THE TREATMENT OF METASTATIC BREAST CANCER IN BONE

The author report clinical experience with 212 cases of mammary cancer metastatic to bone, in 186 of which radiotherapy was given, and in 26 steroid hormone therapy.At least 70 per cent of patients with bone metastasis from breast cancer were relieved of pain by adequate roentgen therapy, the relief lasting for most of the survival time in many instances.About 25 per cent of patients had recalcification or reossification of bony lesions with roentgen therapy; while dramatic, this is not always an indication that relief of pain will continue or that survival time will be lengthened.If and when adequate radiotherapy has not been effective or cannot be administered (for example, in a patient with extremely widespread metastasis, or one residing at a considerable distance from radiotherapeutic service) steroid hormone therapy in adequate dosage is frequently beneficial. From 40 per cent to 75 per cent of patients with bone metastases from breast cancer are relieved of pain by steroid hormone therapy. In about 15 per cent of cases recalcification of the lesion occurs.Effective roentgen therapy may usually be given in a relatively brief period of time (one to two weeks). Effective steroid hormone therapy usually requires from 12 to 24 weeks.Complications of steroid hormone therapy are numerous. Some patients are made considerably worse by such therapy. These complications may only be controlled by reduction or discontinuation of the hormones. For this reason, it is recommended that irradiation always be used as the initial method of palliation.     

Preparation,purification, and properties of E. coli virus T2

1. A method for the preparation of 8 to 10 liter quantities of T₂ virus lysates, titering 2 to 5 x 10¹¹ infectious units per ml. has been described. 2. Procedures have been developed for the concentration and purification of virus to a high specific infectivity. No fractionation procedure of the several used succeeded in further raising the specific infectivity of these purified preparations. 3. Some of the general properties of the better preparations have been determined. They exhibited titers of 2 x 10¹⁵ infective units per gm. of material or 1.2 x 10¹⁶ per gm. of nitrogen. 4. A study of the distribution of nitrogen among the various fractions of the virus showed that about 6 per cent of the total nitrogen is soluble in 4 per cent trichloracetic acid; that the protein nitrogen is about 40 per cent of the total and the nucleic acid nitrogen is 53 per cent. At least 96 per cent of the total phosphorus is in the nucleic acid fraction. Less than 0.5 per cent quantities of lipid and PNA were found.     

ON THE CHEMICAL COMPOSITION OF THE AXOPLASM OF SQUID GIANT NERVE FIBERS WITH PARTICULAR REFERENCE TO ITS ION PATTERN

Investigations dealing with the determination of the major chemical constituents of the axoplasm of the giant nerve fiber of the squid are described. Particular emphasis has been placed on determining the components involved in acid-base balance. It was found that 72 per cent of the total solids of axoplasm, representing 13.5 per cent of the wet material, are of relatively low molecular weight (dialyzable) and consist mainly of charged ionic or dipolar constituents. Of the 520 micromoles per gm. of total base, 72 per cent are balanced by organic acids: aspartic acid (65 micro equivalents per gm.), glutamic acid (10 micro equivalents), fumaric and succinic acids (15 micro equivalents), a new polycarboxylic acid (35 micro equivalents), and isethionic acid, a biologically novel sulfonic acid (220 micro equivalents). Besides potassium, sodium, small amounts of calcium, and magnesium there is a considerable fraction of organic (nitrogenous) base. Other features of the chemical composition of squid axoplasm include a relatively high concentration of taurine (100 micro equivalents) and an ultraviolet absorbing substance possibly identical with N-methylpicolinic acid. The distribution of the phosphates, especially the concentration of ATP, has been investigated. Specific techniques elaborated in connection with this study have been described and the biochemical implications of the analytical results are discussed.     

Growth hormone and prolactin content of hyperplastic anterior pituitary of dehydroepiandrosterone treated rats.

30 days after implantation of 80 mg dehydroepiandrosterone (androst-5-en-3betaol-17-one) hyperplastic enlargement of the anterior pituitary has been observed in about 80 per cent of the female rats. There was an important increase of prolactin content, growth hormone content remained unchanged. The mentioned alterations were found to be reversible, since regression was observed after DEA treatment exceeding 30 days. In females developing no hyperplasia pituitary growth hormone contentration and content has been decreased, prolactin content remained unchanged. In male rats on identical treatment no change of pituitary weight, growth hormone and prolactin concent has been found. The results suggest that, under physiological conditions, DEA does not affect pituitary growth hormone and prolactin content, however response to pharmacological doses was different in male and female rats.     

FAT AND CARBOHYDRATE METABOLISM IN HUMANS—A Study of Nutritional and Hormonal Effects

As an index to the rate of fat utilization in human subjects, the recovery of all radioactive carbon dioxide in the expired air was measured for one hour following intravenous injection of palmitate-1-C¹⁴. In the normal fasted subject, about 10 per cent of the injected dose was recovered, and the proportion was lowered to about 5 per cent by administration of glucose. With prolonged fasting, the recovery of radioactive carbon dioxide did not change, despite a rising concentration of fatty acids in the serum. This was interpreted as due to the development of a balance between increasing mobilization and oxidation and was thought to indicate increasing fatty acid oxidation.In chronic undernutrition and diabetes mellitus there was increased fatty acid oxidation due presumably to adaptation to a chronic increase in fat utilization for energy.Administration of human growth hormone did not increase fat oxidation but prevented the usual inhibition produced by glucose. This was interpreted to mean that growth hormone increases fat utilization only indirectly by inhibiting the usual preferential utilization of glucose over fat.     

PRACTICAL HUMAN GROWTH HORMONE—Preparation and Clinical Use

Human growth hormone was prepared from acetone-dried pituitary powder by hot glacial acetic acid extraction and subsequent precipitation by sodium chloride and cold acetone. The yield was 13 per cent and the preparation was called practical growth hormone in recognition of its complement of corticotropin.Treatment of two dwarfs with practical growth hormone in aqueous solution, 1 or 2 mg intramuscularly on alternate days, accelerated the growth rate and there were no physical signs or laboratory indications of adrenal stimulation or other adverse effects. The preparation is recommended for its safety, simplicity and relatively good yield.     

The influence of biosynthetic human growth hormone on biomechanical properties and collagen formation in granulation tissue

Biomechanical properties and collagen formation in the granulation tissue of cellulose sponges, implanted subcutaneously in male rats for 7, 10 and 16 days, were tested after treatment with biosynthetic human growth hormone given subcutaneously in a dose of 0.5 mg/kg body weight/day. At each implantation period, one group started hormone treatment at the day of implantation and another group started hormone treatment 7 days prior to implantation. After 7 days of implantation, increases in maximum stress (36 per cent), relative failure energy (48 per cent) and strain at maximum stress (25 per cent) were found when treatment was started 7 days prior to implantation. After 10 days of implantation an increase in relative failure energy (60 per cent) was found when treatment was started 7 days prior to implantation. No differences were found after 7 and 10 days of implantation when treatment was started at the day of implantation. After 16 days of implantation, no influence on mechanical strength was found in any of the hormone treated groups. The collagen deposition after 7, 10 and 16 days did not differ in any of the hormone treated groups compared to controls.     

A study of the conformation of native and immobilized human somatotropin using circular dichroism

The conformation of human growth hormone (hGH) as monomer and aggregate as well as of those immobilized in the soluble polysaccharide matrix was investigated. The immobilization resulted in ten per cent decrease of the amount of alpha-helix and in the conformational mobility change of aromatic amino acid side groups. It did not, however, influence the biological activity of the hormone, thus suggesting that the above conformational variations did not affect functionally important portions of the molecule.     

Correlation between [U-14C]glucose metabolism and function in perfused cat brain

In brain perfusion experiments conducted with blood containing [U-14C]glucose the relative specific activity (RSA) of blood glucose carbon incorporated in brain intermediate metabolites was measured. It was demonstrated that the so-called metabolic pattern of Geiger is not constant, but it bears a close relation to the function of the brain. The results of the study may be summarized briefly as follows. (1) In a group (A) of cats with a high level of brain function, the RSA of lactic acid was 75 per cent; that of glutamic acid 80 per cent; aspartic acid 75 per cent; glutamine 61 per cent; GABA 43 per cent; and respiratory CO2 55 per cent. It was observed that the major part of the carbon of amino acids, such as glutamic acid and aspartic acid, which are directly associated with the tricarboxylic acid cycle are derived from blood glucose. (2) In a group (B) showing a low level of brain function, the RSA of each amino acid was considerably lowered. The RSA of glutamic acid and aspartic acid was about 50 per cent and that of respiratory CO2 was 27 per cent. (3) In a group (C) with a still lower level of brain function, each amino acid as well as the respiratory CO2 had still lower RSA values. (4) The metabolic pattern of Geiger corresponds to values obtained during low functional activity of the brain in our experiment.     

The role of succinic acid in the biosynthesis of levorin

The influence of succinic acid as a component of media for biosynthesis of levorin, a polyenic antibiotic was studied. It was shown that with the use of the soybean-corn medium supplemented with succinic acid (0.05-0.4 per cent) the antibiotic content in the fermentation broth was higher than that in the control. The highest stimulating effect (135 per cent) was observed with addition of 0.1 per cent of succinic acid. For providing optimal antibiotic production in the synthetic medium supplemented with succinic acid (0.4 per cent) addition of acetic acid (0.05 per cent) was required. Studies with the soybean-corn medium with and without succinic acid revealed differences in the level of p-aminoacetophenone, an aromatic fragment of the levorin molecule. Under the conditions of the medium with succinic acid the content of p-aminoacetophenone in the mycelium was higher by 10 to 18 per cent as compared to that in the control and depended on the fermentation period. The role of succinic acid in biosynthesis of levorin is discussed.     

CESAREAN SECTION EXPERIENCE AT THE UNIVERSITY OF CALIFORNIA HOSPITAL

A review of the 746 cesarean sections performed at the University of California Hospital from 1907 through 1948 shows an overall cesarean section incidence of 3.91 per cent. The maternal mortality rate associated with these cesarean sections has been 1.61 per cent. There has been a steady decline in mortality over the 40-year period and there have been no deaths from cesarean section in the last ten years. The over-all incidence of morbidity associated with cesarean section has been 40.5 per cent and again there has been a significant improvement in recent years. The fetal mortality associated with cesarean section has been 6.1 per cent. In view of recent experience, standards based on figures collected 20 years ago are no longer tenable.     

ISOLATION AND CHARACTERIZATION OF A SOLUBLE GLUCOSE-CONTAINING SIALOGLYCOPROTEIN FROM THE CORTICAL GREY MATTER OF CALF BRAIN

A sialoglycoprotein has been isolated from the cortical grey matter of calf brain after homogenization in 0.32 M-sucrose or in 0.15 M-NaCl. The sialoglycoprotein is present in the supernatant obtained after centrifugation at 100,000 g for 60 min. It is designated GP-350 on account of its elution with 350 mM-NaCl on a DEAE-cellulose column. From DEAE-cellulose chromatography it is evident that compounds comparable to GP-350 occur in the brain of calf and sheep, whereas they seem to be absent in calf liver and kidney. After purification, with polyacrylamide gel electrophoresis only one band can be shown both at pH 8.9 and 7.5. GP-350 consists of about 83 percent of protein and about 17 per cent of carbohydrate. The polypeptide core has an acidic character: amino acid analysis gives 26 per cent for glutamic acid plus aspartic acid and their amides, with a ratio of acidic to basic amino acids of 3.3. The carbohydrate moiety contains 2.4% sialic acid, 5.5 % hexosamine and 9.4% hexose. It is remarkable that this brain sialoglycoprotein comprises 4% glucose. Care was taken to prevent contamination with glucose-containing materials during the purification procedure of GP-350. The complete absence of other glucose-containing compounds which occur in brain, Le. glycogen and gangliosides, was demonstrated. GP-350 accounts for at least 3 per cent of the total saline-extractable protein and about 20 per cent of the total saline-extractable protein-bound sialic acid of the cortical grey matter of calf brain. These percentages correspond to 390 pg of protein and to 14 μg of sialic acid per g wet weight. GP-350 remains soluble when the pH is brought to 3.9 or when ethanol is added to 70 % (v/v).     

The isolation of myxomyosin,an ATP-sensitive protein from the plasmodium of a myxomycete

1. A procedure has been developed for the preparation of an active concentrate from the myxomycete, Physarum polycephalum. This concentrate responds with a lowered viscosity to the addition of small amounts of ATP. The preparation recovers in viscosity, and the process may be repeated. 2. In the most active concentrates, 75 per cent of the non-dialyzable material moves as a single boundary both in the descending limb in electrophoresis and in the ultracentrifuge. It contains about 10 per cent ribonucleic acid, which is at least in part reversibly bound to the protein. 3. The active material has been designated myxomyosin because of its origin and its similarity to actomyosin in ATP response.     

Electrophoretic isolation and partial characterization of a major secretory glycoprotein from the submandibular glands of the mouse

After either cholinergic or adrenergic stimulation of the submandibular glands of the mouse, a major protein of the incubation medium could be isolated by electrophoresis, designated the AM2 protein. About 5 per cent of the secreted proteins and 2.4 per cent of the secreted protein-bound sialic acid was recovered as the purified AM2 protein. The AM2 protein appeared to be electrophoretically pure in 7.5% polyacrylamide gel both at pH 8.9 and at pH 4.3. In sodium dodecyl sulfate-electrophoresis the molecular weight was estimated to be about 80 000 for the major component and about 40 000 for the minor component. By isoelectric focusing the isoelectric point has been determined to be 4.7. The amino acid analysis indicated Glx, Asx, Leu and Ala as the major amino acids, comprising 15.0, 10.6, 9.2 and 9.1 per cent of the amino acid residues, respectively. The ratio of the acidic amino acids and their amides (Glx plus Asx) to the basic amino acids (Lys plus Arg) was 2.2. The sugar analysis showed that the AM2 glycoprotein consists of 17.3 per cent of carbohydrate, with as major carbohydrate component glucosamine. The molar ratio of the sugars was Man : Gal : Glc : GlcNH2 : sialic acid = 2.3 : 1.0 : 4.7 : 9.8 : 2.9. Galactosamine could be detected as a trace component and fucose was not detectable.     

Crystalline desoxyribonuclease; isolation and general properties; spectrophotometric method for the measurement of desoxyribonuclease activity

A crystalline enzyme capable of digesting thymus nucleic acid (desoxyribonucleic acid) has been isolated from fresh beef pancreas. The enzyme called "desoxyribonuclease" is a protein of the albumin type. Its molecular weight is about 60,000 and its isoelectric point is near pH 5.0. It contains about 8 per cent tyrosine and 2 per cent tryptophane. It is readily denatured by heat. The denaturation is reversible if heated in dilute acid at pH about 3.0. The digestion of thymus nucleic acid by crystalline desoxyribonuclease is accompanied by a gradual increase in the specific absorption of ultraviolet light by the acid. The spectrophotometric measurement of the rate of increase in the light absorption can be conveniently used as a general method for estimating desoxyribonuclease activity. Details are given of the method for isolation of crystalline desoxyribonuclease and of the spectrophotometric procedure for the measurement of desoxyribonuclease activity.     

Effects of beta subunit acylation on lutropin receptor site binding.

The effects of various modifications on the beta subunit of lutropin have been studied using the binding characteristics of the reconstituted hormone in the rat testicular radioligand assay. Conditions for iodinating lutropin and lutropin derivatives were determined which resulted in 15 per cent specific binding when tested immediately and retention of 6 to 7 per cent specific binding even after storage for 6 months. Acetimidinyl, acetyl, and carbamyl derivatives of the beta subunit were prepared and combined with unmodified alpha subunit to form reconstituted lutropin. Modification of the beta subunit was shown to have no effect on the time course of binding to testicular receptors or, with one exception, on the extent of receptor saturation. Very high concentrations of lutropin reconstituted with acetylated beta subunit showed an anomalous binding behavior. Scatchard plots of the binding data support the view that the native hormone has a unique receptor affinity which is irreversibly disrupted by separation of subunits and that derivatization of the beta subunit does not alter this parameter further. These data also suggest that there are no significant differences in the amino groups modified on the beta subunit. Competition and preincubation tests for receptor sites that reacted only with modified lutropin and not with the native hormone were negative.     

Effect of juvenile hormone treatment on caste differentiation in the honeybee, Apis mellifera

Synthetic juvenile hormone (methyl trans,trans,cis-10-epoxy-7-ethyl-3,11-dimethyl-2,6-tridecadienoate, 1 μg/μl acetone per animal) (JH) was topically applied to 2- to 3-day-old worker honeybee larvae in the hive. Eighty per cent of the hormone-treated larvae were removed from their brood cell before pupation. Only 1 out of 42 adults showed characteristics of an intercaste. Fifty per cent of the control larvae (1 μl acetone) developed to adults, all of which were workers.After topical application of JH and feeding on royal jelly under in vitro conditions, the rate of survival is high (up to 85 per cent adults), but up to 67 per cent of queens and 44 per cent of workers exhibit eye malformations with characteristics of somatic mutation. Formation of a more solid web by the spinning larvae, shortening of the diapause by 1 to 2 days, and unusual shapes of mandibles, legs, and abdomen are a consequence of hormone treatment. The effects are less marked after application of 0·1 instead of 1 μg hormone or after its addition to the food (2 μg/g royal jelly). Treatment of the 2- to 3-day-old worker larvae and subsequent rearing on royal jelly is followed by a shift in caste differentiation from queens and workers to intercastes. In no case, are more queens developed after juvenile hormone treatment.Queen bee determinator, partially purified from royal jelly, induces a concentration-dependent shift from workers to queen differentiation. A threefold increase in the natural determinator concentration of royal jelly results in an almost exclusive (98 per cent) queen formation from 2- to 3-day-old worker larvae. In contrast to this direct effect, the influence of JH is explained as an indirect morphogenetic effect not directly coupled with honeybee caste differentiation.     

Fat Metabolism in the West African Oil Palm (Elaeis Guineensis): PART I. FATTY ACID FORMATION IN THE MATURING KERNEL

Using a column chromatographic technique for the estimationand identification of fatty acids, a study has been made offat formation in developing Oil Palm kernels from 10 weeks afterpollination to full maturity (20 weeks), during which time thefat content may increase a hundredfold. Nuts from three differenttrees have been analysed and differences between these in ratesof maturation (as indicated by appearance of the endosperm)can be directly correlated with changes in character of theoil present. Amounts of reducing sugars, sucrose, and starch in the developingendosperm have also been followed, but these carbohydrates arepresent throughout in low concentration, and it is assumed thattranslocation from the rest of the plant to the developing kernelmust account for the major part of storage material. The mature kernel contains in its fat an unusual mixture ofeight different saturated fatty acids. The major such componentis lauric acid (46·1 to 49·5 per cent.) and thereare present two common unsaturated acids, oleic (15·7to 16·5 per cent.) and linoleic acid (0·7 to 3·1per cent.). At the earliest stage examined (10 weeks after pollination)all these acids are.present but in altered proportions, unsaturatedacids forming a larger fraction (36·5 to 81·2per cent., according to the tree investigated), and lauric acid(1·4 to 8·5 per cent.) a smaller. The results suggest that young kernels contain a small quantityof a largely unsaturated ‘protoplasmic’ fat, andthat at a certain stage in development some physiological changein the tissue results in the formation, in large quantities,of a new, highly saturated storage fat. No fatty acid interconversionscould be demonstrated although there is some suggestion thatoleic acid behaves anomalously. There is evidence that free fatty acids are not accumulatedprior to esterification.     

Mineralization of nitrogen in two soil-organic-matter fractions extracted with formic acid

Summary Extraction of a calcareous meadow soil with boiling formic acid containing 10 per cent acetylacetone yielded a fraction of soil organic matter representing about 40 per cent of the total. This fraction contained only 2.2 per cent N. Less than 18 per cent of this was mineralized during incubation for 8 weeks at 28°C. Further extraction of the soil with a formic acid and hydrofluoric acid mixture yielded a second fraction. This represented about 37 per cent of the total organic matter and contained 6.0 per cent N of which up to 41 per cent was mineralized during incubation. Preincubation and leaching had a stabilizing effect on subsequent mineralization of native N of a standard sandy loam soil.