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J Cohen

Publications and source records attributed to J Cohen.

At least 1,027 records · Page 57Linked to original sources
PubMed1990

Further characterization of monoclonal antibodies to lipopolysaccharide of Salmonella Minnesota strain R595.

We have shown here that despite the use of monoclonal antibodies with well-defined epitope-specificities, and despite testing them in the most simple animal model available (i.e., mixing of homologous LPS with Mab prior to injection), we are not yet able to explain why some of the antibodies were effective and others not. For some of the clones (e.g., clone 20), an even better definition of binding sites is currently taking place in an attempt to obtain this understanding. We also do not yet understand why clone 20 was not effective in the mucin model, while using much lower amounts of injected antibody, and much higher challenge doses, this Mab was effective against E. coli in the gentamicin-treated mouse model. Very clear is, however, that in order to be protective in the latter model, Mabs are not required to be specific for lipid A. In the future it will be essential to develop procedures which measure specific interaction between smooth LPS/bacteria and antibodies to the LPS core region. In addition, it will be of great help when the chemical structure of non-substituted, rough-form LPS, as occurring in smooth LPS preparations, would be defined. This applies also to O-substituted core molecules.

Animals↗
PubMed1990

Recognition of paternal pronuclei in human zygotes.

The possibility of pronuclear gender determination using morphological criteria only was investigated in 140 two-pronucleate and 39 tripronucleate zygotes. Zygotes were videotaped on different focal points and the positions of the polar bodies, pronuclear diameters, number and distribution of nucleoli, and presence of sperm tail remnants were indicated on diagrams. The three known criteria used for recognition of the paternal pronucleus in rodent zygotes were investigated. These criteria are (a) the presence of sperm tail remnants, (b) an increased pronuclear diameter, and (c) the farthest distance from the second polar body. Sperm tail remnants were observed in only 3/342 (1%) of the pronuclei. Pronuclear diameters and positions of the largest pronuclei did not reveal any trends. Pronuclei of tripronucleate zygotes were frequently smaller than those of two-pronucleate ones. The parental origin of human pronuclei cannot be determined morphologically using standard light optics. Microsurgical removal of paternal pronuclei from polyspermic zygotes should therefore be implemented with caution.

Cell Nucleus↗
PubMed1990

Nuclear binding of the estrogen receptor: a potential predictor for hormone response in metastatic breast cancer.

We have previously described an in vitro immunohistochemical test employing anti-receptor antibodies, for demonstrating the nuclear binding characteristics of estrogen receptors (ER) in breast carcinomas. Based on a retrospective analysis of twenty-five patients with estrogen receptor-positive (ER+) breast cancer who were treated with hormone therapy and whose clinical responses were evaluable, we were able to demonstrate that this test may be valuable to predict which, among the ER+ tumors (whether or not they are progesterone receptor positive, PR+), are likely to respond to hormone therapy and which may fail. While tumors in which ER exhibited abnormalities in nuclear binding behavior (ligand-independent nuclear binding or no nuclear binding) failed hormone therapy (16 out of 19 patients), those in which nuclear binding of ER appeared normal (ligand-dependent) in the in vitro test, responded to hormone therapy (5/6 patients). While our previous report dealt with the procedural details, specificity of the reagents, and the design of the study, this report addresses the clinical aspects of this study and response correlation.

Biomarkers, Tumor↗
PubMed1990

Inhibition of psoriatic cell proliferation in in vitro skin models by amiprilose hydrochloride.

Amiprilose hydrochloride, a 3-substituted glucose derivative, was found to inhibit the proliferation of human fibroblasts and keratinocytes originating from psoriatic lesions. Fibroblasts and keratinocytes were obtained from skin biopsies of normal donors, and from the biopsies of active/involved and uninvolved sites of psoriatic donors. The cells were cultured as monolayers or as components of tissue equivalent models. Keratinocytes and fibroblasts originating from biopsies of psoriatically involved areas were shown to proliferate at a significantly higher rate than those derived from uninvolved areas. The antiproliferative effect of amiprilose hydrochloride was not observed with normal keratinocytes or fibroblasts from the skin of healthy donors or from uninvolved areas of psoriatic donors. Amiprilose hydrochloride was not cytotoxic to any of these cells at levels below 0.1%. The combination of the low cytotoxicity and the selective antiproliferative effect indicates that this compound may be a useful antipsoriatic agent. The use of monolayer cultures and tissue equivalent models in this study illustrates the utility of such a progressive strategy in the evaluation of potential topical pharmaceuticals.

Cell Division↗
PubMed1990

Sequence analysis of the gene (6) encoding the major capsid protein (VP6) of group C rotavirus: higher than expected homology to the corresponding protein from group A virus.

Two overlapping c-DNA clones, which hybridized in Northern blots to RNA segment 6 of the prototype strain (Cowden) of group C rotavirus, were selected from a c-DNA library in pBR322 and sequenced. The gene 6 sequence obtained was 1349 nucleotides and contained a single long open reading frame encoding a protein of 394 amino acids (total MW, 44,479) which is in line with the size of the major capsid protein VP6. Comparison of the group C sequence with that of the corresponding group A rotavirus gene revealed homology levels of 55 and 42% for nucleotides and amino acids, respectively. These values were surprisingly high in view of previous immunological and nucleic acid hybridization data which failed to show any cross-reaction between group A and non-group A rotaviruses. The epidemiological implications of these observations are discussed.

Amino Acid Sequence↗
PubMed1990

A recombinant vaccinia virus expressing the major capsid protein of Simian rotavirus-induced anti-rotavirus antibodies.

cDNA molecules encoding the major structural protein (VP6) of the Simian rotavirus SA11 were inserted under the control of the vaccinia virus 7.5 kDa promoter into the thymidine kinase gene. Synthesis of VP6 was demonstrated by immunoprecipitation of recombinant virus-infected cell. Mice inoculated via several routes with this recombinant vaccinia produce high titers of antirotavirus antibodies lacking neutralizing activity.

Animals↗
PubMed1990

The challenge of illicit drug addiction for general practice.

Eighty-five drug misusers sought help and treatment from our central London practice in the 12 months between 1st November 1987 and 31st October 1988. They were all accepted for a short course of oral methadone reduction. At the end of the 12 months, according to the best information available from records, family, friends, neighbors, support agencies and patient reports, 19 (22%) were off all illicit drugs and 9 (16%) of those who had been unemployed at presentation had obtained regular employment. On average, our opiate misusers consumed 0.5 g of heroin daily at a daily street cost of approximately 40 pounds or 14,600 pounds annually. Sixty per cent of them admitted to financing their drug habit through criminal activities. Against the huge social cost of illicit drug misuse, the cost of providing primary health care to all these 85 addicts was 8% of each two doctors' consulting time at an annual cost of 2171 pounds per GP (25 pounds per hour of GP time). Thus for the methadone reduction programme for these 85 addicts to be judged effective based on cost alone, one would require a drug abstention ("success") rate of 0.003%.

Adult↗
PubMed1990

Dissociation between Limulus neutralisation and in vivo protection in monoclonal antibodies directed against endotoxin core structures.

Studies with rough mutants of certain Gram-negative bacteria have indicated that monoclonal antibodies (mAbs) to endotoxin core can protect animals and man from endotoxic shock. We assessed the ability of such antibodies to neutralise endotoxin in the Limulus amoebocyte lysate (LAL) assay, and compared this to their protective effect in a murine model of endotoxic shock. We evaluated 11 mAbs raised against Salmonella minnesota R595. Endotoxin neutralisation in the LAL assay, expressed as 50% inhibition titres, ranged between 1/32 and 1/414. However, there was no apparent relationship between the titre required to produce 50% inhibition of LAL and its ability to protect mice from endotoxic shock. We conclude that LAL neutralisation appears unrelated to biological activity; in this system, LAL inhibition by mAb ascites cannot be used to predict protection in vivo.

Animals↗
PubMed1990

Neurite outgrowth in response to transfected N-CAM changes during development and is modulated by polysialic acid.

We have used monolayers of control 3T3 cells and 3T3 cells transfected with a cDNA encoding human N-CAM as a culture substrate for embryonic chick retinal ganglion cells (RGCs). At embryonic day 6 (E6), but not at E11, RGCs extended longer neurites on monolayers of N-CAM-transfected cells. This loss of RGC responsiveness was not associated with substantial changes in the level of N-CAM expression on RGC growth cones. The neurite outgrowth response from E6 RGCs could be inhibited by removal of N-CAM from the monolayer, by removal of alpha 2-8-linked polysialic acid from neuronal N-CAM, or by antibodies that bind exclusively to chick (neuronal) N-CAM. In contrast, the response was not dependent on neuronal beta 1 integrin function. These data provide substantive evidence for a homophilic binding mechanism directly mediating N-CAM-dependent neurite outgrowth, and suggest that changes in polysialic acid expression on neuronal N-CAM may modulate N-CAM-dependent axonal growth during development.

Animals↗
PubMed1990

Optimal collection of blood samples for the measurement of tumor necrosis factor alpha.

We have examined how delayed separation of plasma from cells affects the recovery of recombinant human tumor necrosis factor alpha (rhTNF alpha) from whole blood. Storage of heparinized whole blood samples at room temperature for 1 hr results in a significant (p = 0.036) fall in recovery of plasma TNF alpha from 788 +/- 119 pg/mL to 472 +/- 77 pg/mL, measured by specific enzyme-linked immunosorbent assay (ELISA). Storage of whole blood samples at 4 degrees C for 1 hr reduces but does not prevent the fall in recovery of plasma TNF alpha: 725 +/- 82 pg/mL at time 0, 472 +/- 81 pg/mL after 1 hr, p = 0.038. Recovery of bioactive TNF alpha (cytotoxocity for L929 cells) after 1 hr at room temperature is also significantly reduced from 576 +/- 139 pg/mL to 450 +/- 154 pg/mL, p = 0.036. Studies with 125I-rhTNF alpha confirmed the fall in plasma activity and revealed a rapid commensurate increase in 125I-rhTNF alpha activity in the cell fractions. We recommend that clinical samples for the measurement of cytokines should be kept at 4 degrees C and separated rapidly (within half an hour) before storing the plasma at -70 degrees C.

Animals↗
PubMed1990

Cocaine-related maternal death.

Hemodynamic overload, cardiac ischemia, and arrhythmia are postulated to originate from "sex-cocaine" syndrome resulting in maternal and fetal death. High concentrations of cocaine and metabolites in maternal blood, urine, and nasal secretions confirmed recent ingestion. Changes in the maternal life-style may have contributed to the poor pregnancy outcome.

Adult↗
PubMed1990

Immunosuppression supports implantation of zona pellucida dissected human embryos.

The effect of low dose immunosuppression with methylprednisolone during the first 4 days after oocyte retrieval on potential immune cell invasion of partially zona dissected embryos in utero was investigated in alternate in vitro fertilization patients (n = 32). The incidence of pregnancy was significantly higher in patients receiving methylprednisolone (7 of 18, 39%) than in control patients (1 of 14, 7%). Twenty-eight percent (11 of 39) of the embryos replaced in the corticosteroid treated patients implanted, whereas only 7% (2 of 31) of embryos in control patients had a fetal heart beat. There were no side effects reported in any of the patients receiving corticosteroids. It can be concluded that methylprednisolone supports implantation of embryos with small holes in their zonae. However, the actual mechanisms of corticosteroid support on the interaction between immune cells and micromanipulated embryos are not well understood.

Clinical Trials as Topic↗
PubMed1990

Renin inhibitors based on dipeptide analogues. Incorporation of the hydroxyethylene isostere at the P2/P3 sites.

The synthesis of a series of renin inhibitors in which the P2 and P3 amino acids are replaced with the hydroxyethylene dipeptide isostere is reported. In vitro evaluation of the inhibitors has revealed that this isostere is an acceptable amide-bond replacement in which activity is maintained and stability is enhanced. Structure-activity relationships of this series resemble but do not parallel those of the corresponding dipeptide-containing inhibitors.

Chemical Phenomena↗
PubMed1990

New inhibitors of renin that contain novel phosphostatine Leu-Val replacements.

A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11 substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9 portion of the native substructure and employ novel phosphostatine Leu10-Val11 replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu10 side chain revealed that the LVR derived from L-cyclohexylalanine provided a 130-fold boost in potency over the LVR derived from L-leucine. The dialkyl ester moiety was varied and a loss in potency was incurred when the alkyl ester was chain extended or alpha-branched; dimethyl esters provided optimum potency. The phosphonate moiety was replaced by a half-acid half-ester phosphonate and dimethylphosphinate; both replacements lead to a loss in potency. The more potent inhibitors (IC50 = 20-50 nM) were found to be selective inhibitors for renin over porcine pepsin and bovine cathepsin D (little or no inhibition was observed at 10(-5) M).

Amino Acids↗
PubMed1990

Potent, low molecular weight renin inhibitors containing a C-terminal heterocycle: hydrogen bonding at the active site.

A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl. Molecular modeling suggests that the heterocyclic oxygen hydrogen bonds as an acceptor to the flap region of renin and that the second hydroxyl in the glycol-based inhibitors behaves similarly.

Carbamates↗
PubMed1990

Water-soluble renin inhibitors: design of a subnanomolar inhibitor with a prolonged duration of action.

Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimolar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability.

Animals↗