glutenins of wheat. Normal guinea pigs did, however, have antibodies to oat and maize prolamines. Following parenteral injection with total ethanol-soluble wheat gliadin, guinea pigs developed high-titred antibodies, not only to wheat gliadin fractions 1–8 (α-, β-, γ- and ω- gliadins), but also to all the cereal prolamines except those of rice. These investigations are steps in the evaluation of the role of circulating gliadin antibodies in gluten-sensitive enteropathy.
A Rapid Procedure for Crossed Radio Immunoelectrophoresis
Authors: Uhlin Thomas , Einarsson Roland
Published: August 2009

A procedure for performing crossed radio immunoelectrophoresis (CRIE) with significantly reduced exposure times has been developed. The rapid method has been effected by using a highly sensitive X-ray film (Du Pont Cronex-4) and X-ray intensifying screen (Du Pont Lighting Plus) and by exposing at low temperatures (––70 °C) in a Kodak X-Omatic cassette. Exposure at ––70 °C appears to be critical to obtain optimal radiostaining. Furthermore, the isotope concentration has been increased from 250,000 to 500,000 cpm without any loss of specificity or reproducibility. The rapid CRIE procedure makes it possible to obtain a CRIE screening within 1 day and, furthermore, a complete CRIE classification (CRIE classes A–G) within 5 days.
Changes of Alpha1- and Beta-Adrenergic and Cholinergic Muscarinic Receptors in Guinea Pig Lung Sensitized with Ovalbumin
Authors: Mita Haruhisa , Yui Yasuo , Yasueda Hiroshi , Shida Takao
Published: August 2009

The effect of immunization of guinea pigs with ovalbumin on the number and affinity of alpha1- and beta-adrenergic and cholinergic muscarinic receptors was studied in lung membranes by direct binding techniques using 3H-prazosin, l-3H-dihydroalprenolol and l-3H-quinuclidinyl benzilate. After immunization by intraperitoneal injection of ovalbumin to guinea pigs, the number and affinity of each receptor in sensitized animals were not significantly different from those of control animals. Sensitization of guinea pigs by an aerosol exposure with the antigen resulted in a decreased number of beta-adrenergic receptor (458 ± 29 vs. 687 ± 56 fmol/mg protein; p < 0.01), and an increased number of alpha1-adrenergic receptor (36 ± 2 vs. 25 ± 2 fmol/mg protein; p < 0.01), but no change was observed in the number of muscarinic receptors, as compared with control animals. On the other hand, following a prolonged sensitization of guinea pigs with a low dose of the aerosolized antigen, the number of muscarinic receptors was significantly increased in the lung of sensitized animals (50 ± 2 vs. 42 ± 2 fmol/mg protein; p < 0.01); however, we found no significant differences between sensitized and normal animals in the number of alpha1- and beta-adrenergic receptors. There were no different changes in the affinity of these receptors in all experiments.
Physicochemical Properties and Blood Clearance of Human Serum Albumin Conjugated to Different Extents with Dinitrophenyl Groups
Authors: Skogh T. , Stendahl O. , Sundqvist T. , Edebo L.
Published: August 2009

Human serum albumin (HSA) conjugated to various extents with dinitrophenyl (DNP) groups and labelled with 125I was studied with regard to physicochemical properties and blood clearance after intravenous injection in mice. Increasing the degree of DNP conjugation increased the tendency to hydrophobic interaction, and increased the net negative charge. Heavily DNP-substituted HSA molecules tended to aggregate. The higher the degree of DNP substitution the faster was the conjugate eliminated from the circulation. Blood clearance was independent of serum complement, and was not affected by galactose, N-acetylglucosamine, mannose, α-methyl-D-mannoside, or fucose. It is proposed that the differences in blood clearance between the different DNP-HSA conjugates mainly depend upon differences in the tendency to hydrophobic interaction.
Biosynthesis and Release of Platelet-Activating Factor from Human Monocytes
Authors: Camussi G. , Bussolino F. , Tetta C. , Piacibello W. , Aglietta M.
Published: August 2009

The aim of the present study was to investigate the pathways of platelet-activating factor (PAF) production and release from human monocytes. For this purpose, both phagocytic stimuli and stimuli induced by soluble agents were used. The phagocytic stimuli exerted their effect in a receptor-specific mechanism related to surface Fc, C3b and C3d receptors. Stimuli induced by soluble agents, such as A23187 and pH 10.6, which do not require interaction with specific receptors, were also effective in inducing PAF release. In contrast, C5a, a soluble agent which induces a receptor-mediated release of PAF from neutrophils, failed to induce PAF release from monocytes. PAF release from monocytes could be dissociated from phagocytosis and from release of lysozyme. The PAF release required the presence of extracellular cations, the activation of membrane esterase and phospholipase A2 and the integrity of the microΓilament system. Moreover, PAF release was modulated by lipoxygenase and intracellular cAMP levels. The relevance of an acetylation process in the biosynthesis of PAF was suggested by the increase of PAF yields in the presence of sodium acetate and by the incorporation of 14C-sodium acetate into molecules of active PAF.
Mechanism of BCG-Activated Macrophage-Induced Tumor Cell Cytotoxicity: Evidence for Both Oxygen-Dependent and Independent Mechanisms
Authors: DiStefano John F. , Beck Gregory , Zucker Stanley
Published: August 2009

Activated peritoneal macrophages have been shown to be cytotoxic to cancer cells. Bacillus Calmette-Guerin (BCG)-activated rat peritoneal macrophages have a basal cytolytic potential for 3H-thymidine-labelled Walker 256 cancer cells in vitro that can be markedly enhanced by digitonin. This stimulation of cytotoxicity can be partially inhibited by catalase and the combination of superoxide dismutase plus catalase. This suggests that digitonin stimulates activated macrophages to produce superoxide, hydrogen peroxide and possibly other free radicals which can augment macrophage-induced tumor cell cytotoxicity. After a 2-hour incubation with digitonin, macrophages are no longer stimulated by digitonin. However, after a 2-hour drug preincubation period, inhibitors of serine protease activity (DFP, TLCK, SBTI) and inhibitors of protein synthesis (cycloheximide) are potent inhibitors of basal macrophage-induced tumor cytotoxicity. We suggest that BCG-activated macrophages have two mechanisms for destroying cancer cells: one mediated by proteolytic activity, and a second mechanism dependent on the generation of oxygen-derived free radicals.
Adenylate Cyclase, Cyclic AMP and IgE-Mediated Desensitization in Rat Mast Cells
Authors: Mendoza Guillermo R. , Orner Francine B.
Published: August 2009

Rat peritoneal mast cells were desensitized up to 100% with 1–4 additions of suboptimal concentrations of anti-rat IgE over 60–90 min. Desensitized cells rechallenged with anti-IgE showed a 2- to 10-fold increase in cAMP during the initial 1–5 min. Membrane preparations from desensitized cells showed up to a 100-fold rise in cyclase activity following incubation with anti-IgE, compared to a 5- to 10-fold rise in control cells. Control and desensitized cell membranes rechallenged with anti-IgE showed nearly identical levels of phosphodiesterase activation. We conclude that following desensitization, repetitive low levels of anti-IgE binding induce atypically high and sustained activation of adenylate cyclase which may reflect primary or secondary regulatory events in the development of desensitization.
Cyclosporin A: Alterations of the Cellular Immune Response in S-Antigen-Induced Experimental Autoimmune Uveitis
Authors: Nussenblatt Robert B. , Salinas-Carmona Mario , Waksman Byron H. , Gery Igal
Published: August 2009

We have previously shown that Cyclosporin A (CsA) is effective in preventing S-antigen (S-Ag)- induced experimental autoimmune uveitis (EAU). Lewis rats, which readily develop EAU, were studied for the alterations in cell-mediated immune functions associated with CsA therapy. Lymph nodes draining the site of S-Ag immunization were significantly smaller in the CsA-treated animals when compared to the nonprotected group (p < 0.01 ), and also showed profound histologic alterations when compared to controls. In vitro responses of lymphocytes from lymph node and peripheral blood were greatly diminished in the CsA-treated animals. Sera from rats treated with CsA also were capable of inhibiting in vitro proliferative responses. These findings demonstrate that CsA-treated Lewis rats have alterations in several cell-mediated immune functions, thereby not permitting full development of the immune events that ultimately lead to uveitis.
Antiallergic Activity of Nylidrin Hydrochloride (RHC 3432-A)
Authors: Coutts Stephen M. , Khandwala Atul , Weinryb Ira
Published: August 2009

Nylidrin hydrochloride has weak β-adrenergic agonist properties with rat mast cells, and shows synergy with 3-isobutyl-1-methylxanthine (IBMX) in raising intraceliular cAMP in purified mast cells; both of these properties can be blocked by dl-propranolol. However, the action of nylidrin hydrochloride as an inhibitor of histamine secretion from purified rat mast cells is not antagonized by dl-propranolol, nor is it potentiated by IBMX. Nylidrin-induced elevation of cellular cAMP in purified rat mast cells shows no correlation with nylidrin-induced inhibition of histamine release. Thus, nylidrin hydrochloride inhibits release of histamine from mast cells by a novel, non-adrenergic mechanism, which is not dependent on increased levels of cAMP.
On the Secretory Process of Rat Mast Cells and Rat Basophilic Leukaemia Cells
Authors: Möller Gerd , König Wolfgang
Published: August 2009

The biological role of heat-aggregated IgGa during the secretory process of rat mast cells and rat basophilic leukaemia (RBL) cells was analysed. Incubation of normal rat mast cells and rat basophilic leukaemia cells with heat-aggregated IgGa alone leads to a stabilization of the cells resulting in a reduction of mediator secretion and ion influx. When mast cells from Nippostrongylus brasiliensis-infected animals were incubated with heat-aggregated IgGa and subsequently challenged with anti-IgE, a dual effect with regard to ion influx and histamine release was observed, depending on the concentration of heat-aggregated IgGa or anti-IgE either a pronounced decrease or a marked enhancement was apparent. Our data suggest that heat-aggregated IgGa as well as immune complexes modulate the secretory response of mast cells and may thus play an important role in the allergic disease process.
A C5-Derived Macrophage Chemotactic Factor from DNP-Ascaris Extract-Induced Skin Lesion in Guinea Pigs
Authors: Hirashima Mitsuomi , Hirotsu Yasunobu , Yoshimura Teizo , Hayashi Hideo
Published: August 2009

In complement-depleted condition induced by cobra venom factor (CoF), tissue macrophage reaction and macrophage chemotactic activity (MCA) in skin extract from skin lesions induced by DNP-Ascaris extract (DNP-As) were decreased, respectively. MCA in the fraction containing macrophage chemotactic factor b (B fraction) was decreased completely. While MCA in the fraction containing macrophage chemotactic factor a and c (A fraction) was affected only slightly. These results suggested that the decrease of MCA of Infraction might be associated with depletion of complement system by CoF. Using anti-C5 antibody, it was confirmed that macrophage chemotactic factor-b (MCF-b) (MW 14,000: thermostable) might be derived from C5 fragment in vivo.
Heparin and the Dextran Anaphylactoid Reaction in Rats
Authors: West G.B.
Published: August 2009

Injections of heparin had no effect on the dextran anaphylactoid reaction in rats but neutralised the inhibitory action both of protamine and of borate. Heparin, protamine, and borate did not modify the histamine or 5-hydroxytryptamine responses in rat paws and so their effects on dextran may be due to modification of the release mechanisms of these two amines from tissue mast cells.
Characterization of Anti-Double-Stranded DNA Antibody-Forming Cells in the NZB/W Mouse Spleen
Authors: Okudaira Hirokazu , Terada Eiji , Ghoda Akira , Ogita Tadaatsu , Miyamoto Terumasa , Nomura Tatsuj
Published: August 2009

Characerization of anti-double-stranded (ds) DNA antibody-forming cells in the spleen of the NZB/W mouse was attempted. Anti-ds DNA antibody-forming cells formed antibodies in vitro without any antigenic stimulus. Depletion of T cells in the NZB/W spleen cells did not abolish but enriched the anti-ds DNA antibody-forming capacity. Anti-ds DNA antibody formation was not abolished by 1,000 R of irradiation which suggests that there was no mitotic process involved. An in vivo irradiation experiment using NZB/W mice indicated that persistent anti-ds DNA antibody formation is mediated by radio-restistant antibody-forming cells.
Studies on a New Lymphocyte Mitogen from Pollen Aqueous Extract: Induction of Proliferation in Human and Rodent Lymphocytes
Authors: Anfosso Francine J. , Guillard Pascale M. , Charpin Jacques P.
Published: August 2009

Fraction III (Fr III) mitogen was isolated from the whole aqueous extract (WAE) of plane-tree pollen by Con A-Sepharose chromatography and gel filtration. It stimulated mouse spleen cells, and peripheral blood lymphocytes from plane-tree non-sensitive patients or from cord blood. A 6-day culture gave the best response. The proliferation was not abolished by washing the cells after a short pulse of Fr III given in the initial step but was inhibited by α-D-methylmannoside. These results suggested that Fr III bound to a specific site onto spleen cells. This mitogen was not immunogenic in mice and did not bind to human IgE. It induced the proliferation of T lymphocytes in presence of accessory cells and was a polyclonal activator.
Antigen- and IgE Class-Specific Suppression Mediated by T Suppressor Cells of Mice Treated with Glutaraldehyde-Polymerized Ovalbumin
Authors: HayGlass Kent T. , Strejan Gill H.
Published: August 2009

Various size polymers are obtained following glutaraldehyde treatment of native ovalbumin (OA). OA-POL, approximately 35 × 106 daltons, was prepared at the isoelectric point of OA. Treatment of CBA mice with microgram amounts of OA-POL led to efficient antigen-specific suppression of IgE responses. IgG anti-OA antibodies were not suppressed. Transfer of cells from OA-POL-treated donors into normal, unprimed recipients interfered with the ability of these animals to mount a primary or secondary IgE response. In addition, cotransfer of spleen cells from OA-POL-treated mice along with OA (in alum)-primed cells, into irradiated syngeneic recipients resulted in IgE class-specific suppression that was abrogated by treatment of OA-POL donor cells with monoclonal anti-Thy 1.2 + complement. The presence or absence of T cells in the OA-POL population had no effect on IgG levels in the recipients. Analysis of the antigenic properties of OA-POL revealed 5–15% cross-reactivity with native OA as perceived by IgG or IgE antibodies. In contrast, OA-POL was highly cross-reactive at the T cell level as shown functionally by its potent induction of OA-specific, IgE-selective suppressor T cells. The results suggest that the beneficial effects of glutaraldehyde-modified allergens, recently introduced in the immunotherapy of atopic individuals may be due to the preferential exposure on the polymerized protein, of antigenic determinants generating T suppressor cells and to the selective loss of B cell-reactive determinants.
The Development and Validation of Radioallergosorbent Tests for the Detection of Specific Human IgE Antibody Directed against Laboratory Animal Urinary Proteins
Authors: Edwards R.G. , Lee D. , Beeson M.F. , Dewdney J.M. , Spackman D.A.
Published: August 2009

Radioallergosorbent tests (RAST) using urinary proteins from mice, rats, guinea pigs and rabbits have been developed and used in the diagnosis of laboratory animal allergy (LAA). Of the 273 subjects tested, 15 had been previously diagnosed as laboratory animal allergic and 8 of these (53%) gave one or more positive RAST results. Of the 258 symptom-free individuals, only 9 (3.5%) had one or more positive RAST. Of these 9, 7 had previously worked with animals or had occupational exposure to the appropriate species; the remaining 2 individuals had only some pet exposure. RAST was, therefore, of value in the diagnosis of LAA. During the development of these RAST assays, several sources of potential error were identified. Modest titres of total IgE (600 IU/ml and above) were found to influence the specific RAST index observed and lead to false positive results. The presence of human IgG antibody specific for rabbit serum proteins was also identified in four sera, and was responsible for interference in the rabbit urinary protein RAST system.
Difference of the IgE Memory Cells in SJL and BALB/c Mice
Authors: Hirano Takao , Ovary Zoltan
Published: August 2009

Memory cells for adoptive transfer for IgE production must be primed with Al(OH)3 as adjuvant in the SJL strain of mice, but can be primed also with Freund’s complete adjuvant in the BALB/c strain.
A Reevaluation of the Concanavalin A Induced Suppressor Cell Assay in Man
Authors: Knaab S. , Jeannet M.
Published: August 2009

Several methods are used to evaluate the in vitro suppressor function of human peripheral blood lymphocytes (PBL). Recently however, the validity of these assays has been questioned, because possible artefacts may lead to misinterpretation of the results. A reevaluatoin of these assays has been performed, and a simple and reproducible technique necessitating only one bleeding has been developed. Pretreatment of human PBL with concanavalin A (ConA) results in an inhibition of 3H-thymidine incorporation after ConA stimulation by cocultured untreated autologous or allogeneic PBL collected at the same time and incubated under the same conditions as the inhibitory PBL. It is concluded that true suppression is responsible for the observed inhibition of the response to ConA and that this assay can be used to assess the functional ability of suppressor cells in different clinical situations.
IgG4 Antibodies in Patients with House-Dust-Mite-Sensitive Bronchial Asthma: Relationship with Antigen-Specific Immunotherapy
Authors: Nakagawa Takemase , Takaishi Toshiaki , Sakamoto Yoshio , Ito Koji , Miyamoto Terumasa , Skvaril Frantisek
Published: August 2009

Sera from 40 patients with house-dust-mite (Dermatophagoides farinae)-sensitivebronchial asthma were evaluated by solid-phase radioimmunoassay for their mite-specific IgG4 antibody levels. Asthmatic patients undergoing specific immunotherapy possessed a significantly higher mean value of IgG4 antibodies than normal controls and asthmatics without immunotherapy (p < 0.01 and p < 0.05, respectively). Moreover, evaluation of 11 patients before and after immunotherapy showed that IgG4 antibodies tend to increase during immunotherapy. The clinical significance of the IgG4 subclass as blocking antibodies in immediate allergic reactions is also briefly discussed.
Analysis of Chemotactic Factor Generation in C1q-Deficient Sera
Authors: Leyva-Cobián F. , Clerici N.
Published: August 2009

The roles of the classical and alternative complement pathways in the formation of chemotactic factors in normal human serum and in sera from patients with an inherited selective deficiency of C1q were studied. Monocytic chemotaxis was evaluated in serum activated by zymosan, endotoxin, cobra venom factor, aggregated human IgG and immune complexes. Chemotactic activity was only impaired when the C1q-deficient serum concentration was low or the period of exposure to zymosan, endotoxin or immune complexes was short. No effect was demonstrated when cobra venom factor and aggregated human IgG were used as activating agents even at limited serum concentrations. Chemotactic activity was also impaired when deficient sera were chelated with EGTA and activated with immune complexes during 7 and 60 min. The addition of normal human serum or purified human C1q to the assay resulted in improvement or normalization of the chemotactic function. The observation that the formation of chemotactic factors via the alternative pathway requires a higher serum concentration and/or longer activation time, points out the necessity for an intact classical pathway in order to achieve optimal activation of the alternative pathway.
Monoclonal Antibodies against Gastrointestinal Tumour-Associated Antigens Isolated as Monosialogangliosides
Authors: Lindholm L. , Holmgren J. , Svennerholm L. , Fredman P. , Nilsson O. , Persson B. , Myrvold H. , Lagergård T.
Published: August 2009

Monoclonal antibodies were produced after immunization of mice with a colorectal adenocarcinoma cell line or liver metastasis membranes from a patient with colon adenocarcinoma. Many monoclonal antibodies were found to react with colorectal adenocarcinoma cells but not with normal colon mucosa, blood lymphocytes, myeloma cells or lung epithelial carcinoma cells. Three of these ‘colorectal tumour-specific’ antibodies appear to define different antigens that were found in the complex monosialoganglioside fraction from 60 to 90% of the colorectal and pancreatic adenocarcinoma tumours or metastases examined but essentially lacking in normal colon mucosa and other normal or tumour tissues tested.
Types of Immune Complexes in the Ascitic Fluid of Women with Carcinoma of the Ovary
Authors: Silburn Peter A. , Khoo Soo Keat , Daunter Brian , Hill Ron , Roberts Tim K. , Mackay Eric V.
Published: August 2009

Immune complexes with C1q-fixing properties and those precipitable by polyethylene glycol (PEG) were detected in ascitic fluid from patients with advanced ovarian cancer. The ascitic fluid from 42 of 58 patients (72%) contained these complexes. A positive result with the C1q assay was obtained in 41 % of patients, whilst with the PEG assay a positive result was obtained in 59% (50% in the IgM, 36% in the IgG, and 14% in the IgA fraction). The highest mean level of PEG-precipitable complexes was in the IgG fraction (11.4 mg/100 ml) and lowest in the IgA fraction (3.3 mg/100 ml). These results indicate that gram quantities of the immune complexes may be isolated from the large volumes of ascitic fluid usually present in ovarian cancer. Further studies of ascitic fluid may thus provide data on the nature of the immune responses in these patients.
Antibody Responses to Honey-Bee Venom and Monomethoxy-Polyethylene Glycol-Modified Honey-Bee Venom in Mice
Authors: Ahlstedt S. , Björkstén B. , Åkerblom E.
Published: August 2009

Antibody responses of the IgE isotype were raised in mice with honey-bee venom (HBV) administered in alum or by daily injections without adjuvant. The sensitized mice were treated with single injections of HBV modified with monomethoxy-polyethylene glycol. By such treatment with modified but not with natural HBV, suppression of the IgE antibody responses was achieved. The IgG antibody responses, in contrast, were unchanged or enhanced.
Repetitive Testing and Storage of Human Effector Cells in Natural Killing and Antibody-Dependent Cell-Mediated Cytotoxicity
Authors: Hirsen Daniel J. , Dubin Benjamin A. , Malham Leslie M.
Published: August 2009

Daily variation in natural killer (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) assays is problematic. When fresh peripheral blood mononuclear cells (PBM) from 4 donors were tested repeatedly, the ADCC and NK values tended to fall in the same rank order on each day tested, suggesting that repetitive assay of control donors could serve as an index for daily variation. Cryopreservation of PBM resulted in decreased and quite variable recovery of ADCC and NK. Cryopreservation, therefore, would not be an adequate control for daily variation. Storage of PBM at 4°C for 24 h resulted in better recovery of ADCC and NK activities than did cryopreservation.
Phagocytosis Inhibits the Production of C2 by Human Monocytes
Authors: Morrison Lindsay , Whaley Keith
Published: August 2009

Production of the second complement component by cultured human monocytes was suppressed by the addition of a variety of phagocytosable particles. The degree of suppression was related to the concentration of particles, but was unrelated to particle size, the presence of surface sialic acid, antibody or C3b. The failure to reverse suppression by prostaglandin synthetase inhibitors indicates that it is not mediated by prostaglandins.
Characterization of a Very High Density Lipoprotein Allergen, Dpt 4, from the House Dust Mite Dermatophagoides pteronyssinus
Authors: Stewart G.A. , Butcher A. , Turner K.J.
Published: August 2009

The allergen Dpt 4 from the house dust mite Dermatophagoides pteronyssinus was shown to be a lipoprotein as judged by its Sudan black B staining properties. Ultracentrifugal studies confirmed this finding and showed that Dpt 4 was polydisperse, although the majority of the allergen belonged to a very high density lipoprotein class. Physicochemical studies using gradient polyacrylamide gel electrophoresis showed that Dpt 4 had an apparent molecular weight of 244,000 daltons and a particle diameter of 10.73 nm. Agarose gel electrophoresis showed that the allergen had an electrophoretic mobility 0.86 times that of human α-lipoprotein. The observation that Dpt 4 is a lipoprotein is consistent with earlier studies which showed that the allergen was heterogeneous with regard to its molecular weight and that it contained the hapten phosphorylcholine.
Inhibition of Tγ Rosette Formation by the Sera from Patients with Systemic Lupus erythematosus
Authors: Okudaira Kunio , Tanimoto Kiyoaki
Published: August 2009

The cytotoxic activities of lupus sera were measured against IgG Fc-receptor-bearing T lymphocytes (Tγ cells) and T lymphocytes lacking this receptor [Tγ (––) cells], and the activities were compared with the inhibitory activities of the sera for the formation of rosettes (Tγ rosettes) between T lymphocytes and ox erythrocytes sensitized with IgG antibody. The cytotoxic activities of the sera against both Tγ and Tγ(––) cells well correlated with their Tγ rosette inhibitory rates. Also, the cytotoxic activities after the removal of IgM antibodies strongly correlated with the inhibitory rates. Among them, the highest correlation was observed between IgG Tγ-specific cytotoxic antibodies and Tγ rosette inhibitory rates of the sera. Gel filtration, ultracentrifugation, pepsin digestion, and reduction and alkylation of the sera revealed that main inhibitory activities were contained in IgG fractions. These results suggested that IgG Tγ-specific antibody suppressed Tγ rosette formation and might contribute to the reduction of Tγ cell number in patients with systemic lupus erythematosus.
In vitro Effects of 13-Cis-Retinoic Acid (Ro 4-3780) and Etretinate (Ro 10-9359) on DNA Synthesis and Fine Structure of Guinea Pig and Human Lymphoid Cells
Authors: Nordlind Klas , Thyberg Johan
Published: August 2009

In vitro effects of the retinoids 13-cis-retinoic acid (Ro4-3780) and etretinate (Ro 10-9359) on DNA synthesis and the fine structure of different guinea pig and human lymphoid cells were tested. 13-Cis-retinoic acid caused a dose-dependent inhibition of DNA synthesis most prominently in thymocytes. This effect was not due to an inhibition of thymidine uptake into the cells. Electron microscopically, the cells exhibited swollen Golgi cisternae, enlarged mitochondria often with condensed matrix, and an increased number of autophagic vacuoles. Etretinate, on the other hand, was without effect on DNA synthesis as well as on cell fine structure. The results suggest that the morphological and growth-inhibitory effects of 13-cis-retinoic acid are related.
Correlation of Leukocyte Accumulation with Chemotactic Activity in the Exudate of an Allergic Air-Pouch Inflammation
Authors: Kurihara Atsushi , Ohuchi Kazuo , Tsurufuji Susumu
Published: August 2009

Chemotactic activity at the site of an allergic air-pouch inflammation induced with azobenzene-arsonate-conjugated acetyl bovine serum albumin as an antigen was studied and a close correlation of the chemotactic activity with the intensity of leukocyte migration was demonstrated. In the period of vigorous leukocyte immigration into the fluid in the allergic air-pouch, chemotactic activity of the exudate was maintained at a high level, while no significant activity was detected after the number of leukocytes in the pouch fluid reached maximum.