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Biomedical subjects

H Rubin

Publications and source records attributed to H Rubin.

At least 199 records · Page 11Linked to original sources
PubMed1977

Hormonal control of hyaluronic acid production in fibroblasts and its relation to nucleic acid and protein synthesis.

Whole serum and elevated pH previously had been found to stimulate both cell multiplication and hyaluronic acid production by chick embryo fibroblasts in culture. In a study to determine whether cell multiplication and hyaluronic acid production both respond to a single well-defined substance, insulin was found to stimulate, and cortisol to inhibit both processes coordinately. It appears, therefore, that multiplication and differentiated function in fibroblasts respond to a common underlying regulatory signal. Inhibition of ribosomal RNA synthesis by actinomycin D does not prevent serum stimulation of hyaluronic acid production, but inhibition of total RNA synthesis does. If total RNA synthesis is inhibited only after the hyaluronic acid production has reached a new high level, it continues at that level for the next five hours. The stimulatory treatment causes an increase in the activity of the enzyme hyaluronate synthetase. Inhibition of protein synthesis prevents any increase in hyaluronic acid production, and reduces the basal level of production. Reduction of the availability of Mg2+ in the medium coordinately inhibits DNA synthesis and hyaluronic acid production. The results are discussed in the light of a model for coordinate control growth and metabolism based on the availability of Mg2+.

Cell Division↗
PubMed1977

Coordinate control of collagen synthesis and cell growth in chick embryo fibroblasts and the effect of viral transformation on collagen synthesis.

Using collagenase digestion as an assay for collagen in partially synchronized secondary cultures of chick embryo fibroblasts, we find that the rate of collagen synthesis remains at a constant fraction of overall protein synthesis (5%) regardless of the growth rate of the cells even when the rate of protein synthesis is accelerated 5-fold by adding serum and altering the pH of the culture medium. However, in cells oncogenically transformed by Rous sarcoma virus, the relative rate of collagen synthesis was decreased by 50% 24 hours after infection and was 10% of the initial rate after 5 days. This selective decrease in rate of collagen synthesis could be reversed in cells infected with an RSV temperature-sensitive transformation-defective mutant at the non-permissive temperature, indicating that the decrease in the rate of collagen synthesis was not merely the result of viral infection but was a direct consequence of oncogenic transformation.

Animals↗
PubMed1977

Complexes of inorganic pyrophosphate, orthophosphate, and calcium as stimulants of 3T3 cell multiplication.

Addition of 0.1-0.5 mM sodium PP(i) for 17 hr to confluent cultures of BALB/c 3T3 cells in low serum concentrations stimulated the incorporation of [(3)H]thymidine into DNA to an extent equal to that produced by high serum concentration. PP(i) prevented much but not all of the cell detachment that accompanies decreasing the serum concentration of confluent cultures and it increased the saturation density of cultures in high serum concentrations. The stimulation had a sharp concentration dependence and was associated with the appearance in the medium of a flocculent precipitate. Stimulation and precipitate formation were dependent on Ca(2+) and inorganic orthophosphate (HPO(4) (2-)) and were inhibited by Mg(2+). More than half the Ca(2+) requirement could be met with Sr(2+). In the absence of PP(i), supranormal concentrations of either Ca(2+) or HPO(4) (2-) caused graded increases in [(3)H]thymidine incorporation and total cell yield. The effect of supranormal [Ca(2+)] depended on [HPO(4) (2-)] and vice versa, and the Ca(2+) requirement could be partially met by Sr(2+). The stimulation was associated with increasing turbidity of the medium. Various other complexing agents of Ca(2+), including the divalent cation ionophore A 23187, failed to produce stimulation of 3T3 cells. We conclude that water insoluble complexes of PP(i), HPO(4) (2-), and Ca(2+) or, at much higher concentrations, the latter two together, stimulate 3T3 cells and we speculate that this is brought about by the association of these complexes with the cell membrane.

Calcium↗
PubMed1977

Magnesium and calcium effects on uptake of hexoses and uridine by chick embryo fibroblasts.

Cultures of chick embryo fibroblasts were incubated for varying periods in media containing different concentrations of Ca2+ and Mg2+-Mg2+ deprivation produced a gradual decrease in the Vmax of the glucose transport system for the D-glucose analogues 3-O-[3H]methyl-D-glucose and 2-deoxy-D-[3H]glucose and a parallel decrease in the rate of production of lactate from glucose in the medium. It greatly reduced the rates of [3H]uridine uptake and incorporation by decreasing the Vmax of the uridine transport system. Addition of Mg2+ to Mg2+-deprived cultures rapidly increased the rate of [3H]uridine uptake without requiring protein synthesis and increased the rate of 2-deoxy-D-[3H]glucose uptake without requiring RNA synthesis. These effects of changes in Mg2+ concentration qualitatively reproduce the effects of such variables as cell density and serum and insulin concentrations. Ca2+ deprivation resulted in similar, though much smaller, changes in the activities of the two transport systems, but also greatly increased the "leakiness" of the cells to the nontransported hexose L-[3H]glucose.

Animals↗
PubMed1976

Observations following Corynebacterium parvum administration to patients with advanced malignancy. a phase I study.

There has been increasing interest regarding the use of Corynebacterium parvum (CP) with other modalities in the management of primary cancer. Due to the paucity of specific information available relative to CP toxicity, a Phase I study was carried out in patients with advanced disease. The purpose of the investigation was not to evaluate the effect of CP on tumor growth. from 273 injections of CP in 40 patients it was observed that following intravenous (i.v.) infusion of CP: a) a febrile response and chills of considerable severity occured in almost all patients and did not appreciably diminish in intensity following repetitive administrations; b) nausea, vomiting, headache, and confusion were not infrequent; c) a "flu-like" syndrome lasting 24 to 48 hours occurred following almost all courses of CP; d) blood pressure elevations occurred on occasion and were related to the severity of other-side-effects; hyper- or hypo- tension was not a problem; e) ther were no anaphalactic reactions. Pretreatment with a single administration of 100 mg of hydrocortisone prior to CP infusion markedly and in some instances dramatically diminished the toxicity and made acceptable the use of i.v. CP on an outpatient basis. The use of i.v. CP in patients with cerebral metasteses may be hazardous. Subcutaneously administered CP resulted in a significant number of undesirable local reactions. Evaluation of delayed cutaneous hypersensitivity response, immunoglobulins, complement, and E- and EAC-rosette-forming cells during CP administration failed to demonstrate significant change from injection values. Results were similar whether hydrocortisone pretreatment was or was not employed. From the standpoint of toxicity it now seems appropriate to use i.v. CP, particularly following pretreatment with hydrocortisone, in a controlled clinical trial to evaluate its therapeutic effectiveness in the management of primary cancer.

Acute Kidney Injury↗
PubMed1976

Magnesium deprivation reproduces the coordinate effects of serum removal or cortisol addition on transport and metabolism in chick embryo fibroblasts.

A variety of unrelated effectors stimulate or inhibit coordinately the same array of metabolic reactions in chick embryo fibroblasts, including the uptake of 2-deoxy-D-glucose and uridine, and the incorporation of uridine and thymidine into acid insoluble material. The coordinate inhibition of these reactions by omission of serum or addition of cortisol is reproduced quantitatively by lowering the concentration of magnesium (Mg2+) in medium containing 0.2 mM Ca2+. The response times for the utilization of uridine and thymidine following the removal of addition of Mg2+ are similar to those which follow removal or addition of serum. The effect of serum on the incorporation of choline, which is not part of the coordinate response to unrelated effectors, is not reproduced by varying Mg2+ concentrations. The results support the hypothesis that the availability of Mg2+ within the cell plays a central role in the coordinate control of transport, metabolism and growth by external physiological effectors.

Animals↗
PubMed1976

Mutual potentiation by magnesium and calcium of growth in animal cells.

The effects on DNA synthesis of various combinations of Mg2+ and Ca2+ in cultures of chick embryo cells have been studied. When [Mg2+] larger than or equal to 0.24 mM, reduction of Ca2+ from the standard concentration of 1.72 mM to 0.01 mM had no effect on the incorporation of [3H]thymidine ([3H]dThd) into DNA over a 16-hr period. When Mg2+ was reduced to 0.04 mM, [3H]dThd incorporation into DNA decreased directly with [Ca2+] below 1.72 mM and increased slightly up to [Ca2+] = 5.02 mM, where cell damage began to occur. The change in [Ca2+] necessary to maintain a half-maximal rate of [3H]dThd incorporation was found to depend inversely on the fourth power of the change in [Mg2+]. Chelation of Ca2+ with approximately equimolar ethylene glycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) in the presence of [Mg2+] larger than or equal to 0.24 mM reduced [3H]dThd incorporation about 10-fold, and large excesses of EGTA did not further reduce it. The amount of EGTA required to produce a detectable inhibition of [3H]dThd incorporation was independent of [Mg2+] larger than or equal to 0.24 mM, as was the level of residual incorporation in excess EGTA. When [Mg2+] was reduced to 0.04 mM, however, [3H]dThd incorporation declined even when [EGTA] less than [Ca2+], and vanished when EGTA was in large excess. The results are discussed within the framework of a model for the regulation of cell metabolism and growth in which the availability of free Mg2+ is the central coordinating factor. The metabolic effects of Mg2+ depend on its distribution between elements such as ATP and binding sites on membranes. We propose that the major metabolic effects of varying [Ca2+] are produced indirectly through its competition with Mg2+ for membrane sites, thereby making more or less Mg2+ available for rate-limiting transphosphorylation reactions.

Calcium↗
PubMed1976

Subcellular localization of glyoxylate cycle enzymes in Ascaris suum larvae.

Evidence is presented on the particulate nature of glyoxylate cycle enzymes in metazoa with the use of 15-day old larvae of the nematode Ascaris suum. Homogenization procedures were developed to disrupt the resistant nematode cuticle. Malate synthase and isocitrate lyase, key enzymes of the glyoxylate cycle, consistently sedimented with mitochondrial enzymes in differential pellets while catalase, a major peroxisomal enzyme, was always soluble. Isopycnic sucrose gradient centrifugation of the differential pellet yielded two protein peaks: one at 1.18 g/cm3 (characteristic for mitochondria), and another at 1.23 g/cm3 (common for glyoxysomes and peroxisomes). Electron microscopy of these fractions revealed that the lighter peak consisted primarily of mitochondria, while the heavier band contained proteinaceous bodies termed "dense granules" morphologically resembling microbodies. SIgnificantly, both malate synthase and isocitrate lyase cosedimented with the mitochondrial marker enzymes in the lighter peak (1.18 g/cm3) and not with the dense granules. Further purification of mitochondria, accomplished by separating dense granules with a step gradient before isopycnic centrifugation, substantiated the evidence that microbodies (glyoxysomes) do not occur in these nematode larvae. Rough-surfaced membranes were alternatively considered as the subcellular site, but the evidence tends to favor localization of the glyoxylate bypass enzymes in the mitochondria.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. II. Effect of cortisone acetate.

Studies from this laboratory have demonstrated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. A study of the effect of two different doses of cortisone acetate (CA), administered two or five times weekly, on the tumor inhibitory properties of this chemoimmunotherapeutic regimen indicated that the addition of a corticosteroid to the CY-CP combination did not alter its tumor-inhibitory properties. There was no significant change when CA was administered with CP; however, tumor inhibition was enhanced to a degree approaching statistical significance when CA was added to CY at dose levels of 1.5 and 2.5 mg twice weekly. These results demonstrated that it may be possible in treatment of humans to administer a steroid in combination with a chemoimmunotherapeutic regimen without inhibition of the regimen's antitumor effects.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. III. Effect of C. parvum on cyclophosphamide metabolism.

Results of investigations employing [14C]cyclophosphamide (CY) demonstrated that even though total plasma radioactivity was similar in female C3HeB/FeJ mice treated either with CY alone or Corynebacterium parvum and CY, the proportion of total activity due to nonmetabolized CY was greater when C. parvum was used. These findings indicated that the antitumor effect of C. parvum may not have been entirely due to its immunopotentiating properties but may also have been related to its effect on the metabolism of CY.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by corynebacterium parvum with cyclophosphamide.

The cytotoxic macrophage was further characterized as an important effector cell in the inhibition of tumor growth. When we administered rifampin (a semisynthetic antibiotic that interferes with macrophage function but not viability) with Corynebacterium parvum and/or cyclophosphamide to tumor-bearing C3HeB/FeJ female mice, the tumor growth-inhibitory effects of the C. parvum were reduced. Moreover, when bone marrow cells from those animals were cultured, we found a marked decrease in the cytotoxicity of macrophages comprising clonies arising from colony-forming cells (CFC) in the bone marrow. Such findings supported our contentions that 1) the cytotoxic property of macrophages originates in ancestral stem cells or CFC in bone marrow, and 2) receptor sites of the CFC (or stem cells) that respond to a stimulus for self-replication probably differ from sites that when activated produce progeny with cytotoxic properties. Although the administration of rifampin resulted in macrophages virtually devoid of cytotoxic properties, both relative and absolute numbers of CFC increased.

Animals↗