Search

Spot 14 (S14) is a nuclear protein that communicates the status of dietary fuels and fuel-related hormones to genes required for long-chain fatty acid synthesis. In mammary gland, S14 is important for both epithelial proliferation and milk fat production. The S14 gene is amplified in some breast cancers and is strongly expressed in most. High expression of S14 in primary invasive breast cancer is conspicuously predictive of recurrence. S14 mediates the induction of lipogenesis by progestin in breast cancer cells and accelerates their growth. Conversely, S14 knockdown impairs de novo lipid synthesis and causes apoptosis. We found that breast cancer cells do not express lipoprotein lipase (LPL) and hypothesize that they do not have access to circulating lipids unless the local environment supplies it. This may explain why primary breast cancers with low S14 do not survive transit from the LPL-rich mammary fat pad to areas devoid of LPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential target as well. Future effort will center on validation of S14 as a therapeutic target and producing antagonists of its action.

The present experiments were designed to investigate the ability of electrochemical stimulation of the hypothalamus to induce ovulation in the guinea pig in late diestrus. Unilateral and bilateral electrochemical stimulation in the medial basal hypothalamus (MBH) induced ovulation in the majority of guinea pigs. Similar and more extensive electrochemical stimulation in the medial preoptic area (MPOA) failed to induce ovulation. Comparative studies in the Wistar rat verified the validity of the stimulation system and the results were in agreement with similar findings in other laboratories; that is, both the MPOA and the MBH were sensitive to electrochemical stimulation and ovulation was induced. However, further studies in guinea pigs with nonspecific destruction of the MBH by radiofrequency lesions or surgical cuts revealed additional differences in that no release of gonadotropins occurred, at least not sufficient release to alter the ovarian histology at autopsy. (Endocrinology 95: 933, 1974)

PMS-induced ovulation in immature rats involves a neuroendocrine pathway. Bilateral electrolytic lesions located in the medial preoptic area, basal-medial preoptic area, or ventral medial anterior hypothalamic area prevented the ovulatory response following a single injection of PMS (pregnant mare's serum). Lesions of the medial preoptic area failed to interfere with ovulation following treatment with PMS and HCG (human chorionic gonadotropin). Electrode placement (sham) into the medial preoptic area failed to alter PMS-induced ovulation. PMS-induced ovulation occurred in the presence of bilateral lesions located in other areas of the hypothalamus than those listed above. From these experiments it is concluded that the mechanism of PMS-induced ovulation involves the medial preoptic and basal anterior hypothalamic regions. (Endocrinology 77: 255, 1965)

By techniques of brain stimulation, neural mechanisms initiating pseudopregnancy in rats were distinguished from other neural mechanisms controlling ovulation. Although ovulation can regularly be induced during late diestrus or proestrus by unilateral “electrochemical” stimulation of the medial preoptic area under pentobarbital, pseudopregnancy proved to be an infrequent sequel when such animals were observed for appropriate lengths of time. On the other hand, pseudopregnancy was regularly evoked by unilateral “electrical” stimulation of the tuberal region at sites and with electrical parameters not commonly yielding ovulation. “Electrochemical” stimulation in the present experiments was produced by a small direct current passed briefly through a stainless steel electrode. “Electrical” stimulation through either stainless steel or platinum electrodes was accomplished with trains of biphasic matched pairs of rectangular pulses. All electrodes were concentric bipolar units of 0.4 mm tubing with 0.13 mm core...

The technique of electrical stimulation of the brain has revealed an increased neural threshold in the medial preoptic area anteriorhypothalamus (MPOA-AH) “early”(12 days since last ovulation) in the estrous cycleof the guinea pig when compared to that in thesame region “late” (14 days since last ovulation)in the cycle. With apeak-to-peak current of1 mA, none of the 12 animals stimulated in the MPOA-AH “earlyN in the cycle showed gonadotropichormone release. On the contrary, with stimulation parameters and brain localization of electrodes comparable to the above, stimulation “late” in the estrous cycle induced premature gonadotropic hormone release in 11 of 13animals. Stimulation of the medial basal hypothalamus (MBH) with 1 mA peak-to-peak inducedgonadotropic hormone release either “early” or “late” in the cycle. Furthermore,increasing the current to 2 mA peak-to-peak overcame the apparent refractoriness of theMPOA-AH “early” in the estrous cycle of the guinea pig; all 5 animalsshowed signs ofgonadotropi...

Previous findings revealed long delays from time of stimulation to onset of pseudopregnancy when pentobarbital blockade of ovulation was combined with infertile copulation. An essential factor was the exclusion of competent corpora lutea until the subsequent cyclic estrus. By selective unilateral electrical stimulation of the dorsomedial-ventromedial hypothalamus, it has now been possible to reproduce these long delays. Biphasic pairs of 1 msec rectangular pulses, 100/sec, 200 μamp peak-to-peak, were passed through a concentric platinum bipolar electrode in 30-sec trains at 30-sec intervals for differing lengths of time. Such stimulation, lacking ability to induce ovulation, frequently induced either immediate or delayed pseudopregnancy, depending on circumstances, as follows: A) Immediate pseudopregnancy regularly followed stimulation on diestrus day 1. B) Shortterm delay of pseudopregnancy (1–3 days) followed stimulation on diestrus day 2. C) Longterm delay until an additional estrous cycle was complete...

SKELTON (1–4) has reported that hypertension, associated with characteristic pathologic lesions, develops if one adrenal is removed and the other enucleated and allowed to regenerate in rats sensitized by unilateral nephrectomy and a high sodium chloride intake. The studies reported here were undertaken to determine if we could confirm Skelton’s reports, and if so, to examine the effects of various endocrine and pharmacologic manipulations in enucleate rats. Our results show unequivocally the reality of the syndrome described by Skelton and demonstrate its responsiveness to various treatments. An abstract of this work has been published (5). methods Most of our experiments were performed on female rats of about 150 gm. initial body weight. In addition, observations were made on males of the same size and small females (ca. 58 gm.). One kidney was removed in all cases and 1% sodium chloride substituted for drinking water. This procedure sensitizes animals to the pressor influence of regenerating adrenals a...

Treatment with PMS alone fails to induce ovulation in immature Wistar rats treated with testosterone propionate on the fourth day of postnatal life, but treatment with PMS plus HCG causes ovulation. This is additional evidence that superovulation fol lowing the injection of PMS alone involves endogenous gonadotropin release. {Endocrinology 74: 811, 1964) F rats treated with testosterone during the neonatal period characteristically exhibit precocious vaginal opening and as adults show persistent vaginal cornification, absence of ovulation and decreased ovarian weight (1). In contrast, little is known of the state of the ovary before puberty in the androgen-treated rat. Since ovulation can be readily induced in the normal immature rat, the present study was undertaken to examine the ovarian response to exogenous gonadotropin (PMS alone and PMS plus HCG) in the normal and the androgen-treated immature rat. Materials and Methods Immature rats of the Wistar colonies maintained at Oxford and at Purdue were used. Litter size was reduced within 2 days of birth to 8 in the case of the Oxford colony and to 6 for the Purdue colony. Both groups were weaned at 21 days of age. The androgen treatment consisted of a single subcutaneous injection of 1.25 mg of testosterone propionate in oil on the fourth day of life, i.e., approximately 96 hr after birth. A single injection of PMS was given subcutaneously at 30 days of age for the Oxford colony and at 24 days of age for the Purdue colony. These ages were chosen because a maximal or nearmaximal ovulatory response to PMS alone is obtained at these ages in the 2 colonies. When HCG was also given it was injected subcutaneously 56 hr after the PMS treatment. All animals were killed 72-74 hr after the PMS injection, Received November 18, 1963. 1 Locke Research Fellow of the Royal Society, Oxford. 2 X-R Fellow of the Purdue Research Foundation, Purdue. 3 Senior Post-Doctoral National Science Foundation Fellow (1962-1963), Purdue. and the tubal ova were recovered and counted as previously described (2); in addition, ovarian and uterine weights were determined in the Oxford experiment. Results The ovarian weight of the androgentreated animals was significantly lower than that of the controls at 33 days of age (Table 1). This difference was also seen in animals killed at 26 days of age; the mean body weight of both 9 normal and 9 treated animals was 46 g; the average ovarian weight of the normals was 34.4 ±1.3 mg/100 g body weight and of the androgen-treated animals 21.2 ±1.9 (p

Proestrous rats under pentobarbital anesthesia during the 'critical period' were electrically stimulated in either the medial preoptic area (mPOA) or the anterior basal tuber. In Osborne-Mendel (O-M) and Charles River CD rats, comparisons were made of the ovulatory responses to trains of matched biphasic pulse pairs of different microamperage, 30 sec on and 30 sec off for 45 min. In CD rats, comparisons were made of the relative efficiencies of stimulation through a coaxial platinum electrode near the midline and a pair of platinum electrodes spaced bilaterally 2 mm apart across either the mPOA or the tuber. Other comparisons, with either type of electrode in the basal tuber, were made between 4-day and 5-day cyclic CD rats with respect both to the ovulatory responses and to the serum concentrations of LH 90 min after the start of the 45-min stimulus. In both O-M and CD rats, tuberal stimulation was more effective for ovulation than mPOA stimulation. CD rats were much less responsive to mPOA stimulation (spaced electrodes) than O-M rats, but the responses of both strains to tuberal stimulation were essentially alike. In 4-day cyclic CD rats, the ovulatory responses to mPOA stimulation with the coaxial electrode were much superior to those from spaced-electrode stimulation. In contrast, tuberal stimulation with either type of electrode gave equivalent ovulation frequencies and equivalent tubal ovum numbers in both 4-day and 5-day cyclic rats. However, the serum LH concentrations disclosed somewhat better responses to stimulation with the coaxial electrode (coaxial/spaced=1.57). The advantage of stimulation with the coaxial electrode may be due to high current density or, at least in part, to its more medial location. The results are compatible with the concept of preoptic-tuberal neuronal system, diffuse rostrally and convergent upon the medial basal tuber, controlling the ovulatory surge of LH.

Superovulation was obtained in immature female rats following a single injection of pregnant mare’s serum gonadotropin (PMS). The induced ovulation was blocked by hypophysectomy and various pharmacological agents. A differential drug action was observed with atropine sulfate, chlorpromazine (CPZ), Nembutal and N-(9- fluorenyl) -N-ethyl-β-chloroethylamine hydrochloride (SKF-501) in the time of the blockade of the ovulatory response. The action of atropine was shown to precede that of SKF- 501, Nembutal, hypophysectomy and CPZ. CPZ suppressed LH release at a later period than any of the other agents used. The time of PMS injection, under controlled lighting conditions of 13 hr light and 11 hr dark, had no effect on the ovulatory or blocking response in the 24-day-old rat. PMS-induced ovulation in the immature rat appears to involve a neuroendocrine mechanism which can be inhibited by the action of certain drugs on the central nervous system. (Endocrinology 74: 309, 1964)