Prospective assessment of integrating the existing emergency medical system with automated external defibrillators fully operated by volunteers and laypersons for out-of-hospital cardiac arrest: the Brescia Early Defibrillation Study (BEDS)

AIMS: There are few data on the outcomes of cardiac arrest (CA) victims when the defibrillation capability of broad rural and urban territories is fully operated by volunteers and laypersons. METHODS AND RESULTS: In this study, we investigated whether a programme based on diffuse deployment of automated external defibrillators (AEDs) operated by 2186 trained volunteers and laypersons across the County of Brescia, Italy (area: 4826 km(2); population: 1 112 628), would safely and effectively impact the current survival among victims of out-of-hospital CA. Forty-nine AEDs were added to the former emergency medical system that uses manual EDs in the emergency department of 10 county hospitals and in five medically equipped ambulances. The primary endpoint was survival free of neurological impairment at 1-year follow-up. Data were analysed in 692 victims before and in 702 victims after the deployment of the AEDs. Survival increased from 0.9% (95% CI 0.4-1.8%) in the historical cohort to 3.0% (95% CI 1.7-4.3%) (P=0.0015), despite similar intervals from dispatch to arrival at the site of collapse [median (quartile range): 7 (4) min vs. 6 (6) min]. Increase of survival was noted both in the urban [from 1.4% (95% CI 0.4-3.4 %) to 4.0% (95% CI 2.0-6.9 %), P=0.024] and in the rural territory [from 0.5% (95% CI 0.1-1.6%) to 2.5% (95% CI 1.3-4.2%), P=0.013]. The additional costs per quality-adjusted life year saved amounted to euro39 388 (95% CI euro16 731-49 329) during the start-up phase of the study and to euro23 661 (95% CI euro10 327-35 528) at steady state. CONCLUSION: Diffuse implementation of AEDs fully operated by trained volunteers and laypersons within a broad and unselected environment proved safe and was associated with a significantly higher long-term survival of CA victims

Neuropilin-1 and Integrins as Receptors for Chromogranin A-Derived Peptides

Human chromogranin A (CgA), a 439 residue-long member of the “granin” secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the many biological activities observed in experimental and preclinical models for CgA and its most investigated fragments (vasostatin-I and catestatin), limited information is available on the receptor mechanisms underlying these effects. The interaction of vasostatin-1 with membrane phospholipids and the binding of catestatin to nicotinic and b2-adrenergic receptors have been proposed as important mechanisms for some of their effects on the cardiovascular and sympathoadrenal systems. Recent studies have shown that neuropilin-1 and certain integrins may also work as high-affinity receptors for CgA, vasostatin-1 and other fragments. In this case, we review the results of these studies and discuss the structural requirements for the interactions of CgA-related peptides with neuropilin-1 and integrins, their biological effects, their mechanisms, and the potential exploitation of compounds that target these ligand-receptor systems for cancer diagnosis and therapy. The results obtained so far suggest that integrins (particularly the integrin avb6) and neuropilin-1 are important receptors that mediate relevant pathophysiological functions of CgA and CgA fragments in angiogenesis, wound healing, and tumor growth, and that these interactions may represent important targets for cancer imaging and therapy

Development and characterization of a microfluidic model of the tumour microenvironment

The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening

Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin

Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an αvβ3 integrin-binding motif regulating endothelial cell adhesion and proliferation. By NMR and molecular dynamics studies, we analyzed the structure of CisoDGRC (isoDGR-2C), a cyclic β-peptide mimicking the FN-I5 site, and compared it with NGR, RGD, or DGR-containing cyclopeptides. Docking experiments show that isoDGR, exploiting an inverted orientation as compared with RGD, favorably interacts with the RGD-binding site of αvβ3, both recapitulating canonical RGD-αvβ3 contacts and establishing additional polar interactions. Conversely, NGR and DGR motifs lack the fundamental pharmacophoric requirements for high receptor affinity. Therefore, unlike NGR and DGR, isoDGR is a new natural recognition motif of the RGD-binding pocket of αvβ3. These findings contribute to explain the different functional properties of FN-I5 before and after deamidation, and provide support for the hypothesis that NGR → isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function

Oxidation-induced structural changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin binding and signaling

Background: Asparagine deamidation at Asn-Gly-Arg (NGR) sites leads to the isoAsp-Gly-Arg (isoDGR) integrin-binding motif formation. Results: Ceruloplasmin (Cp), which contains two NGR sites and is oxidized in cerebrospinal fluid (CSF) in neurodegenerative diseases, can, undergo oxidation-induced structural changes fostering NGR deamidation with gain of integrin binding and signaling properties, in vitro and ex vivo in pathological CSF. Conclusion: Cp NGR motifs can deamidate acquiring integrin-binding functions. Significance: Cp structural changes favor NGR deamidation. Asparagine deamidation occurs spontaneously in proteins during aging; deamidation of Asn-Gly-Arg (NGR) sites can lead to the formation of isoAsp-Gly-Arg (isoDGR), a motif that can recognize the RGD-binding site of integrins. Ceruloplasmin (Cp), a ferroxidase present in the cerebrospinal fluid (CSF), contains two NGR sites in its sequence: one exposed on the protein surface (568NGR) and the other buried in the tertiary structure (962NGR). Considering that Cp can undergo oxidative modifications in the CSF of neurodegenerative diseases, we investigated the effect of oxidation on the deamidation of both NGR motifs and, consequently, on the acquisition of integrin binding properties. Weobserved that the exposed 568NGRsite can deamidate under conditions mimicking accelerated Asn aging. In contrast, the hidden 962NGR site can deamidate exclusively when aging occurs under oxidative conditions, suggesting that oxidationinduced structural changes foster deamidation at this site. NGR deamidation in Cp was associated with gain of integrin-binding function, intracellular signaling, and cell pro-Adhesive activity. Finally, Cp aging in the CSF from Alzheimer disease patients, but not in control CSF, causes Cp deamidation with gain of integrin-binding function, suggesting that this transition might also occur in pathological conditions. In conclusion, both Cp NGR sites can deamidate during aging under oxidative conditions, likely as a consequence of oxidative-induced structural changes, thereby promoting a gain of function in integrin binding, signaling, and cell adhesion

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest

Phase Ib study of NGR–hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

Contains fulltext : 81937timmer-bonte.pdf (publisher's version ) (Closed access)BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development

A Leadless Ventricular Pacemaker Providing Atrioventricular Synchronous Pacing in the Real-World Setting: 12-Month Results from the Micra AV Post-Approval Registry.

BACKGROUND Advances in leadless pacemaker technology have enabled accelerometer-based atrioventricular (AV) synchronous pacing by sensing atrial mechanical contraction. OBJECTIVES To report performance of the Micra AV leadless pacemaker from the worldwide Micra AV post-approval registry (PAR) through 12-months. METHODS The Micra AV PAR is a prospective single-arm observational registry designed to assess safety and effectiveness of Micra AV in a real-world setting. For the present interim analysis, major complications and system revisions through 12-months were summarized and compared to a historical cohort of 2,667 transvenous dual-chamber pacing patients. RESULTS The device was successfully implanted in 796 of 801 patients (99.4%) at 97 centers in 19 countries. Micra AV patients were older (74.1 vs. 71.1 years, P90%. CONCLUSIONS The Micra AV leadless pacemaker was implanted with a high rate of success in patients with multiple co-morbidities, with a significantly lower rate of complications and system revisions through 12-months compared to a historical cohort of patients with transvenous dual-chamber pacemakers

Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation

AIMS: To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. METHODS AND RESULTS: Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57-1.42), P = 0.64 and 1.00 (0.60-1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09-0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10-0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03-0.70, P = 0.016) for HF mortality. CONCLUSION: Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death