Modulation of cellular response to cisplatin by a novel inhibitor of DNA polymerase beta.

DNA polymerase beta (Pol beta) is an error-prone enzyme whose up-regulation has been shown to be a genetic instability enhancer as well as a contributor to cisplatin resistance in tumor cells. In this work, we describe the isolation of new Pol beta inhibitors after high throughput screening of 8448 semipurified natural extracts. In vitro, the selected molecules affect specifically Pol beta-mediated DNA synthesis compared with replicative extracts from cell nuclei. One of them, masticadienonic acid (MA), is particularly attractive because it perturbs neither the activity of the purified replicative Pol delta nor that of nuclear HeLa cell extracts. With an IC50 value of 8 microM, MA is the most potent of the Pol beta inhibitors found so far. Docking simulation revealed that this molecule could substitute for single-strand DNA in the binding site of Pol beta by binding Lys35, Lys68, and Lys60, which are the main residues involved in the interaction Pol beta/single-strand DNA. Selected inhibitors also affect the Pol beta-mediated translesion synthesis (TLS) across cisplatin adducts; MA was still the most efficient. Therefore, masticadienonic acid sensitized the cisplatin-resistant 2008C13*5.25 human tumor cells. Our data suggest that molecules such as masticadienonic acid could be suitable in conjunction with cisplatin to enhance anticancer treatments.

[Obstructive sleep apnea syndrome in adults and cardiovascular risk]. / Syndrome d'apnées obstructives du sommeil de l'adulte et risque cardiovasculaire.

Sleep obstructive apnea syndrome (SOAS) is a common condition with a strong male predominance. Its incidence is more than 1 percent in the population as a whole. It exists in snorers. Both snoring and SOAS are linked to the presence of abnormalities (congenital or acquired) of the upper respiratory tract. The nocturnal cardiovascular consequences of SOAS are directly linked to apnea. Bradycardia occurs during apnea and tachycardia when ventilation restarts. Paroxysmal nocturnal hypertension is a constant feature. Even in individuals who are normotensive during the day, each restarting of ventilation is accompanied by peaking of blood pressure. The pulmonary artery pressure curve follows that of systemic blood pressure. Complications begin when SOAS has been present for several years: 1) Chronic: permanent systemic hypertension is common (56 percent of SOAS). It is often refractory to antihypertensive treatment. 2) Acute: the onset of myocardial infarction and of cerebrovascular accidents explains the heavy mortality of SOAS (37 percent at 8 years in untreated individuals with a number of episodes of apnea exceeding 20 per hour of sleep). Other acute complications are less common: acute pulmonary edema, nocturnal sudden death. These events may be prevented by treatment suppressing apnea: actuarial survival curves are then superimposable upon those of the population as a whole. Thus SOAS is a cardiovascular risk factor which is remarkably reversible by specific treatment, though which most often passes unrecognized.

[Conduction disorders in Cheyne-Stokes respiration caused by cardiac insufficiency]. / Troubles de la conduction au cours de la respiration de Cheyne-Stokes due à l'insuffisance cardiaque.

This report describes a case of Cheyne-Stokes respiration linked to heart failure, with periodic disturbances of atrioventricular conduction during the augmentation phase of the tidal volume. The circulatory retardation caused by heart failure induced a phase lag of the negative retroaction system and secondarily an oscillation in the respiratory command. The conduction disturbances resulted from vagal stimulation of multifactorial origin. The atrioventricular conduction disturbances were analogous to those seen in other periodic respiratory diseases.

[Rapid development of mitral and aortic stenoses with chronic hemodialysis. A report of 2 cases]. / Sténoses mitrale et aortique de constitution rapide chez les hémodialysés chroniques: a propos de deux observations.

Chronic renal failure is associated with a high incidence of calcifications of the mitral anulus, which if severe enough may result in mitral stenosis or regurgitation. Aortic valve calcifications, though less frequent, may also occur and cause aortic valve stenosis, as observed in two patients. In hemodialysed patients, identification of valvular aortic stenosis might be difficult on a clinical basis since the systolic ejection murmur might be attributed to aortic sclerosis or a high output state and left ventricular hypertrophy to previous hypertensive disease. Calcific aortic stenosis may easily be detected using echocardiography combined with the continuous Doppler technique.