Laboratory of Systems Approaches and Non Communicable Diseases

Rome, Italy

Laboratory of Systems Approaches and Non Communicable Diseases

Rome, Italy
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Antonicelli A.,University of Milan | Antonicelli A.,Saronno Regional Hospital | Cafarotti S.,Thoracic Surgery EOC Unit San Giovanni Hospital | Indini A.,Italian National Cancer Institute | And 13 more authors.
International Journal of Medical Sciences | Year: 2013

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs). This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient- tailored therapy could be closer than commonly expected.

Russo P.,Laboratory of Systems Approaches and Non Communicable Diseases | Del Bufalo A.,Laboratory of Systems Approaches and Non Communicable Diseases | Milic M.,Laboratory of Systems Approaches and Non Communicable Diseases | Milic M.,Institute for Medical Research and Occupational Health | And 3 more authors.
Current Molecular Medicine | Year: 2014

Epithelial cells not innervated by cholinergic neurons express nicotinic and muscarinic acetylcholine (ACh) receptors (nAChR, mAChR). nAChR and mAChR are components of the auto-/paracrine-regulatory loop of non-neuronal ACh release. The cholinergic control of non-neuronal cells may be mediated by different effects (synergistic, additive, or reciprocal) triggered by these receptors. The ionic events (Ca+2 influx) are generated by the ACh-opening of nAChR channels, while the metabolic events by ACh-binding to G-protein-coupled mAChR. Effective inter-and intracellular signaling is crucial for valuable cancer cells proliferation and survival. Depending on cancer cell type, different AChR have been identified. The proliferation of airways epithelial cancer cells and pancreatic cancer cells may be under the control of α7-nAChR and M3-mAChR, while breast cancer cells and colon cancer cells are regulated by α9-nAChR, and M3-mAChR, respectively. In turn, these receptors may activate different pathways (Ras-Raf-1-Erk-AKT) as well as other receptors (β-adrenergicR). nAChR or mAChR antagonists may inhibit cancer growth. Inhibition of M3 by antisense or antagonists (Darifenacin, Tiotropium) reduces lung or colon cancer proliferation, as well as inhibition of α9-nAChR [polyphenol (-)-epigallocatechin-3-gallate] diminishes breast cancer cells growth. α7-nAChR silencing inhibits lung cancer proliferation. Moreover, inhibition of the nAChR-β-adrenergicR pathway (β-blockers) could be also useful. This review will describe the future translational perspectives of cholinergic receptors drug-inhibition in a complex disease such as cancer that poses compelling treatment challenges. Cancer happens as consequence of disease-perturbed molecular networks in relevant organ cells that change during progression. The framework for approaching these challenges is a systems approach. © 2014 Bentham Science Publishers.

Cazzola M.,University of Rome Tor Vergata | Calzetta L.,Laboratory of Systems Approaches and Non Communicable Diseases | Page C.P.,King's College London | Rogliani P.,University of Rome Tor Vergata | And 3 more authors.
European Journal of Pharmacology | Year: 2014

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2-adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine (Emax: 97.5±2.6% and 96.4±1.1%; pEC50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles (Emax: 68.1±4.5% and 99.0±5.6%; pEC50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P<0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P<0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6 h post-treatment (+55.1±9.4%; P<0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic. © 2014 The Authors.

Russo P.,Laboratory of Systems Approaches and Non Communicable Diseases | Taly A.,CNRS Laboratory of Design and Application of Bioactive Molecules
Current Drug Targets | Year: 2012

In the years from 1856 to 1936, when the Nobel Prize for Physiology/Medicine was awarded to Dale and Loewi for their discoveries relating to chemical transmission of nerve impulses, the nicotinic acetylcholine receptor (nAChR) emerged from an assumption to a reality. Its biochemical isolation in 1970 represents a major breakthrough in pharmacology. The α7-nAChR subunit forms homo-oligodimeric nAChR with unique distinctive properties, such as high permeability to calcium and modulation by the extracellular calcium concentrations, the possibility of binding two-five molecules of agonist, function modulation via phosphorylation and/or via calcium-dependent serine/threonine kinases and modulating transmitter release and activation of GABAergic interneurons. In the brain, the α7-nAChR plays several important functions running from synaptic plasticity, regulation of neuronal growth, differentiation and survival to enhance learning and cognition. The detection of its occurrence on non-neuronal cells raises question related to their specific activity, since in these cells it appears involved in modulation of cell death, migration and signaling. Its unbalance might involve it in different diseases such as Alzheimer, Parkinson and cancer. However, the peculiarity of α7-nAChR offers rational bases to develop new drugs and new therapeutic strategies. In conclusion, α7-nAChR roughly in 150 years of life, instead to be an old actor became an important player in regulating cell signaling. © 2012 Bentham Science Publishers.

Cesario A.,Area of Systems Medicine | Auffray C.,European Institute for Systems Biology and Medicine | Russo P.,Laboratory of Systems Approaches and Non Communicable diseases | Hood L.,Institute for Systems Biology
Current Pharmaceutical Design | Year: 2014

This monographic issue of Current Pharmacological Design discusses extensively on the innovative paradigms for disease control in Active and Healthy Ageing. Wellness, as a status to be achieved and maintained in our lives, getting longer and hopefully healtier, is the new and comprehensive declination of “health” itself, leading the shaping of research and research policy in the health domain worldwide. Many of the contributions describe the state of the art –and beyond- approaches for the most common diseases based on the available medical knowledge; two, in particular (Bousquet J et al., Cesario A, et al.), extend to the innovative approaches defined in the framework of the holistic and integrative philosophy of the Predictive, Preventive, Personalized and Participatory (P4) Systems Medicine. The availability of more and more powerful technologies to extract data coupled with the inclusion of information coming from the nonstrictly- medical sphere of the patient/individual and his/her lifestyle along with the increase in computational power, will definitely set the stage for a paradigm-shift in bio-medicine with deep ethical and societal impact. The brief comment that follows speculates about the implications of this transition from the educational perspective taking stock of the direct experience of the Authors in the consultation process active in the scientific community. © 2014 Bentham Science Publishers.

Neri M.,Unit of Clinical and Molecular Epidemiology | Bonassi S.,Unit of Clinical and Molecular Epidemiology | Russo P.,Laboratory of Systems Approaches and Non Communicable Diseases
Current Drug Targets | Year: 2012

The presence of memory impairment and cognitive deficits in the Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Pick's disease (PiD) has been associated to dysfunction of cholinergic transmission, possibly due to the loss of cholinergic neurons and to the elimination of nAChR in dementia patients. Alternative hypotheses take into account molecular interactions of the β-amyloid peptide A β with nAChR, which may lead to deregulation of the receptor function. Genetic polymorphisms of CHRNA7 and CHRFAM7A, a fusion gene containing a partial CHRNA7 duplication, have been investigated as possible susceptibility traits to dementia, potentially useful either to identify high risk individuals or as therapeutic targets. To summarize the existing evidence, a systematic re-evaluation of published papers has been performed (PubMed database, no language restriction, updated to 1 st August 2011). Eleven articles reporting data on genetic variations in CHRNA7 or CHRFAM7 and risk of dementia fulfilled selection criteria and were evaluated. Published evidence on the association between variations in CHRNA7 or CHRFAM7A and the risk of dementia is still sparse and inconclusive. Further studies are needed to establish whether some polymorphisms may really affect the probability of developing AD or other forms of dementia. Additional and more conclusive results may come from the ongoing GWAS studies investigating high numbers of genetic variants in large samples, that have the potential to assess the role of genetic susceptibility in dementia. © 2012 Bentham Science Publishers.

Matera M.G.,The Second University of Naples | Calzetta L.,Laboratory of Systems Approaches and Non Communicable Diseases | Rogliani P.,University of Rome Tor Vergata | Cesario A.,IRCSS San Raffale Pisana | Cazzola M.,University of Rome Tor Vergata
Current Pharmaceutical Design | Year: 2014

In elderly people the respiratory function is affected by anatomical and physiological modifications caused by aging. Elderly COPD patients are characterized by a complexity due to an increasing prevalence of comorbidities related to the age that suggest peculiar care in prescribing the therapy in those patients, also considering other disabilities that are not related with respiratory disorders as physical and mental limitations. Nowadays a therapy that allows modifying the long-term decline in lung function of patients suffering from COPD does not yet exist and, therefore, the treatment of this disease is mainly focused on the administration of bronchodilators and the use of inhaled glucocorticoids. As for younger subjects, also in elderly patients the main classes of bronchodilators used in the treatment of COPD include β2-agonists, anticholinergics and methylxanthines. The inflammatory response suppression represents another mechanistic approach for treating COPD in the elderly, although the use of inhaled corticosteroids is limited to specific indications. Indeed, nowadays there is a strong medical need for novel treatments of COPD in the elderly. These are mainly represented by agents that reduce the spillover of inflammatory mediators from the lung and by compounds that inhibit the chronic systemic inflammatory syndrome. The therapeutic approach of COPD in elderly patients remains a topic of increasing interest, however the development of novel compounds for preventing the COPD progression in the elderly, other than bronchodilators and corticosteroids, remains a challenge. © 2014 Bentham Science Publishers.

Nastrucci C.,Laboratory of Systems Approaches and Non Communicable Diseases | Cesario A.,Laboratory of Systems Approaches and Non Communicable Diseases | Cesario A.,Catholic University | Russo P.,Laboratory of Systems Approaches and Non Communicable Diseases
Recent Patents on Anti-Cancer Drug Discovery | Year: 2012

Discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs derived from the marine environment are continuously developing and increasing. One of the most promising area is cancer therapy. Currently, there are two drugs approved by the Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products (EMA) in cancer treatment, namely Cytarabine (Cytosar-U1®) and Eribulin (E7389 or Halaven®). Trabectedin (ET-743 or Yondelis1®), approved by EMA, is completing key Phase III studies in the U.S. for final approval. It was estimated that 118 marine natural products (MNPs) are currently in preclinical trials, 22 MNPs in clinical trials and 3 MNPs on the market. The characteristics and selectivity profiles of new drugs for cancer therapy, as well as drugs disclosed in related patent applications, will be the focus of this review, providing a brief and ready to use reference. © 2012 Bentham Science Publishers.

Cesario A.,Laboratory of Systems Approaches and Non Communicable Diseases | Cesario A.,Catholic University | Russo P.,Laboratory of Systems Approaches and Non Communicable Diseases | Nastrucci C.,Laboratory of Systems Approaches and Non Communicable Diseases | Granone P.,Catholic University
Current Drug Targets | Year: 2012

This paper discusses the potential therapeutic effect of α7-nAChR antagonists for NSCLC (non small cell lung cancer) and MPM (malignant pleural mesothelioma). This therapeutic approach is based on the experimental observations that: (a) functional α7-nAChR are expressed in NSCLC and MPM cells, (b) the activation of these receptors by agonists, namely nicotine, induces cell proliferation and inhibits apoptosis, whereas antagonists have a pro-apoptotic effect. Among competitive α7-nAChR antagonists, d-tubocurarine and α-cobratoxin (α-CbT), from the snake venom of Naja, emerged as possible drug candidates. However, some aspects of the samples must be particularly taken into account, such as the particular nature of the sample. Thus, when using natural compounds purified from snake venom, it is important to take into account the factors such as whether the venom sample was derived from different animals, purified by different methods, or contained contaminants of the same molecular weight. Finally, biological activity may be different for different batches, which could also have been stored under different conditions (e.g. temperature, dilution, suspension medium etc.). These factors, affecting the experimental results, are also discussed. © 2012 Bentham Science Publishers.

PubMed | Laboratory of Systems Approaches and Non Communicable Diseases
Type: Journal Article | Journal: Experimental animals | Year: 2014

Nowadays, because of increasing employment of swine for experimental studies and medical training, it is hopeful to investigate novel and effective anaesthetic protocols for preserving the animal welfare in medical investigation and concurrently improving the quality of research. Therefore, the aim of this study was to investigate a novel and effective anaesthetic protocol in swine undergoing major surgery, by translating know-how of combined anaesthesia from human protocols. Seven landrace swine were anaesthetized for three hours by a combined trial anaesthetic protocol (sedation: medetomidine, acepromazine, atropine and tramadol; induction: propofol, medetomidine and acepromazine; anaesthesia: isofluorane, propofol, medetomidine and acepromazine) and both clinical and haemodynamic parameters were compared with those of five swine anaesthetized with a control protocol (sedation: diazepam, ketamine and atropina; induction: diazepam and ketamine; anaesthesia: isofluorane). Both cardiac frequency (CF) and mean blood pressure (MBP) were significantly (P<0.05) more stable in trial protocol (CF: 78.3 4.6-81.1 5, MBP: 63.9 10.7-96.4 13.0) compared to control protocol (CF: 93.7 5.5-102.5 8.5, MBP: 71.0 6.6-108.7 7.2). The body temperature remained stable in trial protocol (C: 36.9 0.7-37.2 0.3) compared to control anaesthesia (C: 36.4 0.3-37.3 0.2, P<0.05). Haematosis improved undergoing combined anaesthesia (+2%, P<0.05) whereas did not change in control animals. There were no differences in respiratory rate between trial and control protocols. This study demonstrates that the proposed balanced intravenous-inhalant protocol permits to carry out a very effective, stable and safe anaesthesia in swine undergoing deep anaesthesia.

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