Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer.

Dendritic cells (DCs) are the most potent antigen-presenting cells and are thought to reflect the interaction between the host immune system and tumor cells. In a retrospective study, we analyzed the presence of DCs and memory lymphocytes in tumor biopsy specimens of 18 patients with ovarian cancer. These patients were followed up for 10 to 37 months. Within this period, 9 patients had no evidence of disease (NED, group A), and 9 patients had recurrence (group B). In group A, 5 cases were stage III, 1 was stage I, and 1 was stage II. In group B, 5 cases were stage III, 1 was stage III-IV, and 3 were stage IV. Our results show that the mean number of cells expressing the DC phenotype, HLA-DR(+) CD1a(+), in tumor biopsies was substantially higher in group A than in group B (HLA-DR(+): 37.8 +/- 18.2 v. 10.7 +/- 2.2, respectively; P <.005; CD1a(+): 9.5 +/- 11.3 v 2.1 +/- 3.7). On the other hand, the number of cells expressing the DC phenotype S-100 protein was substantially lower in group A than in group B (S-100(+): 9.7 +/- 9.9 v 16.2 +/- 12.7), although the difference was not statistically significant. There was no difference in the number of tumor-infiltrating CD45RO(+) cells between groups A and B (CD45RO(+): 39.1 +/- 28.5 v 34.2 +/- 19.1). Our results show that the presence of relatively high numbers of defined DC subpopulations may have prognostic value in ovarian tumors.

Synthesis and anticancer activity of novel chiral D-glucose derived bis-imidazoles and their analogs.

A series of novel D-glucose derived bis-imidazoles and their analogs, which possess potential in bioorganic and supramolecular chemistry, were designed and synthesized from methyl alpha-D-glucoside through protection, bis-bromination, N-alkylation and deprotection. All new compounds were characterized by HRMS, 1H, 13C and DEPT NMR spectroscopy as well as elemental analysis. The 1H-(1)H and 1H-(13)C 2D NMR spectra for some compounds were also recorded. Some regular features of 13C and 1H NMR spectra were summarized. The anticancer activity of some compounds was evaluated.

New 3'-deoxythymidines bearing a nucleophilic 3'-substituent.

New potential cancer-driven as well as HIV-driven nucleoside heteroanalogs, such as 3'-thio- and 3'- as well as 5'-selenosubstituted thymidines, have been synthesized. We also report an effective method for the preparation of novel nucleoside derivatives, bis(deoxynucleoside) diselenides, in nearly quantitative yields. The North conformation is significantly populated in the conformational equilibrium for 3'-alpha-alkylthiothymidines.

Conformational preferences for 3-piperideines: an Ab initio and molecular mechanics study.

Conformational preferences in alkyl- as well as Ph-substituted 3-piperideines (1,2,3,6-tetrahydropyridines) have been characterized by ab initio and molecular mechanics calculations. A set of rules and subrules for estimation of the conformational equilibrium (in terms of preferred substituent orientation) in these systems. with differently positioned ring substituent (-s), is presented. Examples of the revision of some previous stereochemical assignments demonstrate the reliability of these rules.

Peptide conjugation: unexpected ring opening of azacrown ether nucleophiles in the oxazolone-based coupling.

Unexpected cleavage of the macrocylic ring of secondary azacrown ethers when interacting with the Aib8 (Aib = alpha-aminoisobutyric acid) oxazolone indicates the possibility for a new mechanism of peptide racemization due to transformations of the oxazolones formed from the N-derivatives of alpha-amino acids in peptide synthesis.

Absence of RBM expression as a marker of intratubular (in situ) germ cell neoplasia of the testis.

RBM (RNA-binding motif) protein is a marker of male germ cells. This protein is encoded by the Azoospermia factor region-b (AZF-b) of the human Y chromosome and is expressed exclusively in the male germ cell line, that is, spermatogonia, spermatocytes, and round spermatids. The authors analyzed the expression of the RBM gene in germ cell tumors and in the seminiferous tubules in the vicinity of these tumors to identify the presence of IGCN. Sections from testicular germ cell tumors of 21 patients were stained with anti-RBM antibody by using an immunohistochemical method. Distal tubules showing spermatogenesis were immunopositive for RBM protein. All of the germ cell tumors studied were completely immunonegative for RBM. Defined areas of IGCN also showed an absence of RBM expression. Tubules with spermatocyte-like cells, which were expected to express RBM, did not express this protein. This result enabled the identification of tubules as being IGCN. RBM is a novel marker consistently expressed in normal male germ cells but not in malignant germ cell tumors or IGCN. Thus, the absence of RBM expression in germ cells provides a new diagnostic tool of preinvasive malignancy of the testis.

Di-tert-butyl dicarbonate and 4-(dimethylamino)pyridine revisited. Their reactions with amines and alcohols

The reaction of BOC2O in the presence and absence of DMAP was examined with some amines, alcohols, diols, amino alcohols, and aminothiols. Often, unusual products were observed depending on the ratio of reagents, reaction time, polarity of solvent, pKa of alcohols, or type of amine (primary or secondary). In reactions of aliphatic alcohols with BOC2O/DMAP, we isolated for the first time carbonic-carbonic anhydride intermediates; this helps explain the formation of symmetrical carbonates in addition to the O-BOC products. In the case of secondary amines, we succeeded to isolate unstable carbamic-carbonic anhydride intermediates that in the presence of DMAP led to the final N-BOC product. The effect of N-methylimidazole in place of DMAP was also examined.

Antennal response and field attraction of the predator Elatophilus hebraicus (Hemiptera: Anthocoridae) to sex pheromones and analogues of three Matsucoccus spp. (Homoptera: Matsucoccidae).

The predator Elatophilus hebraicus is closely associated with its prey, the pine bast scale, Matsucoccus josephi, and utilizes the M. josephi sex pheromone as a kairomone. Kairomonal activity of E. hebraicus was studied by GC-EAD and field bioassays. The sex pheromone of M. josephi [2E,5R,6E,8E)-5,7-dimethyl-2,6,8-decatrien-4-one [(R)-E-M.j.] elicited a strong EAD response and attracted large numbers of the predator. The sex pheromone of two allopatric Matsucoccus spp., Matsucoccus feytaudi, (3S,7R,8E,10E)-3,7,9-trimethyl-8,10-dodecadien-6-one [(S,R)-E-M.f.] and Matcucossus matsumurae, (2E, 4E,6R,10R)-4,6,10,12-tetramethyl-2,4-tridecadien-7-one [(R,R)-E-M.m.], were also EAD-active and attracted significant numbers of E. hebraicus in the forest. Increasing the lure load of (S,R)-E-M.f. and (R,R)-E-M.m., in order to compensate for their lower volatility relative to (R)-E-M.j., resulted in similar attraction of E. hebraicus to each of the three pheromones. Other Matsucoccus pheromone stereoisomers displayed no behavioral activity. There was a significant difference in the activity of sex pheromone analogues, (6E/Z,8E)-5,7-dimethyl-6,8-decadien-4-one (52% E + 48% Z, ANLG 1) and (6E/Z,8E)-2,4,6-trimethyl- 1,6,8-nonatrien-3-one (60% E + 40% Z, ANLG 2). The (E) isomer of ANLG 1 evoked a strong EAD response from E. hebraicus and the mixture of E/Z ANLG 1 attracted the predator in moderate numbers, whereas ANLG 2 was inactive both in EAD and field tests. Conversely, M. josephi males were not attracted to M. feytaudi and M. matsumurae pheromones or pheromone analogues. Cross-activity of E. hebraicus to M. feytaudi and M. matsumurae pheromones may be based on structural similarity of the compounds. Alternatively, E. hebraicus may respond specifically to the pheromones of two allopatric Matsucoccus spp. If true, kairomonal attraction of E. hebraicus to these pheromones may have evolved during speciation of Matsucoccidae and may have been preserved despite the allopatry of M. josephi, M feytaudi and matsumurae.

Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production.

The effect of oral supplementation of L-arginine, the substrate of nitric oxide, (1.25 g/liter water) and captopril (15 mg/liter water) was studied in 5/6 nephrectomized rats for a period of three months. N-omega-nitro L-arginine, a nitric oxide synthase inhibitor, was given orally (70 mg/liter water) with or without L-arginine or captopril. The urinary excretion of nitrite (NO2) + nitrate (NO3), the known metabolites of nitric oxide, was taken as an index of nitric oxide production. Chronic renal failure rats were characterized by a low creatinine clearance, high FENa%, proteinuria, hypertension and a low urinary excretion of NO2 + NO3; 0.152 +/- 0.06 (P < 0.001) nmol/micrograms creatinine compared with 0.481 +/- 0.004 (P < 0.001) in normal rats and 0.479 +/- 0.11 (P < 0.001) in untreated sham-operated rats. Both L-arginine and captopril were effective in the normalization of all these parameters. The combination of L-arginine and captopril had no additive effects. The nitric oxide synthase inhibitor significantly diminished the captopril beneficial effect. It is concluded that chronic renal failure in rats is a low nitric oxide production state. The supplementation of L-arginine is shown to overcome this condition. It is suggested that the beneficial effect of captopril on chronic renal failure is through a specific L-arginine--nitric oxide synthase--nitric oxide pathway.

Outdoor attractancy of males ofMatsucoccus josephi (Homoptera: Matsucoccidae) andElatophilus hebraicus (Hemiptera: Anthocoridae) to synthetic female sex pheromone ofMatsucoccus josephi.

The active component of the sex pheromone ofMatsucoccus josephi is (2E,6E,8E)-5,7-dimethyl-2,6,8-decatrien-4-one; the chemical is also a powerful kairomone of adult males and females of the bugElatophilus hebraicus the principal predator ofM. josephi. The presence of theZ isomer (2E,6Z,8E)-5,7-dimethyl-2,6,8-decatrien-4-one does not interfere with the attractancy of the activeE component forM. josephi males or the bug. Our results show a clear dose-response between trap catch ofM. josephi males andE. hebraicus. Conversely, increasing amounts of theZ isomer in the mixture did not affect the attraction of the scale insect males or the bug. The catch ofM. josephi males did not differ significantly among traps of different color, and was significantly higher with traps attached to the tree trunk than those suspended between trees. Comparison of the catch ofM. josephi among the three forests and between pine species suggests that the level of infestation ofPinus halepepsis andPinus brutia ssp.brutia is similar, despite the fact that the latter pine is resistant to the scale insect. Both sexes ofE. hebraicus were trapped in much lower numbers at the more infested sites. This may be related to interference with the activity ofE. hebraicus due to deterioration and drying of parts of the tree crowns and heavy colonization by generalist predators in injured trees.

Isotype-specific regulation of human lymphocyte production of immunoglobulins by sustained exposure to vasoactive intestinal peptide.

Exposure of lymphocytes to nanomolar to micromolar concentrations of vasoactive intestinal peptide (VIP) for 1 to 3 days only modestly suppressed or enhanced the production of IgA and IgM, but not IgG. The effects of twice daily additions of 10(-12) to 10(-7) mol/L VIP for up to 18 days on pokeweed mitogen-stimulated peripheral blood mononuclear cells (PBMCs) from normal human subjects was examined by quantifying the production of IgG, IgM, and IgA. The maximum suppression of IgG by 10(-9) mol/L VIP was 79% +/- 33% (mean +/- SD) (range, 41% to 97%; p < 0.015) on day 9 and 84% +/- 1% (range, 74% to 96%; p < 0.0001) on day 14 and was significant at 6 x 10(-10) to 4 x 10(-9) mol/L VIP. Suppression of IgM production by 10(-9) mol/L VIP was significant and was observed first on day 5 and persisted through day 14. VIP did not alter IgA production or affect the proliferation or viability of PBMCs. The production of IgE by interleukin-4 stimulated PBMCs was enhanced consistently in two subjects but not in two other subjects. The duration of exposure to nanomolar concentrations of VIP is thus a critical determinant of its immunoregulatory effect, as manifested by late suppression of production of IgG and IgM and concurrent enhancement of production of IgE in some subjects.

Biologic response modifiers in primary immunodeficiency disorders.

OBJECTIVE: To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders. DATA SOURCE: Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications), and human immunomodulators (and subclassifications). STUDY SELECTION: Articles were critically reviewed and included if relevant. DATA SYNTHESIS: The primary immunodeficiency disorders are classified according to functional abnormalities, specifically, abnormalities in early cellular maturation, differentiation, regulatory cell function, enzymatic function, and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation, gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2, thymic hormones, transfer factor, and levamisole appear to affect multiple functional defects. CONCLUSIONS: Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders, and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.

Neuropeptides, mast cells and allergy: novel mechanisms and therapeutic possibilities.

Diverse neuropeptides are released by neuroendocrine and immune cells at the sites of allergic and inflammatory reactions. The neuropeptides and other neuromediators affect functions of smooth muscle, microvasculature and secretory cells, and are potent stimuli of mast cell, lymphocyte and other leucocyte contributions to such reactions. The distinctive immune sources, structures and cellular receptors for neuromediators suggest the possibility of novel pathogenetic mechanisms and levels of pharmacological intervention specific for neuroregulation of immunity and hypersensitivity.

The importance of creatine kinase determination in identifying acute myocardial infarction among patients complaining of chest pain in an emergency room.

The contribution of serum creatine kinase (CK) levels to the diagnosis of acute myocardial infarction (AMI) in an emergency room was studied in 252 patients presenting with chest pain. Thirty percent were ultimately diagnosed as having AMI. The electrocardiogram (ECG) identified 66% of patients with AMI who were evaluated within 4 h of onset of symptoms; while CK serum levels were elevated in only 9%. Among patients evaluated more than 4 h after the onset of symptoms, the ECG was helpful in diagnosing AMI in only 36.6%, while serum CK levels were high in 63.4%. CK testing added significantly to the diagnosis of AMI in patients already studied by ECG. We suggest that determination of serum CK levels in the emergency room is of value in the evaluation of patients complaining of chest pain 4 or more hours after the onset of symptoms.

Development of Hodgkin's disease in the course of liver cirrhosis and impaired monocyte function.

The monocyte function, as measured by phagocytosis and killing of Candida albicans and Candida pseudotropicalis by peripheral blood monocytes, was found impaired in a patient with cirrhosis of the liver on two separate determinations before the occurrence of bleeding from oesophageal varices. Unexpectedly, Hodgkin's disease was diagnosed in enlarged abdominal lymph nodes found on the occasion of an emergency portocaval shunt operation.

Isotype-specific human suppressor T cells for IgE synthesis activated by IgE-anti-IgE immune complexes.

The ability of human IgE-anti-IgE (mouse hybridoma anti-Fc) immune complexes (IC) to generate suppressor T cells for human myeloma IgE synthesis in vitro was tested. T cells incubated with 0.1 micrograms/ml of IC that had an IgE to anti-IgE ratio of 1:1 inhibited myeloma IgE synthesis by 16% more than the control (p less than 0.01). Inhibition was also seen with IC in which the IgE to anti-IgE ratio was higher (2:1 and 4:1), but these differences in synthesis were smaller and were not statistically significant (8 and 3%, respectively, p greater than 0.05). Thymidine incorporation by T cells incubated 3 days with 0.1 microgram/ml of IC at the 1:1 or 2:1 ratio was consistently greater (p less than 0.0025 and less than 0.0125, respectively) than by controls. The IC lost their ability to generate suppressor T cells when the cytophilic site on the IgE molecule was destroyed with heat treatment (0% inhibition with IC at 1:1 and 4% inhibition with IC at 2:1). The activation of T cells with IC showed isotype specificity because the activated T cells failed to suppress IgG and IgA synthesis by the lymphoblastoid cell lines GM-1500 and GM-1056, respectively. T cells were fractionated by incubation with IC and then were panned on plates coated with goat anti-mouse IgG. The adherent cells spontaneously suppressed IgE by 25% when compared to controls (p less than 0.005). These cells failed to suppress IgG and IgA. The activation of the T cells was not due to the panning process itself because activation did not occur with cells that adhered to plates coated with bovine serum albumin (p greater than 0.05) when compared to untreated T cell controls or the IC nonadherent population. These experiments extend previous findings that isotype-specific suppressor T cells for IgE synthesis can be generated in vitro.

Lack of cross-reactivity between aztreonam , a monobactam antibiotic, and penicillin in penicillin-allergic subjects.

Monobactam antibiotics are a new class of beta-lactam antibiotics. In contrast to penicillins or cephalosporins, monobactams possess a monocyclic beta-lactam structure. IgE or immediate hypersensitivity cross-reactivity between aztreonam (a monobactam) and penicillin was investigated, since this will be an important consideration when therapy is chosen. The maximum concentration of aztreonam reagents not giving false-positive skin tests was determined in normal subjects who were not allergic to penicillin. Subsequently, 41 subjects with IgE antibody to one or more penicillin moieties, as determined by positive skin reactions, were tested with the aztreonam reagents. Thirty-seven of these persons showed no reactivity while four showed equivocal tests. Repeat tests in those four persons were negative to the aztreonam reagents, while their penicillin tests remained unchanged. These in vivo data suggest that there is no cross-reactivity between IgE antibodies to penicillin and aztreonam and provide a basis for investigating the therapeutic use of monobactams in patients who are allergic to penicillin.