Effects of antiprogestins RU486 and ZK98299 on the expression of cell cycle proteins of a medroxyprogesterone acetate (MPA)-induced murine mammary tumor.

This study links the tumor inhibitory effect of anti-progestins RU486 and ZK98299 to the expression of cell cycle proteins. Medroxyprogesterone acetate-induced ductal mammary adenocarcinoma-bearing female BALB/c mice were treated daily either with RU486 or ZK98299, observing tumor growth retardation. p21 increased after 24 h treatment, peaked at day 4 and returned to control levels at day 7. Cyclin D1, cyclin E, CDK2 and CDK4, did not change during treatment. These results suggest that p21 might play a role in early inhibitory stages of tumor growth induced by RU486 and ZK98299.

Differential expression of and responsiveness to transforming growth factor-beta (TGF-beta) isoforms in hormone-dependent and independent lines of mouse mammary tumors.

Transforming growth factor-beta2 (TGF-beta2) and -beta3 mRNA expressions were studied in ductal hormone-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. MPA treatment of HD tumors induced a significant decrease in TGF-beta2 and -beta3 mRNA levels. Progression to an HI phenotype of ductal tumors was associated with reduced TGF-beta2 and -beta3 expressions, as compared with their HD counterparts. Exogenously added TGF-beta1, -beta2, and -beta3 (1 ng/ml) inhibited the proliferation of primary cultures of epithelial cells from ductal HD and HI tumors. In addition, TGF-beta expression and effects were studied in the other type of MPA-induced mammary tumors, which are of lobular origin and lack steroid hormone receptors and evidence an HI behavior. These lobular HI lines showed TGF-beta2 levels similar to those found in HD lines growing in MPA-treated mice. In contrast, TGF-beta3 mRNA levels were 12- to 20-fold higher than in HD tumors. Primary cultures of lobular HI epithelial cells required either TGF-beta concentrations of 10 ng/ml to show an inhibitory response, or were completely resistant to TGF-beta inhibition. Studies of the molecular mechanisms involved in reduction or loss of TGF-beta responsiveness in lobular HI tumors showed that cell surface type II TGF-beta receptor levels were lower in these tumors than those present in HD tumors. Our results support the hypothesis that TGF-beta could play a role as an autocrine growth inhibitor in HD and HI ductal tumors. Autonomous growth of lobular HI tumors could be favored by undetectable or low TGF-beta1 and -beta2 expressions and by reduced or lost sensitivity of epithelial cells to TGF-beta's antiproliferative effects. However, the extremely high levels of TGF-beta3 expression in lobular HI tumors, in spite of reduced sensitivity to TGF-beta3 inhibitory growth effect in tumor epithelial cells, suggest a net positive role for TGF-beta3 in these tumors.

A mitogenic and hormonal signalling network regulate mammalian cell division commitment time.

A basic property of mammalian cells is to retain the mitogenically induced "commitment" to undergo DNA replication even in the absence of stimuli. Recent findings on PGF2 alpha and hormone-induced Swiss 3T3 cell multiplication, reveal that this crucial cell cycle event can be regulated by several signalling mechanisms.

Prostaglandin F2 alpha (PGF2 alpha) triggers protein kinase C (PKC) and tyrosine kinase activity in cultured mammalian cells.

Prostaglandin F2 alpha (PGF2 alpha) added to confluent resting Swiss 3T3 cells triggers tyrosine kinase (PTK) activation characterized by the phosphorylation of a set of 75, 86, 110 and 140 kD proteins. PGF2 alpha induces this event independently of PKC activation. However, both PKC and PTK activities appear to act concertedly to cause mitogenesis. Here we discuss their relevance in the control of mammalian cell division.

Mevalonate dependency of the early cell cycle mitogenic response to epidermal growth factor and prostaglandin F2 alpha in Swiss mouse 3T3 cells.

Lovastatin (LOV), a hydroxy-methylglutaryl-coenzyme A (HMGCoA) reductase competitive inhibitor, blocks epidermal growth factor (EGF)- or prostaglandin F2 alpha (PGF2 alpha)-induced mitogenesis in confluent resting Swiss 3T3 cells. This inhibition occurs even in the presence of insulin, which potentiates the action of these mitogens in such cells. LOV exerts its effect in a 2-80 microM concentration range, with both mitogens attaining 50% inhibition at 7.5 microM. LOV exerted its effect within 0-8 h following mitogenic induction. Mevanolactone (10-80 microM) in the presence of LOV could reverse LOV inhibition within a similar time period. LOV-induced blockage of PGF2 alpha response is reflected in a decrease in the rate of cell entry into S phase. Neither cholesterol, ubiquinone, nor dolichols of various lengths could revert LOV blockage. In EGF- or PGF2 alpha-stimulated cells, LOV did not inhibit [3H]leucine or [3H]mannose incorporation into proteins, while tunicamycin, an inhibitor of N' glycosylation, prevented this last phenomenon. Thus, it appears that LOV exerts its action neither by inhibiting unspecific protein synthesis nor by impairing the N' glycosylation process. These findings strongly suggest that either EGF or PGF2 alpha stimulations generate early cell cycle signals which induce mevalonate formation, N' glycoprotein synthesis, and proliferation. The causal relationship of these events to various mechanisms controlling the onset of DNA synthesis is also discussed.

Transforming growth factor beta 1, insulin and prostaglandin E1 enhance prostaglandin F2 alpha mitogenic action in Swiss 3T3 cells via separate events.

Transforming growth factor beta 1 (TGF beta 1) had no mitogenic effect in Swiss 3T3 cells, but could increase prostaglandin F2 alpha (PGF2 alpha)-induced DNA synthesis. Insulin, but not prostaglandin E1 (PGE1), further enhanced PGF2 alpha action at low TGF beta 1 concentrations. TGF beta 1 also acted concertedly with the protein kinase C (PKC) activator 1-oleoyl-2-acetylglycerol to induce mitogenesis. Thus, it appears that TGF beta 1 and insulin act via separate signals, while TGF beta 1 and PGE1 might share a common pathway not involving TGF beta 1-mediated prostaglandin synthesis. These results suggest that TGF beta 1 might elicit various signalling mechanisms to enhance PGF2 alpha-triggered events.

[Recurrence of nasosinusal polyposis after ethmoidectomy by endonasal approach. Functional, endoscopic, x-ray tomographic aspects and surgical implications]. / Récidive de la polypose nasosinusienne après ethmoidectomie par voie endonasale. Aspects fonctionnels, endoscopiques, tomodensitométriques et implications chirurgicales.

Recurrent polyposis after 116 endonasal ethmoidectomies performed in 61 patients were investigated on the basis of functional, endoscopic and tomodensitometric data. The results of the endoscopic examinations revealed that the anterior ethmoid was involved most often (41%) with either a single localization or in combination with other sites in the sinuses. Functional rhinosinus symptomatology was satisfactory in most cases after a mean follow-up of 22 months, especially for nasal obstruction which was initially predominant (91%). Headaches, especially fronto-orbial localizations, clearly decreased after the operation but there was no correlation between the presence of headache after the operation and the recurrence of the polyposis. Computed tomography gave results similar to those obtained by endoscopy. However, a distinction could not be made between radio-opaque images of polyposis and certain cicatricial or inflammatory reactions. Unlike the functional outcome, ethmoidectomy had little effect on these images. Recurrent polyps appeared most often on the anterior ethmoid and the role of the initial infundibulotomy can be debated. It would appear that the prognosis of polyposis is not modified by extended anterior ethmoidectomy, suggesting that a more conservative surgical approach may be appropriate for frontal ethomoidal polyps.

[Primary carcinoid of the larynx. Apropos of a case. Review of the literature]. / Carcinoïdes primitifs du larynx. A propos d'un cas. Revue de la littérature.

We report a new case of primary atypical carcinoid of the larynx. This rare neuro-endocrine neoplasm of the larynx was initially mis diagnosed in 50% of the cases published. Since, characteristically these are lesions of the epilarynx causing dysphonia at early stages of development, the diagnosis should be kept in mind when the work-up for dysphonia reveals a small tumor of the epiglottis or aryepiglottic folds. The histological diagnosis should be oriented by Grimelius staining and confirmed immunoperoxidase marker studies for chromogranin and cytokeratin. Although, atypical carcinoids of the larynx are aggressive malignant tumors, the prognosis for early lesions of less than 1 cm is excellent. However, unlike early squamous cell carcinomas, these tumors do not respond well to radiation therapy. Primary surgery is the treatment of choice.

Early cell cycle diacylglycerol (DAG) content and protein kinase C (PKC) activity enhancement potentiates prostaglandin F2 alpha (PGF2 alpha) induced mitogenesis in Swiss 3T3 cells.

R59022, a diacylglycerol kinase inhibitor, enhances the prostaglandin F2 alpha (PGF2 alpha)-induced diacylglycerol (DAG) synthesis in Swiss 3T3 cells. It also potentiates the PGF2 alpha-mediated protein kinase C (PKC)-dependent 80 kDa protein (80K) phosphorylation and initiation of DNA replication. R59022 enhances the PGF2 alpha mitogenic response by increasing the rate of entry into the S phase. Insulin does not cause 80K phosphorylation, and does not enhance its induction but it potentiates the PGF2 alpha mitogenic response. These results suggest that mitogenically triggered fluctuations in DAG content and PKC activity play a pivotal role in controlling the PGF2 alpha-induced DNA synthesis while insulin acts via a different mechanism.

Prostaglandin F2 alpha decreases the affinity of epidermal growth factor receptors in Swiss mouse 3T3 cells via protein kinase C activation.

Prostaglandin F2 alpha (PGF2 alpha) selectively decreases the binding of 125I-labelled epidermal growth factor ([125I]EGF) to intact Swiss 3T3 cells. Scatchard analysis reveals that PGF2 alpha decreases the number of high-affinity EGF binding sites without changing the total number of receptors. Prostaglandins E1 (PGE1), E2 (PGE2) or F2 beta (PGF2 beta) do not alter the EGF binding to these cells and do not enhance the PGF2 alpha effect. R-59022 and R-59949, two diacylglycerol kinase inhibitors, enhance the inhibitory effect of PGF2 alpha, whereas down-modulation of protein kinase C (PKC) abolishes the effect. These results indicate that PGF2 alpha decreases EGF binding in Swiss 3T3 cells via PKC activation.

Stimulation of protein kinase C (PKC) activity in resting Swiss 3T3 cells by prostaglandin F2 alpha.

Prostaglandin F2 alpha (PGF2 alpha), a mitogen for resting Swiss 3T3 cells, rapidly stimulates phosphorylation of an 80 kDa protein (80 K). 1-Oleoyl-2-acetylglycerol (OAG) and 12-O-tetradecanoyl phorbol-13-acetate (TPA) both protein kinase C (PKC) activators, also elicit 80 K phosphorylation. In contrast PGE1, PGE2 or PGF2 beta, which are non-mitogenic in these cells, had little or no action on this event. However PGE1 and PGE2 potentiate the PGF2 alpha proliferative effect but do not enhance its action on 80 K phosphorylation. These results suggest that PGF2 alpha mitogenic induction involves PKC signalling pathway activation while its enhancement by PGE1 or PGE2 occurs through a different mechanism(s).

Tunicamycin inhibits the initiation of DNA synthesis stimulated by prostaglandin F2 alpha in Swiss mouse 3T3 cells.

Tunicamycin, an inhibitor of the asparagine-linked protein N-glycosylation, blocks the initiation of DNA synthesis in Swiss 3T3 cells stimulated by prostaglandin F2 alpha alone or with insulin. This effect is exerted only when tunicamycin is added from 0 to 8 h after stimulation and it decreases the rate of entry into S phase. Blocking of labeled sugar incorporation to proteins occurs regardless of the time of PGF2 alpha stimulation. In contrast tunicamycin does not inhibit protein synthesis. These results suggest that N-glycoprotein synthesis early during the prereplicative phase is an important event controlling the mitogenic action of PGF2 alpha.

A prospective study of patients' psychological reactions to rhinoplasty.

One hundred twenty-one of 200 patients requesting a rhinoplasty completed a study designed to assess their psychological reactions to the operation. Preoperatively, each patient filled out a questionnaire about their expectations (both cosmetic and psychological), relationships, self-confidence, self-esteem, what they disliked about their noses, and other questions pertinent to an evaluation of the psychological effects of rhinoplasty. They also completed the Brief Symptom Inventory (BSI), a standardized psychological test. One month and 6 months postoperatively, they completed similar questionnaires. Preoperative and postoperative information was also obtained from the surgeon and nurse. Statistical analysis showed several interesting findings. A number of patients had increased self-confidence and self-esteem. Male patients did not show any sustained changes on the BSI, but female patients did with improved scores on the obsessive-compulsive, interpersonal sensitivity, depression, anxiety, and phobic anxiety scales. A number of patients described mild-to-moderate depression postoperatively. This was correlated with preoperatively high levels of anxiety. The surgeon was usually more critical of the surgical result than were the patients. The patients whose strong positive feelings about the results he most misjudged were actually depressed. These and other findings are noteworthy to enhance the understanding of postoperative psychological reactions and provide insight into the psychological management of rhinoplasty patients.

[Amyloidosis of the nasopharynx. Apropos of a case]. / Amylose du cavum. A propos d'une observation.

Rhinopharyngeal localization of amyloidosis is particularly rare. The authors report a case of isolated amyloidosis of the cavum, and provide a brief summary of the amyloid substances and other localizations of this pathology.

[Transeptal approach to the pituitary fossa. A simplified technic via an exclusively endonasal approach]. / Voie transeptale pour la fosse hypophysaire. Technique simplifiée par voie endonasale pure.

An updated Segura operation, this technique combines a pure endonasal septal approach and the insertion of a compact adapted autostatic retractor. It has the benefit of simplicity, has fewer disadvantages and represents an appreciable gain in time. Difficulties have not been encountered provided the usual landmarks associated with transeptal surgery are taken into account.