mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation.

Breast cancer is the leading cause of cancer-related deaths among women. Approximately 75% of breast cancers are estrogen receptor-α (ERα) positive, underscoring the dependence of cancer cells on estrogen for growth and survival. Patients treated with endocrine therapy often develop resistance, either de novo or acquired, which in some cases is caused by aberrations within the growth factor signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) has emerged as a critical node in estrogenic signaling. We have previously shown that mTORC1 can phosphorylate and activate ERα on S167 via its effector-the 40S ribosomal S6 kinase 1 (S6K1). Presently, we have uncovered a direct link between mTORC1 and ERα. We found that ERα binds to regulatory-associated protein of mTOR (Raptor) and causes it to translocate to the nucleus upon estrogen stimulation. In addition, we identified mTOR as the kinase that phosphorylates ERα on S104/106 and activates transcription of ER target genes. Our findings show a direct link between mTORC1 and ERα, which further implicates mTORC1 signaling in the pathogenesis of ER-positive breast cancer and provides rationale for FDA-approved use of mTORC1 inhibitors in combination with endocrine agents for treatment of this disease.

Enterobius egg granuloma of the vulva and peritoneum: review of the literature.

Two cases of Enterobius granuloma containing eggs only are reported. The first case involved the vulva, where no such granuloma has been reported previously. The coexistence of peritoneal granuloma and rectal adenocarcinoma in the second case suggests the possibility of direct penetration of the damaged colonic wall by the parasite, as emphasized by several previous reports of neoplastic involvement and perforation of the intestinal wall in cases of ectopic infections. The diagnostic criteria of Enterobius eggs granuloma, which might be a diagnostic dilemma for pathologists who are not familiar with such criteria, are described herein.

Effects of alternate modes of administration on Rorschach performance of deaf adults.

This study examined two modes of administering the Rorschach Inkblot Technique to determine which was more appropriate for a college-educated, deaf population. Twenty-four prelingually deaf adults took the Rorschach in sign language and in written English, using a counterbalanced test-retest design, and their sign and written scores were compared to each other and to 1986 norms for Exner's Comprehensive System. Seventeen variables measuring such areas as perceptual accuracy, perceptual complexity, and self-focus were found to vary more than one standard deviation from Exner's norms. Differences between sign and written conditions on several affective variables were found. Written administration can be used by examiners who are informed about deafness and aware of variables that may be underreported by written inquiry.

The nonutility of chest roentgenographic examination in asymptomatic patients with positive tuberculin test results.

To determine the value of chest roentgenograms in the management of asymptomatic persons with positive tuberculin skin test results, we undertook a retrospective review of all tests administered by our Employee Health Service, North Shore University Hospital, Manhasset, NY, between July 1, 1983 and November 1, 1987. Of 5200 tests, 247 results were positive. Two hundred twenty-one of these charts were reviewed for roentgenographic results and the presence of symptoms. All persons were asymptomatic. Chest roentgenograms revealed the following: normal, 188; unrelated abnormalities, 24; apical pleural thickening, 5; granulomas, 2; calcified hilar node, 1; and calcified node plus granuloma, 1. We noted no active tuberculosis, nor did the chest roentgenographic results influence recommendations for isoniazid prophylaxis. We conclude that chest roentgenograms are of value in 0% to 1.3% of asymptomatic people with positive tuberculin test results. A larger study should be undertaken to further define the usefulness of chest roentgenograms in this population.

Glucagon, not insulin, may play a secondary role in defense against hypoglycemia during exercise.

The sympathochromaffin system, probably sympathetic neural norepinephrine, plays a primary role in the prevention of hypoglycemia during exercise in humans. Our previous data indicated that changes in pancreatic islet hormones are not normally critical but decrements in insulin, increments in glucagon, or both become critical when catecholamine actions are blocked pharmacologically. To distinguish between the role of insulin and that of glucagon in this secondary line of defense against hypoglycemia during exercise in humans, glucoregulation during moderate exercise (approximately 55% of maximum O2 consumption over 60 min) was studied in people who could not decrease insulin but could increase glucagon, i.e., patients with insulin-dependent diabetes mellitus (IDDM). While receiving constant intravenous infusions of regular insulin, in individualized doses shown to result in stable plasma glucose concentrations of approximately 95 mg/dl before exercise, patients with IDDM were studied under two conditions: 1) a control study (n = 13) and 2) an adrenergic blockade study (propranolol infusion, n = 8). In the control study, mean plasma glucose concentrations did not change (from 95 +/- 2 to 100 +/- 11 mg/dl) during exercise despite constant plasma free insulin levels. In the adrenergic blockade study plasma glucose declined (from 96 +/- 2 to 74 +/- 7 mg/dl, P less than 0.01) but stabilized; hypoglycemia did not occur. Exercise-associated increments in plasma glucagon were comparable in the two studies. These data confirm that decrements in insulin are not critical to the prevention of hypoglycemia during moderate exercise in humans and indicate that compensation for deficient catecholamine action does not require decrements in insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics.

We tested the hypothesis that during decrements in plasma glucose concentration, symptoms of hypoglycemia may occur at higher glucose concentrations in patients with poorly controlled insulin-dependent diabetes mellitus than in persons without diabetes. Symptoms of hypoglycemia and counterregulatory neuroendocrine responses were quantified during hypoglycemic and euglycemic clamp studies in eight patients with insulin-dependent diabetes mellitus selected because their hemoglobin A1 levels were above 10 percent. These data were compared with similar observations in 10 nondiabetic subjects studied previously. Glycemic thresholds--the plasma glucose concentrations during each hypoglycemic clamp study at which a given symptom or biochemical measurement first exceeded its 95 percent confidence interval determined in the euglycemic clamp studies--were calculated for each variable. The mean (+/- SE) glycemic threshold for the symptoms of hypoglycemia was 4.3 +/- 0.3 mmol per liter (78 +/- 5 mg per deciliter) in patients with poorly controlled diabetes--significantly higher (P less than 0.001) than the value of 2.9 +/- 0.1 mmol per liter (53 +/- 2 mg per deciliter) in subjects without diabetes. The mean glycemic thresholds for growth hormone, epinephrine, and cortisol secretions were not significantly different in the two groups. Thus, during decreases in the plasma glucose concentration, patients with poorly controlled insulin-dependent diabetes mellitus may experience symptoms of hypoglycemia at higher plasma glucose concentrations than persons without diabetes. The mechanism underlying this observation remains to be defined.

Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.

To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.

Epinephrine is not critical to prevention of hypoglycemia during exercise in humans.

We documented stability of plasma glucose concentrations and glucose production and utilization rates, and levels of other metabolic substrates and regulatory factors, during the islet clamp (somatostatin infusion with glucagon and insulin replacement) in the absence of an intervention in five normal humans and further applied this technique to the study of glucoregulation during moderate exercise. Based on previous evidence that sympathochromaffin activation plays a primary role in the prevention of hypoglycemia during exercise, the role of adrenomedullary catecholamines was assessed by exercise (60% of maximum oxygen consumption for 60 min) studies in four bilaterally adrenalectomized, epinephrine-deficient humans under two conditions: control (saline infusion) and islet clamp. Increased glucose utilization and production rates were matched and plasma glucose was unchanged during exercise under both conditions. Thus adrenomedullary catecholamines including epinephrine are not critical to glucoregulation during moderate exercise in humans even when changes in insulin and glucagon are prevented. These findings provide further support for the suggestion that sympathetic neural norepinephrine is the operative catecholamine in the prevention of hypoglycemia during exercise in humans.