Clinical and Molecular Genetics of the Phosphodiesterases (PDEs).

Endocr Rev. 2013 Dec 5;

Authors: Azevedo MF, Faucz FR, Bimpaki E, Horvath A, Levy I, de Alexandre RB, Kahn FA, Manganiello V, Stratakis CA

Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.

PMID: 24311737 [PubMed - as supplied by publisher]

Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy.

J Cancer. 2013;4(9):736-754

Authors: Domvri K, Zarogoulidis P, Darwiche K, Browning RF, Li Q, Turner JF, Kioumis I, Spyratos D, Porpodis K, Papaiwannou A, Tsiouda T, Freitag L, Zarogoulidis K

Abstract
Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term "maintenance" treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials.

PMID: 24312144 [PubMed - as supplied by publisher]

Importance of Smoking Cessation in a Lung Cancer Screening Program.

Curr Surg Rep. 2013 Dec;1(4)

Authors: Munshi V, McMahon P

Abstract
Early detection of lung cancer and smoking cessation interventions can decrease lung cancer mortality, but information on the effectiveness and interaction between smoking cessation and lung cancer screening is sparse and inconsistent. This review aims to synthesize recent studies in two major areas of interest. First, we explore the interactions and potential for synergies between lung cancer screening programs and smoking cessation by summarizing reported changes in smoking behavior observed in major screening trials in the United States and Europe, as well as attempts to use smoking cessation interventions to augment the benefits from lung cancer screening programs. Second, we review the interaction between smoking habits and pre/post-operative pulmonary resection outcomes, including changes in smoking behavior post-diagnosis and post-treatment. Information from these areas should allow us to maximize benefits from smoking cessation interventions through the entire lung cancer screening process, from the screen itself through potential curative resection after diagnosis.

PMID: 24312745 [PubMed - as supplied by publisher]

Related Articles

Adherence to inhaled corticosteroids by asthmatic patients: measurement and modelling.

Int J Clin Pharm. 2013 Dec 1;

Authors: Taylor A, Chen LC, Smith MD

Abstract
Background Poor adherence to inhaled corticosteroids (ICS) is known as the main cause for therapeutic failure in asthma treatment and associated morbidity. To improve adherence, targetted and effective interventions need to be developed ideally based on using longitudinal follow-up of a large study cohort to establish patterns and influences on adherence. Objective To develop an annual measure of asthma patients' adherence to ICS using primary care prescribing data over consecutive annual intervals, and to statistically model ICS adherence controlling for a range of patient factors. Setting A retrospective cohort study between 1997 and 2010 using United Kingdom general practice prescribing data on asthma patients aged between 12 and 65 years, without a diagnosis of chronic obstructive pulmonary disease. Method Patient's ICS prescriptions are used to calculate the 'number of days prescribed during calendar year' divided by 'number of days in the interval' to form an annual prescription possession ratio (PPR) for each patient. Several definitions of PPR are considered and compared when calculating numerator and denominator. Adherence, measured by the preferred PPR, is then modelled to estimate the effect of asthma exacerbation, severity, control and other patient factors on adherence. Main outcome measure PPR, being a proxy measure for adherence. Results Annual PPR by all strategies gave a similar frequency profile. ICS were either over- or under-prescribed for over half of the follow-up time. Adherence was lower in younger patients, those newer to the study timeframe, those with less severe asthma, those with good control, with lower previous adherence, and who had not previously experienced an exacerbation. Conclusion The chosen PPR simulated clinical use of ICS most closely; including overlapping days, excess days passed to the next interval, considering gaps in the denominator, with censoring at 100 %. The PPR is a useful measure for signalling or measuring adherence changes over time. The modelling results identified many characteristics which would indicate which asthma patients and at what points in their treatment cycle they would be at increased risk of low adherence.

PMID: 24293333 [PubMed - as supplied by publisher]