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S Cohen

Publications and source records attributed to S Cohen.

At least 721 records · Page 40Linked to original sources
PubMed1985

In vitro migration of tumor cells from human neoplasms: inhibition by lymphokines.

We have previously described a noncytotoxic lymphokine, TMIF, with the capacity of inhibiting the in vitro migration of a variety of serially passaged experimental animal tumors, but not non-neoplastic cells. In the present study, we describe conditions for the assay of human tumor cell movement utilizing agarose microdroplets. Using this procedure, we were able to demonstrate that TMIF is as effective in inhibiting the in vitro migration of suspensions of tumor cells obtained from spontaneous human neoplasms, as it is in inhibiting model tumor systems. This finding demonstrates that responsiveness to TMIF is not merely a property conferred on tumor cells by prior serial passage. Also, by demonstrating that tumors of human origin are responsive, the present study raises the possibility that studies of TMIF in neoplastic disease may provide information of prognostic value. Also, they provide the hope that if TMIF proves therapeutically effective in animal models, those results may be translated to human disease.

Cell Migration Inhibition↗
PubMed1985

The tumor disappearance reaction: an in vivo effect of a noncytotoxic lymphokine active against tumor cells.

A lymphokine, tumor migration inhibition factor (TMIF), that can inhibit the migration of tumor cells in vitro without cytotoxic effect has been described. TMIF can be produced in vitro or in vivo. In the present study, it is demonstrated that administration of TMIF can lead to a transient decrease in recoverable tumor cells from the peritoneal cavities of otherwise untreated mice. This result, which appears to be due to a direct effect of the mediator, rather than a consequence of inflammatory cell accumulation, is analogous to the effect of macrophage migration inhibition factor (MIF) on macrophages in the well known macrophage disappearance reaction. These findings demonstrate that TMIF can exert an effect in vivo predicted from its in vitro properties, and raise the possibility that this effect can be exploited in an appropriate therapeutic model.

Animals↗
PubMed1985

Spectral and chemical evidence for the formation of zinc-porphyrin in aged, initially metal-free, porphyrin-IX solutions.

The appearance of new additional bands, at 580 and 630 nm, in the fluorescence spectra of porphyrins, upon the aging of their aqueous solutions, was investigated for four porphyrin systems: The deutero, the hemato, the hemato-derivative, and the proto. The conditions for quantitative conversion to the new spectra were sought. To that end the concentration levels investigated were adjusted to have each porphyrin system in a monomer-dominant state. The species fluorescing at 580 nm was denoted f580 and its rate of appearance was found to fit first-order kinetics, for each porphyrin, the range of the rate constants being 0.03-0.10 hr-1. Two key issues were probed: (a) The identity of f580, the effort directed towards zincporphyrin. (b) Its origins--a contaminant unmasked, or a species newly formed, during the aging. Testing f580 for zincporphyrin properties, spectral at neutral pH, acid/base de/remetalation, EDTA competition, and chromatography gave in each case positive results, allowing the identification of f580 as zincporphyrin. On the basis of the data obtained and the known sources for the contamination of aqueous solutions by zinc, the case is made for zinc porphyrin formation upon aging. The relevance of the phenomena to the therapeutic activities of porphyrins is discussed.

Chromatography, Thin Layer↗
PubMed1985

The regulation of DNA synthesis in quiescent lymphocytes by cytoplasmic inhibitors.

We previously have shown that proliferating lymphoid cells contain an extractable cytoplasmic protein that is capable of inducing DNA synthesis in isolated quiescent nuclei (activator of DNA replication, ADR). ADR is present in continuously proliferating (transformed) lymphoblastoid cell lines and in mitogen- or interleukin 2-stimulated human peripheral blood leukocytes (PBL) but is not detectable in extracts from resting (unstimulated) PBL. In the present study, we investigated the possibility that quiescent PBL may contain a factor than can inhibit ADR activity. We found that unstimulated human PBL contain a heat-stable protein greater than or equal to 50,000 Da that is capable of suppressing the induction of DNA synthesis in isolated nuclei by ADR derived from both normal and neoplastic sources. The inhibitor was not detectable in freshly isolated PBL but appeared within the cells after a brief (2-6 hr) culture period. Depletion experiments revealed that the inhibitor was neither derived from nor dependent upon the macrophage component of the PBL cultures. These results suggest that one mechanism by which resting lymphocytes may maintain quiescence may involve the suppression of cytoplasmic mitogenic signals by intracellular inhibitors. In addition, the implications of our findings provide a possible explanation for the loss of growth control in abnormal proliferative states, such as neoplasia.

Cell Cycle↗
PubMed1985

Characterization of the activation of Na+/H+ exchange in lymphocytes by phorbol esters: change in cytoplasmic pH dependence of the antiport.

Phorbol 12-myristate 13-acetate and other phorbol esters induce an intracellular alkalinization in rat thymic lymphocytes. An extracellular acidification can be recorded concomitantly. This transmembrane H+ (equivalent) flux is dependent on external Na+ and is amiloride sensitive. Phorbol esters also stimulate an amiloride-sensitive uptake of 22Na+, suggesting activation of Na+o/H+i exchange. Only those phorbol derivatives that are tumor promoters and activators of protein kinase C stimulate the antiport. Activation of the Na+/H+ exchange is brought about by a change in the cytoplasmic pH sensitivity of the antiport. Activation of the Na+/H+ exchanger by phorbol esters results in membrane hyperpolarization, due to indirect stimulation of the electrogenic Na+/K+ pump by the increased intracellular Na+ concentration. Increased Na+/H+ exchange also produces cell swelling, which may be one of the earliest manifestations of the growth-promoting properties of the phorbol esters.

Amiloride↗
PubMed1985

Osmotic and phorbol ester-induced activation of Na+/H+ exchange: possible role of protein phosphorylation in lymphocyte volume regulation.

The Na+/H+ antiport is stimulated by 12-O-tetradecanoylphorbol-13, acetate (TPA) and other phorbol esters in rat thymic lymphocytes. Mediation by protein kinase C is suggested by three findings: (a) 1-oleoyl-2-acetylglycerol also activated the antiport; (b) trifluoperazine, an inhibitor of protein kinase C, blocked the stimulation of Na+/H+ exchange; and (c) activation of countertransport was accompanied by increased phosphorylation of specific membrane proteins. The Na+/H+ antiport is also activated by osmotic cell shrinking. The time course, extent, and reversibility of the osmotically induced and phorbol ester-induced responses are similar. Moreover, the responses are not additive and they are equally susceptible to inhibition by trifluoperazine, N-ethylmaleimide, and ATP depletion. The extensive analogies between the TPA and osmotically induced effects suggested a common underlying mechanism, possibly activation of a protein kinase. It is conceivable that osmotic shrinkage initiates the following sequence of events: stimulation of protein kinase(s) followed by activation of the Na+/H+ antiport, resulting in cytoplasmic alkalinization. The Na+ taken up through the antiport, together with the HCO3- and Cl- accumulated in the cells as a result of the cytoplasmic alkalinization, would be followed by osmotically obliged water. This series of events could underlie the phenomenon of regulatory volume increase.

Adenosine Triphosphate↗
PubMed1985

Mechanism of osmotic activation of Na+/H+ exchange in rat thymic lymphocytes.

The activity of the Na+/H+ exchange system of rat thymic lymphocytes was determined by means of intracellular (pHi) and extracellular pH (pH0) measurements. In isotonic media, the antiport is virtually quiescent at physiological pHi (7.0-7.1), but is greatly activated by cytoplasmic acidification. At normal pHi, the antiport can also be activated by osmotic shrinking. Osmotic activation occurs after a delay of 20-30 s and is reversed several minutes after iso-osmolarity is restored. The mechanism of activation was analyzed by comparing the kinetic parameters of transport in resting (isotonic) and hyperosmotically stressed cells. The affinities of the external substrate site for Na+ and H+ are not altered in shrunken cells. In contrast, the Hi+ sensitivity of the antiport (which is largely dictated by an allosteric modifier site) was increased, which accounted for the activation. The concentration of free cytoplasmic Ca2+ [( Ca2+]i) increased after osmotic shrinking. This increase was dependent on the presence of extracellular Ca2+ and Na+ and was blocked by inhibitors of Na+/H+ exchange, which suggests that it is a consequence, rather than the cause, of the activation of the antiport. It is concluded that the shift in the pHi dependence of the modifier site of the Na+/H+ antiport is the primary event underlying the regulatory volume increase that follows osmotic shrinkage.

Amiloride↗
PubMed1985

Enthalpy-entropy relationship in drug-cholinoceptor interaction: a new approach.

The partial molal volume at infinite dilution, V2, was determined in toluene, benzene and acetonitrile for fifteen different drug molecules comprising muscarinic agonists, partial agonists and antagonists. The difference in V2 between a given drug, X, and hyoscine, expressed as (V2x - V2h) was then multiplied by the internal pressure of the holding phase (Pi approximately cohesive energy density) in order to obtain an estimate of the excess enthalpy (delta H) over hyoscine in the interaction of drug molecule X with a common cholinoceptor. As a working hypothesis, delta H for hyoscine is taken as zero, hyoscine having the lowest V2/affinity ratio of any drug in the series investigated. The corresponding change in entropy (delta S) was then calculated from the relationship: RT ln Kx = Pi(V2x - V2h) - T delta S, where Kx is the affinity constant of drug molecule X to the common cholinoceptor, obtained independently. Linear regression of Pi (V2x - V2h) congruent to delta H from the data in acetonitrile over delta S gave a satisfactory isoequilibrium plot, r2 = 0.954, slope (beta) = 231 degrees K. The present approach offers a new course for the study of the enthalpy-entropy relationship in the interaction of drug molecules in a given series with a common receptor. It could provide an alternative to the Van't Hoff procedure for the estimation of relative delta H, and is independent of the free energy of binding (delta G).

Acetonitriles↗
PubMed1985

Opiate nerves mediate feline pyloric response to intraduodenal amino acids.

Intraluminal pressures and myoelectric activity were recorded from the feline antrum, pylorus, and duodenum in response to intraduodenal amino acid solutions. Mixed amino acids (0.02 mg/ml, 3.0 ml) increased the amplitude of pyloric contractions (59.7 +/- 7.9 mmHg) and pyloric spike activity (73.7 +/- 6.8% of slow waves with spike activity) compared with a saline control (P less than 0.001). The selectivity of these responses was determined with specific amino acids. L-Tryptophan (10 or 40 mM) produced a response similar to the mixed amino acid response, while L-phenylalanine or L-glycine (10 or 40 mM) had no effect. Intra-arterial tetrodotoxin, intraluminal ethyl aminobenzoate, or intravenous naloxone (1.0 mg/kg) abolished the pyloric responses to amino acids (P less than 0.02). Bilateral cervical vagotomy had no effect. Cholecystokinin octapeptide (CCK-OP) produced dose-dependent increases in the amplitude of pyloric contractions and in pyloric spike activity. The ED50 dose of CCK-OP (1.0 microgram/kg iv) gave an increase in pyloric pressure of 155.6 +/- 49.9 mmHg and in spike activity of 77.7 +/- 9.4%, similar to mixed amino acids or tryptophan. These effects of CCK-OP were not antagonized, however, by a dose of naloxone (1.0 mg/kg) that blocked the maximal pyloric response to leucine-enkephalin. We concluded intraduodenal mixed amino acids or tryptophan increase phasic, spike-dependent pyloric contractions in the cat via nonvagal, naloxone-sensitive neural pathways, phenylalanine, a structurally similar essential amino acid, had no effect on the feline gastroduodenal junction, and the pyloric responses to exogenous CCK-OP are mediated by pathways distinct from the responses to tryptophan or mixed amino acids.

Amino Acids↗
PubMed1985

Simultaneous reflex inhibition of lower esophageal sphincter and crural diaphragm in cats.

We have previously suggested that both the lower esophageal sphincter and diaphragm contribute to the high-pressure zone (HPZ) at the gastroesophageal junction. The purpose of this study in anesthetized cats was to compare changes in diaphragmatic electrical activity with changes in the intraluminal pressure profile in the HPZ following either balloon distension of the esophagus or swallowing evoked by pharyngeal stimulation. Intraluminal pressure was continuously recorded by a perfused manometric assembly anchored to the gastric fundus through an abdominal surgical approach. Integrated EMG was simultaneously measured in the costal and crural parts of the diaphragm. Our results indicate that simultaneous relaxation of the lower esophageal sphincter (LES) and crural diaphragm follows both swallowing and balloon distension of the esophagus; during swallowing both inhibitory reflexes depend on the initiation of esophageal peristalsis; crural relaxation abolishes respiratory-induced pressure oscillations in the HPZ during LES relaxation; ventilation is maintained during relaxation of the HPZ in part by continued contraction of the costal diaphragm; and different neural pathways control LES relaxation and crural relaxation. The data support the view that the crural diaphragm augments the intrinsic smooth muscle sphincter mechanism at the gastroesophageal junction and that crural relaxation may be an important factor in mouth-to-gastric transit.

Animals↗
PubMed1985

Mechanisms for the association of gastroesophageal reflux and bronchospasm.

The mechanism for the association between gastroesophageal reflux and bronchospasm is probably multifactorial. Our data support the view that microaspiration into the trachea may be an important mechanism for bronchospasm induced by gastroesophageal reflux and needs to be distinguished from simple reflux into the esophagus. Intraesophageal acidification alone quantitatively produces a much smaller airway response than does intratracheal acidification. A challenge test should be developed to correlate airway response following intraesophageal acidification to airway hyperactivity. We believe that the relationship of the diaphragm to the antireflux barrier deserves further study.

Animals↗
PubMed1985

Stability and distinctness of borderline personality disorder.

In a 3-year follow-up study the authors examined the diagnostic stability of borderline personality disorder over time, its relation to affective disorder, and the severity of functional impairment. The data support the usefulness of borderline personality disorder as a diagnostic construct.

Adolescent↗