Multiple mechanisms of action of ZR2002 in human breast cancer cells: a novel combi-molecule designed to block signaling mediated by the ERB family of oncogenes and to damage genomic DNA

The mechanism of action of ZR2002, a chimeric amino quinazoline designed to possess mixed EGFR tyrosine kinase (TK) inhibitory and DNA targeting properties, was compared to those of ZR01, a reversible inhibitor of the same class and PD168393, a known irreversible inhibitor of EGFR. ZR2002 exhibited 4-fold stronger EGFR TK inhibitory activity than its structural homologue ZR01 but was approximately 3-fold less active than the 6-acrylamidoquinazoline PD168393. It preferentially blocked EGF and TGFalpha-induced cell growth over PDGF and serum. It also inhibited signal transduction in heregulin-stimulated breast tumour cells, indicating that it does not only block EGFR but also its closely related erbB2 gene product. In contrast to its structural homologues, ZR2002 was capable of inducing significant levels of DNA strand breaks in MDA-MB-468 cells after a short 2 hr drug exposure at a concentration as low as 10 microM. Reversibility studies using whole cell autophosphorylation and growth assays in human breast cell lines showed that in contrast to its reversible inhibitor counterpart ZR01, ZR2002 induced irreversible inhibition of EGF-stimulated autophosphorylation in MDA-MB-468 cells and irreversible inhibition of cell growth. Moreover despite possessing a weaker binding affinity than PD168393, it induced a significantly more sustained antiproliferative effect than the latter after a pulse 2 hr exposure. More importantly, in contrast to ZR01 and PD168393, ZR2002 was capable of inducing significant levels of cell death by apoptosis in MDA-MB-468 cells. The results in toto suggest that the superior antiproliferative potency of ZR2002 may be due to its ability to induce a protracted blockade of receptor tyrosine kinase-mediated signaling while damaging cellular DNA, a combination of events that may trigger cell-killing by apoptosis.     

Evidence for an Association of Human Papillomavirus and Breast Carcinomas

Human papillomavirus (HPV) DNA has been detected in breast carcinoma by different laboratorial techniques, suggesting the virus could play a role in the pathogenesis of this tumor. The aim of the present study is to investigate the presence of HPV in patients with breast carcinoma and the correlation of the viral infection with prognostic factors for the disease outcome. Between June 2001 and July 2002, 101 paraffin embedded breast carcinoma specimens were analyzed through polymerase chain reaction (PCR) and sequencing of HPV-E6 gene. Twenty specimens of reduction mammoplasty and 21 specimens of fibroadenomas were also studied as a non-malignant control group. Two different specific primer sets targeting E6 region of the HPVs 16 and 18 were used for the analysis. The HPV DNA was detected in 25 breast carcinomas (24.75%), but in none of the benign breast specimens ( p < 0.001). Out of the 25 positive cases, 14 were HPV-16 positive (56%) and 10 were HPV-18 positive (40%). An original finding was the detection of both HPV-16 and -18 in a single tumor (4%). The amplified viral sequences confirmed the presence of HPV-16 and -18. No correlation between the presence of HPV DNA and specific prognostic predictors for the disease outcome was observed. Our results suggest that the presence in the breast of either HPV-16 or -18 might be related to development of the malignant phenotype. Further studies are warranted.     

Possible induction of mania or hypomania by atypical antipsychotics: an updated review of reported cases

BACKGROUND: Atypical antipsychotics are widely used in clinical practice for several psychiatric disorders. Between 1994 and 1999, 26 cases of manic and hypomanic syndromes were reported with olanzapine and risperidone and were described in a previous review article. METHOD: An updated MEDLINE search (1999-2003) using the terms atypical antipsychotics, amisulpride, aripiprazole, clozapine, flupenthixol, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine, hypomania, and mania showed that 34 new cases of induced hypomanic or manic syndromes have been published, not only with olanzapine (N = 5) and risperidone (N = 6), but also with quetiapine (N = 5) and ziprasidone (N = 11) treatment. Six cases have been reported with flupenthixol and 1 with amisulpride, two antipsychotics considered as "partial" atypicals. RESULTS: A critical analysis of these case reports revealed that the effects on mood were insufficiently documented in some of the reports but that for 20 of them, evidence is highly suggestive of a causative role of atypical antipsychotics in the induction of manic/hypomanic symptomatology. CONCLUSION: This updated review continues and extends the results of the initial review and suggests that atypical antipsychotics have some intriguing effects on mood. Such effects have never been reported with conventional antipsychotics. The mechanisms involved in this phenomenon of mood switch remain to be elucidated.     

Factors influencing compulsory admission in first-admitted subjects with psychosis

Abstract. Background: There is a growing body of evidence that patients with early psychosis have undesirable pathways to care, yet few studies have explored the factors related to compulsory admission in patients with psychosis. The aim of the present study was to examine the demographic and clinical factors and pathways to care influencing compulsory admission in first-admitted subjects with psychosis. Methods: Pathways to care, clinical and demographic characteristics, were assessed using multiple sources of information in 86 subjects with psychosis first admitted in two hospitals of South-Western France. Characteristics independently associated with compulsory admission were explored using logistic regressions. Results: Nearly two-thirds of the subjects (61.6%) were compulsorily admitted. Compulsory admission was independently predicted by being a male (adjusted OR = 3.2, 95% CI 1.2–8.6, p = 0.02), having a diagnosis of schizophrenia broadly defined (adjusted OR = 2.8, 95% CI 1.02–7.4, p = 0.04) and absence of depressive or anxiety symptoms (adjusted OR = 0.05, 95 % CI 0.005–0.5, p = 0.01). Conclusion: These results suggest that factors related to the disease itself play an important role in decisions concerning compulsory admission. The high frequency of compulsory admission as the first mode of contact with psychiatric hospital in subjects with psychosis constitutes a major public health issue. Further research on the strategies aimed at avoiding compulsory admission in subjects with incipient psychosis is necessary.     

MRI findings in pituitary-hypothalamic axis Langerhans cell histiocytosis

Pituitary-hypothalamic axis Langerhans cell histiocytosis is an uncommon entity. It is a rare disease in adults. The CT and MR study provides us the best anatomo-topographic evaluation and determine the precise size of the lesion which are necessary to the treatment. We report a case of hypothalamic involvement by Langerhans cell histiocytosis accompanied by lesions in bone affecting a 31-year-old woman. The clinical, histiotological and CT/MR findings of histiocytosis X are described in this article.     

Coronary-pulmonary arterial fistula in the adult: report of 6 cases and review of the literature

Six new patients and 33 previously reported with coronary-to-pulmonary artery fistula were reviewed. The mean age at the time of diagnosis was 51 years. A male predominance was found (65%). Angina was the most common symptom. The artery mostly involved was the left anterior descending coronary artery and the fistula drained more often to the main pulmonary artery. The left-to-right shunt is small in the majority of patients and the associated significant coronary artery disease was detected in 18% of cases. Good results of surgical closure of the fistula are usually obtained. An alternative to surgical treatment is percutaneous transcatheter embolization of coronary artery fistulas.     

Weill Marchesani syndrome. Report of a case

Weill Marchesani syndrome is a congenital disease that combines microspherophakia and skeletal abnormalities. The authors report a 19-year-old male, born of a consanguineous marriage, with a progressive decrease in visual acuity. The general examination showed a squat look, dwarfism, muscle hypertrophy, short hands and feet, and joint stiffness. The ophthalmological examination showed that visual acuity was limited to hand motion in the right eye despite correction and no perception of light in the left eye. Intraocular pressure was 36 mmHg in the right eye and 40 mmHg in the left eye. The anterior chamber was irregular with iridophakodonesis and microspherophakia of both lenses. The zonula was partially ruptured in the right eye. The iridocorneal angle was narrow. Fundus eye examination showed a pale optic disc with an excavation of 9/10 on the right. In the left eye, the optic disc was totally excavated. Cardiovascular check-up revealed rheumatic aortic valvular cardiopathy. The therapy consisted of combined surgery: phakophagia with anterior vitrectomy plus trabeculectomy operated on the right eye. Weill Marchesani syndrome is a rare congenital affection with a recessive autosomal transmission. The visual prognosis is dominated by secondary glaucoma due to pupillary blockage by the mobile eye lens. This observation illustrates the seriousness of spontaneous progression in Weill Marchesani syndrome, justifying the necessity of lens extraction before the onset of complications.     

Cardiopericardial Hydatid Cysts

apd: 18 December 2000     

Brugada syndrome

The Brugada syndrome is a clinical-electrocardiographic diagnosis characterised by syncopal or sudden death episodes in patients with a structurally normal heart with a characteristic electrocardiographic pattern consisting of ST segment elevation in the precordial leads V1 to V3 and a morphology of the QRS complex resembling a right bundle branch block. In many patients with the Brugada syndrome, the electrocardiographic manifestations transiently normalize; leading to underdiagnosis of the syndrome. The administration of sodium channel blockers such as ajmaline, flecainide or procainamide accentuate the ST segment elevation and can be used to unmask concealed and intermittent forms of the disease. The incidence of sudden death in this syndrome is very high and can only be prevented by implanting a cardioverter-defibrillator. Because of high incidence of familial occurrence, the extension of the testing to family members is important.