Expression of the immediate early IE180 protein under the control of the hTERT and CEA tumor-specific promoters in recombinant pseudorabies viruses: Effects of IE180 protein on promoter activity and apoptosis induction.

Since the pseudorabies virus (PRV) genome encodes for a single immediate-early protein, IE180, we reasoned that this strong transactivating protein could represent a key regulatory switch that could be genetically manipulated in order to alter its tropism towards cancer cells. We therefore initiated studies to test whether the human telomerase reverse transcriptase (hTERT) and carcinoembryonic antigen (CEA) tumor promoters could functionally replace the IE180 promoter. We show that both promoters can functionally substitute the IE180 promoter in plasmid constructs and recombinant viruses, and observed that IE180 differentially auto-regulated each promoter tested, with PRV IE180 negatively regulating the hTERT promoter but positively hyper-activating the CEA promoter. Interestingly, we also observed that the recombinant PRV-TER and PRV-CEA viruses preferentially replicated in diverse cancer cell lines compared to control non-cancer cells, and the PRV-CEA was capable of additionally inducing a profound apoptotic phenotype which we correlated to the overexpression of IE180.

Involvement of α2- and ß2-adrenoceptors on breast cancer cell proliferation and tumour growth regulation.

BACKGROUND AND PURPOSE: ß-Adrenoceptors are expressed in human and experimental animal breast cancer cells. However, the effect of the agonists and antagonists reported on cell proliferation and tumour growth was paradoxical, precluding their utilization as possible adjuvant therapy, mainly in the cases of refractory tumours. EXPERIMENTAL APPROACH: ß-Adrenoceptor expression was analysed by immunofluorescence and RT-PCR. Cell proliferation was assessed by [(3) H]-thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting. KEY RESULTS: ß(2) -Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α(2) -adrenoceptor action) and decreased in every tested cell line by the ß-adrenoceptor agonist isoprenaline and the ß(2) -adrenoceptor agonist salbutamol. Isoprenaline and salbutamol reduced tumour growth in every tumour tested (mouse C4-HD and CC4-3-HI and human IBH-4, IBH-6 and MDA-MB-231 cell lines growing as xenografts in nude mice). These effects were reversed by the ß-adrenoceptor antagonist propranolol. The α(2) -adrenoceptor antagonist rauwolscine and the ß(2) -adrenoceptor agonist salbutamol were equally effective in diminishing tumour growth. ERK 1/2 activation analysed in IBH-4 tumours correlated with tumour growth, with the ß-adrenoceptor agonists decreasing its activation. Inhibition of ERK 1/2 phosphorylation in vitro was mainly mediated by the PKA pathway. CONCLUSIONS AND IMPLICATIONS: In our experimental models, the ß-adrenoceptor agonists inhibited breast cancer cell proliferation and tumour growth, probably mediated by inhibition of ERK 1/2 phosphorylation. The ß-adrenoceptor agonists were as effective as the α(2) -adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer.

Adrenoceptors: non conventional target for breast cancer?

Epinephrine and Norepinephrine, typically released during stress bind to nine different adrenoceptors (AR) which classically control the cardiovascular and respiratory systems. New targets were described for the many agonists and antagonists developed for these AR, as the central nervous system. During the last three decades, AR expression and action on the mammary gland/breast were extensively investigated. In the cow mammary gland, good milkability was associated with low density of beta(2)-AR and high density of alpha(2)-AR. In the rat normal mammary gland, beta-AR are expressed in the epithelial cells, alveoli, ducts, and adipocytes showing an exquisite regulation by steroid hormones and prolactin. In rat dimethylbenz(a)anthracene (DMBA) tumors, a close correlation was observed between tumor growth and beta-AR concentration. beta(2)-AR were described in numerous human cell lines and breast tumors. The action of beta-adrenergic compounds on cell proliferation is contradictory. While some authors found that beta-agonists significantly inhibit cancer cell proliferation and tumor growth in mice, others described a significant reduction in DNA synthesis by beta-blockers. Also, positive effects of beta-AR on human carcinoma cell migration have been described. alpha(2)-AR are expressed in human breast cancer and non-cancer cell lines, their stimulation being associated with increased cell proliferation. In vivo clonidine increased tumor growth and alpha (2)-adrenergic antagonists completely reversed this effect. When administered alone, rauwolscine inhibited tumor growth behaving as an inverse agonist. Therefore, the numerous adrenergic beta- and alpha-AR agonists or antagonists could prove to be unexpected therapeutic options for mammary gland/ breast and mainly breast cancer.

Alpha2-adrenoceptor action on cell proliferation and mammary tumour growth in mice.

BACKGROUND AND PURPOSE: Breast cancer, the most common cancer in women in most countries, is a highly stressful disease. Catecholamines released during stress bind to adrenoceptors and we have recently described alpha(2)-adrenoceptors in human breast cell lines, linked to enhanced cell proliferation. The purpose was to assess the in vivo effects of compounds acting on alpha(2)-adrenoceptors in a reliable model of breast cancer. EXPERIMENTAL APPROACH: The expression of alpha(2)-adrenoceptors was confirmed by immunocytochemistry, immunofluorescence and reverse transcription-PCR in the mouse mammary tumour cell line MC4-L5. Proliferation was assessed by [(3)H]thymidine incorporation and tumours were measured daily. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labelling. KEY RESULTS: Incubation for 2 days with alpha(2)-adrenoceptor agonists (clonidine and dexmedetomidine) significantly enhanced proliferation of the mouse mammary tumour cell line MC4-L5. These agonists also significantly stimulated tumour growth of the progestin-dependent tumour C4-HD even in the presence of medroxyprogesterone acetate (MPA). In every tumour tested (C4-HD, CC4-2-HD and CC4-3-HI), regardless of MPA sensitivity, clonidine significantly enhanced tumour growth in the absence of MPA. The alpha(2)-adrenoceptor antagonists, yohimbine and rauwolscine, completely reversed the effects of clonidine. However, the group receiving yohimbine alone showed a nonsignificant but constant increase in tumour growth, whereas rauwolscine alone diminished tumour growth significantly, behaving as a reverse agonist. In CC4-3-HI tumours, rauwolscine treatment enhanced apoptosis and diminished the mitotic index, whereas clonidine had the inverse effect. CONCLUSIONS AND IMPLICATIONS: Alpha(2)-adrenoceptor agonists enhanced tumour growth and rauwolscine behaved in vivo as a reverse agonist, suggesting that it may be tested for adjuvant treatment.

Rigidity and/or flexibility of calixarenes. effect of the p-sulfonatocalix[n]arenes (n = 4, 6, and 8) on the electron transfer process [Ru(NH3)5pz]2+ + Co(C2O4)3(3-).

The reaction [Ru(NH3)5pz]2+ + Co(C2O4)33- has been studied in aqueous solutions of p-sulfonatocalix[n]arene (n = 4, 6, and 8). The results are interpreted by using the pseudophase model. Results show that the rigidity and/or flexibility of the assembled rings have a great effect on the thermodynamics of inclusion of the guest into the host and, therefore, on the kinetics of the electron transfer processes that take place in these media. The obtained results are discussed from the viewpoint of two types of interactions: electrostatic and nonelectrostatic. From surface potential measurements, the guest-host interactions have been demonstrated to be mainly due to nonelectrostatic interactions, although the species are charged. So, the nonelectrostatic contribution to the equilibrium constant in all the calixarenes studied is 1 order of magnitude higher than the electrostatic one (Knel = 144 and 884 mol-1 dm3 for p-sulfonatocalix[n]arene (n = 4 and 6, respectively) and Kel approximately 10 mol-1 dm3). Electrostatic interactions also affect the kinetic results.

[Spontaneous extraperitoneal bladder rupture. Report of a case]. / Rotura vesical extraperitoneal espontánea. Presentación de un caso.

The spontaneous extraperitoneal bladder rupture is an uncommon event and the diagnosis is very difficult. It is defined like the rupture of bladder wall in absence of traumatism or iatrogenic techniques. The extravasation usually is produced into the peritoneal cavity, because of the greater weakness of the vesical dome. The diagnosis is based on the retrograde cystography, being necessary the surgical treatment in the intraperitoneal rupture, while the extraperitoneal one, could be treated in a conservative way with a vesical catheter. Here we present a case of spontaneous extraperitoneal bladder rupture, with oliguria, abdominal pain and a right hypochondrius mass as clinic presentation. Due to this, the diagnosis was made by the TAC, in which it was appreciated a continuity solution in the anterior bladder wall, with a contrast extravasation through the anterior abdominal wall. The retrograde cystography confirmed the definitive diagnosis. The treatment followed was based on the keeping of the vesical catheter and antibiotherapy.

Rotura vesical extraperitoneal espontánea. Presentación de un caso / Spontaneous estraperitoneal bladder rupture. A propos of a case

La rotura vesical espontánea es una entidad muy poco común y de difícil sospecha diagnóstica. Se define como la rotura de la pared vesical en ausencia de traumatismos o maniobras iatrógenas. La extravasación suele producirse en la cavidad peritoneal, por la mayor debilidad de la cúpula vesical. El diagnóstico se basa en la cistografía retrógrada, siendo necesario el tratamiento quirúrgico en la rotura intraperitoneal, mientras que la extraperitoneal puede ser manejada de forma conservadora, con sondaje vesical. Presentamos un caso de rotura vesical espontánea extraperitoneal, con oliguria, dolor abdominal y masa en hipocondrio derecho como presentación clínica. Debido a ello el diagnóstico fue realizado mediante la realización de una TAC, donde se apreciaba una solución de continuidad en vertiente anterior de vejiga, distribuyéndose el extravasado por la pared abdominal anterior. La cistografía retrógrada confirmó el diagnóstico definitivo. El tratamiento aplicado se basó en el mantenimiento del sondaje vesical y antibioterapia (AU)

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[Churg-Strauss syndrome with pericardial and myocardial involvement]. / Síndrome de Churg-Strauss con afectación pericárdica y miocárdica.

We report the case of a 63-year-old female diagnosed with Churg-Strauss syndrome with both pericardial tamponade and myocardial involvement with congestive heart failure. Allergic granulomatosis and angiitis (Churg-Strauss syndrome) is classically characterized by hypereosinophilia and systemic necrotizing vasculitis of medium and small arteries in patients with previous allergic rhinitis or bronchial asthma. Subsequently the disease has been shown to be associated with cardiac involvement and is responsible for higher morbidity and mortality. The literature for Churg-Strauss syndrome of the heart is reviewed and recent advances in the clinical management of the disease according to appropriate therapeutic strategies are recommended.

[Congenital aneurysm of the sinus of Valsalva ruptured to right ventricle with a ventricular septal defect and aortic regurgitation]. / Aneurisma congénito del seno de Valsalva roto a ventrículo derecho, comunicación interventricular e insuficiencia aórtica.

We report the case of a patient with a congenital aneurysm of the sinus of Valsalva ruptured in the right ventricle, aortic valvular regurgitation and ventricular septal defect that remained asymptomatic for many years and presented clinically with severe volume overload of the heart and congestive heart failure. We describe the anatomic, echocardiographic and angiographic findings of this unusual entity with a review of the literature.

[A hydatid cyst in the vena cava inferior and right atrium with venous flow obstruction and pulmonary dissemination]. / Quiste hidatídico en vena cava inferior y aurícula derecha con obstrucción del flujo venoso y diseminación pulmonar.

We report the case of a 62-year-old female patient operated for a hepatic hydatid cyst that years later was found to have a hydatid cyst in the inferior vena cava and right atrium that was the source of disseminated pulmonary spread of the disease and occlusion of the inferior vena cava blood flow. Cardiac hydatid disease is very uncommon and is frequently associated with a poor prognosis. The literature for hydatid disease of the heart is reviewed and the clinical and echocardiographic relevant findings of this patient are discussed.

[Acute endocarditis of the native aortic valve caused by Propionibacterium acnes]. / Endocarditis aguda sobre válvula aórtica nativa por Propionibacterium acnes.

Propionibacterium acnes is often considered to be a contaminant but it has also been found to be the principal pathogen in serious infections. P. acnes is a rare cause of infective endocarditis. It has been suggested that aortic root abscesses are caused by bacteria that are particularly virulent. The strongest risk factor for serious infections by this bacteria is the presence of foreign bodies. A case is presented in which endocarditis of a native aortic valve caused by P. acnes was associated with an aortic root abscess. Transesophageal echocardiography is particularly helpful in the diagnosis of this severe complication of infective endocarditis. The literature for P. acnes endocarditis is reviewed.

[Cardiac papillary fibroelastoma. Different forms of the clinical presentation]. / Fibroelastoma papilar cardíaco. Diferentes formas de presentación clínica.

Papillary fibroelastoma is an uncommon cardiac tumor rarely diagnosed during life. Although most fibroelastomas are incidental findings at autopsy, a few cases have been associated with cardiac symptoms that include angina, arterial embolism and sudden death. We report the case of two patients, a 35-year-old male with an acute myocardial infarction and ventricular fibrillation and a 53-year-old asymptomatic female, with cardiac masses first detected by transthoracic echocardiography. A more detailed morphological study was provided by transesophageal echocardiography. After cardiac surgery, the anatomical study demonstrated that both tumors were papillary fibroelastomas. The literature concerning papillary fibroelastoma is reviewed.

Vasospastic angina mimicking graft failure and spontaneously appearing after left ventriculography.

A 49-year-old female with significant (75%) left main coronary artery stenosis was initially considered to have developed early obstruction of a saphenous vein graft to the left anterior descending coronary artery, because of recurrent postoperative angina. In a second catheterization study, left ventriculography showed normal contractility of all segments and was immediately followed by the onset of angina and angiographic demonstration of diffuse spasm of the entire left coronary artery system beyond the stenosis. Vasospasm of the left coronary artery before or during ventriculography was unlikely in the absence of regional contractility impairment. The close temporal association between the left ventricular angiogram and the angiographic demonstration of vasospasm suggested a direct cause and effect relationship.