Phage displayed peptides/antibodies recognizing growth factors and their tyrosine kinase receptors as tools for anti-cancer therapeutics.

The basic idea of displaying peptides on a phage, introduced by George P. Smith in 1985, was greatly developed and improved by McCafferty and colleagues at the MRC Laboratory of Molecular Biology and, later, by Barbas and colleagues at the Scripps Research Institute. Their approach was dedicated to building a system for the production of antibodies, similar to a naïve B cell repertoire, in order to by-pass the standard hybridoma technology that requires animal immunization. Both groups merged the phage display technology with an antibody library to obtain a huge number of phage variants, each of them carrying a specific antibody ready to bind its target molecule, allowing, later on, rare phage (one in a million) to be isolated by affinity chromatography. Here, we will briefly review the basis of the technology and the therapeutic application of phage-derived bioactive molecules when addressed against key players in tumor development and progression: growth factors and their tyrosine kinase receptors

Dati VIIRS-Nightfire per il monitoraggio del gas flaring in Amazzonia: il caso Yasun\ued

L\u2019estrazione di combustibili fossili \ue8 un\u2019attivit\ue0 che ha ormai raggiunto aree remote ad alta diversit\ue0 biologica e culturale, tra le quali desta gran preoccupazione l\u2019espansione della frontiera petrolifera in Amazzonia occidentale, specialmente nella Riserva della Biosfera Yasun\uec (YBR), uno dei luoghi pi\uf9 biodiversi del pianeta e casa ancestrale degli indigeni Waorani. In prossimit\ue0 di questa zona, gli impatti socio-ambientali diretti e indiretti delle varie fasi dell\u2019estrazione petrolifera sono ampiamente documentati. Tra queste attivit\ue0, la distribuzione spaziale e gli impatti ambientali del gas flaring non sono stati ancora investigati a fondo, anche a causa della mancanza di un sistema di monitoraggio e documentazione delle posizioni dei flare e dei volumi di gas bruciato. Negli ultimi anni si sta assistendo per\uf2 a un\u2019inversione di tendenza, grazie allo sviluppo di vari metodi di monitoraggio da remoto, attraverso l\u2019analisi multispettrale da satellite. Lo scopo di questo studio \ue8 mappare l\u2019attivit\ue0 di gas flaring nell\u2019area dello YBR, analizzando diacronicamente e valutando gli impatti potenziali sia sulla biodiversit\ue0 che sulle comunit\ue0 locali. I dati giornalieri prodotti dalla NOAA da gennaio 2017 a marzo 2018, basate sull\u2019elaborazione di immagini dal sensore \u201cVisible Infrared Imaging Radiometric Suite\u201d del satellite Suomi-SNPP per il monitoraggio delle attivit\ue0 di gas flaring, sono stati analizzati e geoprocessati con dati sulle aree protette e comunit\ue0 indigene. Per il corretto posizionamento dei flare, quando possibile, \ue8 stato fatto riferimento ai dataset annuali della NOAA, per i nuovi flare \ue8 stato usato il centroide delle rilevazioni. I risultati preliminari mostrano la presenza di un nuovo sito di flare nel campo petrolifero Tiputini vicino all\u2019 \u201cArea Nucleo\u201d della YBR; tre flare sono stati rilevati nella zona buffer e 19 nella zona di transizione della YBR. spaziale ha inoltre identificato 6 comunit\ue0 indigene in un raggio di 6 Km dai flare. Questo studio rivela l\u2019enorme potenziale degli open data come Nightfire della NOAA per il monitoraggio di aree remote ad elevata importanza per la conservazione della biodiversit\ue0 e dei territori indigeni

Comparative analysis of mesenchymal stromal cells biological properties

The stromal progenitors of mesodermal cells, mesenchymal stromal cells (MSCs), are a heterogeneous population of plastic adherent fibroblast-like cells with extensive proliferative capacity and differentiation potential. Human MSCs have now been isolated from various tissues including bone marrow, muscle, skin, and adipose tissue, the latter being one of the most suitable cell sources for cell therapy, because of its easy accessibility, minimal morbidity, and abundance of cells. Bone marrow and subcutaneous or visceral adipose tissue samples were collected, digested with collagenase if needed, and seeded in Iscove's medium containing 5% human platelet lysate. Nonadherent cells were removed after 2-3 days and the medium was replaced twice a week. Confluent adherent cells were detached, expanded, and analyzed for several biological properties such as morphology, immunophenotype, growth rate, senescence, clonogenicity, differentiation capacity, immunosuppression, and secretion of angiogenic factors. The results show significant differences between lines derived from subcutaneous fat compared to those derived from visceral fat, such as the higher proliferation rate of the first and the strong induction of angiogenesis of the latter. We are convinced that the identification of the peculiarities of MSCs isolated from different tissues will lead to their more accurate use in cell therapy

No difference in surgical outcomes between Open and Closed exposure of palatally displaced maxillary canines

Purpose: To investigate differences in the surgical outcomes between Open and Closed exposure for palatally displaced maxillary cuspids (PDC). Methods: A multicenter, RCT involving two parallel groups. The settings were one dental teaching hospital in, and two hospital units near Sheffield, UK. Participants were aged <20 years with a unilateral PDC, who provided informed consent. They were randomly allocated to either receive the Open (O) or the Closed (C) surgical procedure. The outcomes were time spent in the operating room and 10-day post-operative patient questionnaire. Statistical differences between the two techniques were tested using independent t tests for continuous variables and chi-squared tests for frequencies. Results: The final study sample was composed of 71 participants (64% females). There were no differences in the gender ratios (O: F=27, M=13; C: F=25, M=16) or mean ages of the two groups (O: 14.3 yrs SD 1.3; C: 14.1 yrs SD 1.6) at the start. The mean operating times for the Open and Closed techniques were 34.3 mins (SD 11.2) and 34.3 mins (SD 11.9) respectively (p=.986). There were no statistically significant differences between the two treatment groups for any of the patient-assessed outcomes (p>.05). Conclusions: There were no differences in the surgical outcomes investigated in this study between Open and Closed exposure for PDC

Galactic axions search with a superconducting resonant cavity

To account for the dark matter content in our Universe, post-inflationary scenarios predict for the QCD axion a mass in the range (10-10^3)\,\mu\mbox{eV}. Searches with haloscope experiments in this mass range require the monitoring of resonant cavity modes with frequency above 5\,GHz, where several experimental limitations occur due to linear amplifiers, small volumes, and low quality factors of Cu resonant cavities. In this paper we deal with the last issue, presenting the result of a search for galactic axions using a haloscope based on a 36\,\mbox{cm}^3 NbTi superconducting cavity. The cavity worked at T=4\,\mbox{K} in a 2\,T magnetic field and exhibited a quality factor $Q_0= 4.5\times10^5$ for the TM010 mode at 9\,GHz. With such values of $Q$ the axion signal is significantly increased with respect to copper cavity haloscopes. Operating this setup we set the limit g_{a\gamma\gamma}<1.03\times10^{-12}\,\mbox{GeV}^{-1} on the axion photon coupling for a mass of about 37\,$\mu$eV. A comprehensive study of the NbTi cavity at different magnetic fields, temperatures, and frequencies is also presented

Human iPSC modeling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes

AIMS: Atrial Fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood.Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes differentiated from induced pluripotent stem cells (iPSC). METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells toward the cardiac lineage. Electrophysiological characterization of patient-derived cardiomyocytes (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed afterdepolarizations of bigger amplitude and more ectopic beats than CTRL cells. CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF

Coronary stenting and surgery: Perioperative management of antiplatelet therapy in patients undergoing surgery after coronary stent implantation [Stent coronarico e chirurgia: La gestione perioperatoria della terapia antiaggregante nel paziente portatore di stent coronarico candidato a intervento chirurgico]

The management of antiplatelet therapy in patients with coronary stents undergoing surgery is a growing clinical problem and often represents a matter of debate between cardiologists and surgeons. It has been estimated that about 4-8% of patients undergoing coronary stenting need to undergo surgery within the next year. Surgery represents one of the most common reasons for premature antiplatelet therapy discontinuation, which is associated with a significant increase in mortality and major adverse cardiac events, in particular stent thrombosis. In addition, surgery confers an additional risk of perioperative cardiac ischemic events, being high in these patients because of the pro-inflammatory and pro-thrombotic effects of surgery. Current international guidelines recommend to postpone non-urgent surgery for at least 6 weeks after bare metal stent implantation and for 6-12 months after drug-eluting stent implantation. However, these recommendations provide little support with regard to managing antiplatelet therapy in the perioperative phase in case of urgent operations and/or high hemorrhagic risk. Furthermore, ischemic and hemorrhagic risk is not defined in detail on the basis of clinical and procedural characteristics. Finally, guidelines shared with cardiologists and surgeons are lacking. The present consensus document provides practical recommendations on the management of antiplatelet therapy in the perioperative period in patients with coronary stents undergoing surgery. Cardiologists and surgeons contributed equally to its creation. An ischemic risk stratification has been provided on the basis of clinical and procedural data. All surgical interventions have been defined on the basis of the hemorrhagic risk. A consensus on the most appropriate antiplatelet regimen in the perioperative phase has been reached on the basis of the ischemic and hemorrhagic risk. Dual antiplatelet therapy should not be withdrawn for surgery at low bleeding risk, whereas aspirin should be continued perioperatively in the majority of surgical operations. In the event of interventions at high risk for both bleeding and ischemic events, when oral antiplatelet therapy withdrawal is required, perioperative treatment with short-acting intravenous glycoprotein IIb/IIIa inhibitors (tirofiban or eptifibatide) should be considered. \ua9 2012 Il Pensiero Scientifico Editore

A simplified (modified) Duke Activity Status Index (M-DASI) to characterise functional capacity: A secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study

Background Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity. Methods In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg −1 min −1 and peak oxygen consumption (VO 2 peak) >16 ml kg −1 min −1, cut-points that represent a reduced risk of postoperative complications. Results Five questions were identified to have dominance in predicting AT>11 ml kg −1 min −1 and VO 2 peak>16 ml.kg −1min −1. These items were included in the M-DASI-5Q and retained utility in predicting AT>11 ml.kg −1.min −1 (area under the receiver-operating-characteristic [AUROC]-AT: M-DASI-5Q=0.67 vs original 12-question DASI=0.66) and VO 2 peak (AUROC-VO2 peak: M-DASI-5Q 0.73 vs original 12-question DASI 0.71). Conversely, in a sensitivity analysis we removed one potentially sensitive question related to the ability to have sexual relations, and the ability of the remaining four questions (M-DASI-4Q) to predict an adequate functional threshold remained no worse than the original 12-question DASI model. Adding a dynamic component to the M-DASI-4Q by assessing the chronotropic response to exercise improved its ability to discriminate between those with VO 2 peak>16 ml.kg −1.min −1 and VO 2 peak<16 ml.kg −1.min −1. Conclusions The M-DASI provides a simple screening tool for further preoperative evaluation, including with cardiopulmonary exercise testing, to guide perioperative management

Integration of the Duke Activity Status Index into preoperative risk evaluation: a multicentre prospective cohort study.

BACKGROUND: The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications. METHODS: The analysis included 1546 participants (≥40 yr of age) at an elevated cardiac risk who had inpatient noncardiac surgery. The primary outcome was 30-day death or myocardial injury. The secondary outcomes were 30-day death or myocardial infarction, in-hospital moderate-to-severe complications, and 1 yr death or new disability. Multivariable logistic regression modelling was used to characterise the adjusted association of preoperative DASI scores with outcomes. RESULTS: The DASI score had non-linear associations with outcomes. Self-reported functional capacity better than a DASI score of 34 was associated with reduced odds of 30-day death or myocardial injury (odds ratio: 0.97 per 1 point increase above 34; 95% confidence interval [CI]: 0.96-0.99) and 1 yr death or new disability (odds ratio: 0.96 per 1 point increase above 34; 95% CI: 0.92-0.99). Self-reported functional capacity worse than a DASI score of 34 was associated with increased odds of 30-day death or myocardial infarction (odds ratio: 1.05 per 1 point decrease below 34; 95% CI: 1.00-1.09), and moderate-to-severe complications (odds ratio: 1.03 per 1 point decrease below 34; 95% CI: 1.01-1.05). CONCLUSIONS: A DASI score of 34 represents a threshold for identifying patients at risk for myocardial injury, myocardial infarction, moderate-to-severe complications, and new disability