Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatment.

Since response to platinum-based therapy in non-small-cell lung cancer (NSCLC) is poor, the present study was designed to rationally identify novel drug combinations in cell models including the A549 cell line and the cisplatin-resistant subline A549/Pt, characterized by reduced sensitivity to cisplatin-induced apoptosis and by upregulation of efflux transporters of the ATP binding cassette (ABC) superfamily. Given the molecular features of these cells, we focused on compounds triggering apoptosis through different mechanisms, such as the mitochondria-targeting drug arsenic trioxide and the phenanthridine analog sanguinarine, which induce apoptosis through the extrinsic pathway. Sanguinarine, not recognized by ABC transporters, could overcome cisplatin resistance and, when used in combination with arsenic trioxide, was synergistic in A549 and A549/Pt cells. The arsenic trioxide/sanguinarine cotreatment upregulated genes implicated in apoptosis activation through the extrinsic pathway. Drug combination experiments indicated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment improved arsenic trioxide/sanguinarine efficacy, a feature associated with a striking apoptosis induction, particularly in the cisplatin-resistant variant. Thus, a synergistic interaction between sanguinarine and arsenic trioxide could be obtained independent of relative cell sensitivity to arsenic trioxide, and an enhanced apoptosis induction could be achieved in combination with TRAIL through modulation of the extrinsic apoptotic pathway. Antitumor activity studies supported the interest of drug combinations including TRAIL in NSCLC, indicating that drug-resistant NSCLC cells can efficiently be killed by the combination of proapoptotic agents. Our results suggest that the molecular changes occurring in treated cells may be exploited to rationally hit surviving cells.

Chronic cough in patients with sleep-disordered breathing.

Chronic cough can be the sole presenting symptom for patients with obstructive sleep apnoea. We investigated the prevalence, severity and factors associated with chronic cough in patients with sleep-disordered breathing (SDB). We invited 108 consecutive patients who had been referred for evaluation of SDB to complete a comprehensive questionnaire on respiratory and sleep health, which included the Leicester Cough Questionnaire (cough specific quality of life; LCQ), Epworth Sleepiness Scale (ESS) and the Mayo Clinic gastro-oesophageal questionnaire. Chronic cough was defined as cough for a duration of >2 months. 33% of patients with SDB reported a chronic cough. Patients with a chronic cough had impaired cough related-quality of life affecting all health domains (mean+/-sem LCQ score 17.7+/-0.7; normal = 21). Patients with SDB and chronic cough were predominantly females (61% versus 17%; p<0.001) and reported more nocturnal heartburn (28% versus 5%; p = 0.03) and rhinitis (44% versus 14%; p = 0.02) compared to those without SDB. There were no significant differences in ESS, respiratory disturbance index, body mass index, or symptoms of breathlessness, wheeze, snoring, dry mouth and choking between those with cough and those without. Chronic cough is prevalent in patients with SDB and is associated with female sex, symptoms of nocturnal heartburn and rhinitis. Further studies are required to investigate the impact of continuous positive airway pressure therapy on cough associated with SDB to explore the mechanism of this association.

ABC transporters as potential targets for modulation of drug resistance.

ATP binding cassette transporters are implicated in multidrug resistant phenotypes of tumor cells and may be cancer stem cell markers. Inhibitors of drug efflux pumps represent an emerging group of potentially useful agents for the improvement of antitumor therapy. Here we provide an overview of drug transporter functions and modulation.

[Myopotentials and unipolar cardiac stimulation. Asynchronous conversion of generators]. / Miopotenziali e stimolazione cardiaca unipolare. Conversione in asincrono dei generatori.

During routine control of unipolar demand pacemakers (SSI) and the myopotential effects by means of chest wall stimulation (CWS) we have observed a non-inhibition and a pacemaker asynchronous conversion. With the arm recovery this phenomenon disappears. A concealed effect of myopotentials is possible. This is an effect depending on anti-interference function (EMI) of demand pacemakers. Chest wall stimulation analysis is an additional technique for a complete study of muscular activity effects.

[Acute myocardial infarction in subjects under 40 years of age. Coronary risk factors]. / L'infarto miocardico acuto in soggetti di età inferiore ai 40 anni. Fattori di rischio coronarico.

Myocardial infarction in the under-40s is rare. A series of 19 patients, 3.07% of a two-year series of coronary cases, is presented with a view to evaluating the incidence of risk factors, with special attention to familial factors and dyslipoproteinaemia. Risk factors are discussed together with the statistical importance of family aspects in two previous generations. Family factors and the abnormal lipoprotein profile are statistically important while other risk factors such as arterial hypertension, obesity and the use of oral contraceptive are insignificant. Cigarette smoking was a factor in more than 50% of cases and this strengthens the effects of other factors (obesity and hypertension) which, alone, do not appear to have any inductive importance in the genesis of coronary disease in this particular age segment.

[Inter-electrode distance and atrial sensing. Our experience with atrial-guided pacing (VDD) in the biennium 1990-1991]. / Distanza interelettrodica e sensing atriale. Nostra esperienza con stimolazione atrio-guidata (VDD) nel biennio 1990-1991.

We implanted 47 Phymos VDD pacemakers (53.7% for complete atrioventricular block-42.57% for symptomatic lower heart block) in the 1990-91 period. In this series of cases with EDE 830-830S leads by means Holter technique we evaluated the atrial trigger. A high percentage of atrial sensing (97.8%) was found with 11 cm leads. The right atrial motion study is realized to explain the atrial sensing with floating leads.

[Abnormalities of the sensing function. Further contributions to the current classification]. / Le anormalità della funzione di sensing. Ulteriori apporti alla attuale classificazione.

With systemic unipolar pacemaker control by chest wall stimulation and interference we have obtained further data of the sensing function in more the 5000 clinical controls. A better classification of abnormal sensing function is important for a full electrocardiographic interpretation. We have established that the oversensing is always a primary evident or concealed phenomenon. Undersensing is a primary or secondary phenomenon provoked by a concealed oversensing in refractory period.

Novel insights into targeting ATP-binding cassette transporters for antitumor therapy.

ATP-binding cassette (ABC) transporters are a large family of proteins implicated in physiological cellular functions. Selected components of the family play a well-recognized role in extruding conventional cytotoxic antitumor agents and molecularly targeted drugs from cells. Some lines of evidence also suggest links between transporters and tumor cell survival, in part unrelated to efflux. However, the study of the precise mechanisms regulating the function of drug transporters (e.g., posttranslational modifications such as glycosylation) is still in its infancy. A better definition of the molecular events clarifying the regulation of transporter levels including regulation by microRNAs may contribute to provide new molecular tools to target such a family of transporters. The present review focuses on the biological aspects that implicate ABC transporters in resistance of tumor cells, including cancer stem cells. Molecular analysis of well-known preclinical systems as well as of cancer stem cell models supports the notion that ABC transporters represent amenable targets for modulation of the efficacy of antitumor agents endowed with different molecular features. Recent achievements regarding tumor cell biology are expected to provide a rationale for developing novel inhibitors that target ABC transporters implicated in drug resistance.

Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin-based treatment.

The targeting of specific DNA repair mechanisms may be a promising strategy to improve the efficacy of antitumor therapy. The cytotoxic effects of the clinically relevant topoisomerase 1 (Top1) poison camptothecins are related to the generation of DNA lesions and tumor cells may be resistant to DNA damaging agents due to increased repair. Tyrosyl- DNA phosphodiesterase 1 (TDP1) is implicated in the repair of strand breaks by removing abortive Top1/DNA complexes. Thus, a role for TDP1 in counteracting DNA damage induced by camptothecins has been proposed. Here, we review the role of TDP1 in DNA repair with particular reference to TDP1 function, its cooperation with other pathways and the development of pharmacological inhibitors.