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1. A phage-targeting strategy for the design of spatiotemporal drug delivery from grafted matrices

Author

Sawada, Ritsuko, Peterson, Carrie Y, Gonzalez, Ana Maria, Potenza, Bruce M, Mueller, Barbara, Coimbra, Raul, Eliceiri, Brian P, and Baird, Andrew

Abstract

Abstract Background The natural response to injury is dynamic and normally consists of complex temporal and spatial cellular changes in gene expression, which, when acting in synchrony, result in patent tissue repair and, in some instances, regeneration. However, current therapeutic regiments are static and most rely on matrices, gels and engineered skin tissue. Accordingly, there is a need to design next-generation grafting materials to enable biotherapeutic spatiotemporal targeting from clinically approved matrices. To this end, rather then focus on developing completely new grafting materials, we investigated whether phage display could be deployed onto clinically approved synthetic grafts to identify peptide motifs capable of linking pharmaceutical drugs with differential affinities and eventually, control drug delivery from matrices over both space and time. Methods To test this hypothesis, we biopanned combinatorial peptide libraries onto different formulations of a wound-healing matrix (Integra®) and eluted the bound peptides with 1) high salt, 2) collagen and glycosaminoglycan or 3) low pH. After three to six rounds of biopanning, phage recovery and phage amplification of the bound particles, any phage that had acquired a capacity to bind the matrix was sequenced. Results In this first report, we identify distinct classes of matrix-binding peptides which elute differently from the screened matrix and demonstrate that they can be applied in a spatially relevant manner. Conclusions We suggest that further applications of these combinatorial techniques to wound-healing matrices may offer a new way to improve the performance of clinically approved matrices so as to introduce temporal and spatial control over drug delivery.

Published
2011

2. Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project

Author

Trifiro, G., Isgro, V., Ingrasciotta, Y., Ientile, V., L'Abbate, L., Foti, S. S., Belleudi, V., Poggi, F., Fontana, A., Moretti, U., Lora, R., Sabaini, A., Senesi, I., Sorrentino, C., Puzo, M. R., Padula, A., Fusco, M., Giordana, R., Solfrini, V., Puccini, A., Rossi, P., Del Zotto, S., Leoni, O., Zanforlini, M., Ancona, D., Bavaro, V., Garau, D., Ledda, S., Scondotto, S., Allotta, A., Tuccori, M., Gini, R., Bucaneve, G., Franchini, D., Cavazzana, A., Biasi, V., Spila Alegiani, S., Massari, M., Andretta, I., Tanaglia, M., Carriero, A., Sassano, S., De Sarro, G., Mirarchi, S., Palleria, C., Sarro, C., Balestrieri, M., Rostan, S., Capuano, A., Bernardi, F. F., Trama, U., Russo, A., Fumo, M. G., Addis, A., Musicco, F., Sapigni, E., Mazzetti, I., Podetti, D., Potenza, A. M., Nikitina, V., Ricciardelli, R., Mogheiseh, N., Croce, S., Pettinelli, A., Ejlli, L., Fortino, I., Ercolanoni, M., Mazzone, A., Nisic, A., Schiatti, S., Ludergnani, M., Mancini, M., Patregnani, L., Fabbietti, P., Antonicelli, E., Mangano, A., Campomori, A., Urru, S. A., Costa, G., Guarrera, G. M., Stella, P., Serra, E., Carta, P., Vannacci, A., Lucenteforte, E., Parrilli, M., Convertino, I., De Giorgi, M., Rocchi, R. E., Rossi, M., Scroccaro, G., Deambrosis, P., Grindelli, G., Ferroni, E., Trifiro, G., Isgro, V., Ingrasciotta, Y., Ientile, V., L'Abbate, L., Foti, S. S., Belleudi, V., Poggi, F., Fontana, A., Moretti, U., Lora, R., Sabaini, A., Senesi, I., Sorrentino, C., Puzo, M. R., Padula, A., Fusco, M., Giordana, R., Solfrini, V., Puccini, A., Rossi, P., Del Zotto, S., Leoni, O., Zanforlini, M., Ancona, D., Bavaro, V., Garau, D., Ledda, S., Scondotto, S., Allotta, A., Tuccori, M., Gini, R., Bucaneve, G., Franchini, D., Cavazzana, A., Biasi, V., Spila Alegiani, S., Massari, M., Andretta, I., Tanaglia, M., Carriero, A., Sassano, S., De Sarro, G., Mirarchi, S., Palleria, C., Sarro, C., Balestrieri, M., Rostan, S., Capuano, A., Bernardi, F. F., Trama, U., Russo, A., Fumo, M. G., Addis, A., Musicco, F., Sapigni, E., Mazzetti, I., Podetti, D., Potenza, A. M., Nikitina, V., Ricciardelli, R., Mogheiseh, N., Croce, S., Pettinelli, A., Ejlli, L., Fortino, I., Ercolanoni, M., Mazzone, A., Nisic, A., Schiatti, S., Ludergnani, M., Mancini, M., Patregnani, L., Fabbietti, P., Antonicelli, E., Mangano, A., Campomori, A., Urru, S. A., Costa, G., Guarrera, G. M., Stella, P., Serra, E., Carta, P., Vannacci, A., Lucenteforte, E., Parrilli, M., Convertino, I., De Giorgi, M., Rocchi, R. E., Rossi, M., Scroccaro, G., Deambrosis, P., Grindelli, G., and Ferroni, E.

Subjects
Male, medicine.medical_specialty, Population, Postmarketing surveillance, Rate ratio, REGISTRIES, Retrospective Studie, Internal medicine, BIOSIMILARS, medicine, Adalimumab, Humans, Pharmacology (medical), Original Research Article, education, Adverse effect, ANTI-TNF THERAPY, RHEUMATOID-ARTHRITIS, RISK, PHARMACOVIGILANCE, BIOSIMILARS, EXPERIENCE, REGISTRIES, PSORIASIS, MEDICINES, ACCESS, Biosimilar Pharmaceuticals, Retrospective Studies, RISK, Delivery of Health Care, Female, Infliximab, Italy, SARS-CoV-2, COVID-19, Pharmacology, education.field_of_study, PSORIASIS, business.industry, Biosimilar, ANTI-TNF THERAPY, General Medicine, medicine.disease, RHEUMATOID-ARTHRITIS, PHARMACOVIGILANCE, MEDICINES, EXPERIENCE, Immune-mediated inflammatory diseases, ACCESS, business, Human, Biosimilar Pharmaceutical, Biotechnology, medicine.drug
Abstract

Background Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. Objective The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. Methods A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010–2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. Results From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015–2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. Conclusion The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010–2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-021-00498-3.

Published
2021

5. Safety of COVID-19 Vaccines Among the Paediatric Population: Analysis of the European Surveillance Systems and Pivotal Clinical Trials

Author

Ahmadizar F., Luxi N., Raethke M., Schmikli S., Riefolo F., Saraswati P. W., Bucsa C., Osman A., Liddiard M., Maques F. B., Petrelli G., Sonderlichova S., Thurin N. H., Villalobos F., Trifiro G., Sturkenboom M., Moretti U., Bellitto C., Ciccimarra F., Gonella L. A., Arzenton E., Chiamulera C., Lora R., Bellantuono D., Sabaini A., Firenze A., Zodda D., Guidotti F., Zappone M., Alagna B., Cutroneo P. M., Minore C., Costantino C., Vitale F., D'Alessandro G., Morreale I., Marsala L., Farinella D., Bavetta S., Fantini M. P., Reno C., Raschi E., Poluzzi E., Sapigni E., Potenza A. M., Podetti D., Nikitina V., Ricciardelli R., Mogheiseh N., Croce S., Paltrinieri B., Castellani S., Sangiorgi E., Selleri M., Lucchesi S., Catucci G., Savini D., Sacripanti C., Faccioli M., Romio M. S., Rossi L., Radici S., Negri G., Fares L., Ajolfi C., Fadda A., Chiarello A., Pieraccini F., Gavioli B., Palazzi S., Tuccori M., Vannacci A., Bonaiuti R., Ravaldi C., Lombardi N., Crescioli G., Gori F., Tessari R., Zandona E., Zanoni G., Senna G., Crivellaro M. A., Cancian M., Venturini F., Ferri M., Leonardi L., Orzetti S., Caccin E., Baldo P., Capuano A., Rafaniello C., Ferrajolo C., Pagliaro C., Mercaldo M., di Giorgio A., Tari M., Manna S., Farina G., Di Mauro C., De Carlo I., Senesi I., Pileggi C., Palleria C., Gallelli L., De Sarro G., de Sarro C., Verduci C., Papadopoli R., Trabace L., Morgese M., Schiavone S., Tucci P., Bove M., Lapi F., Cricelli C., Racagni G., Tonolo S., Fava G., Giuffrida S., Amato V., Gambera M., Montresor V., Mastropasqua D., Ahmadizar F., Luxi N., Raethke M., Schmikli S., Riefolo F., Saraswati P.W., Bucsa C., Osman A., Liddiard M., Maques F.B., Petrelli G., Sonderlichova S., Thurin N.H., Villalobos F., Trifiro G., Sturkenboom M., Moretti U., Bellitto C., Ciccimarra F., Gonella L.A., Arzenton E., Chiamulera C., Lora R., Bellantuono D., Sabaini A., Firenze A., Zodda D., Guidotti F., Zappone M., Alagna B., Cutroneo P.M., Minore C., Costantino C., Vitale F., D'Alessandro G., Morreale I., Marsala L., Farinella D., Bavetta S., Fantini M.P., Reno C., Raschi E., Poluzzi E., Sapigni E., Potenza A.M., Podetti D., Nikitina V., Ricciardelli R., Mogheiseh N., Croce S., Paltrinieri B., Castellani S., Sangiorgi E., Selleri M., Lucchesi S., Catucci G., Savini D., Sacripanti C., Faccioli M., Romio M.S., Rossi L., Radici S., Negri G., Fares L., Ajolfi C., Fadda A., Chiarello A., Pieraccini F., Gavioli B., Palazzi S., Tuccori M., Vannacci A., Bonaiuti R., Ravaldi C., Lombardi N., Crescioli G., Gori F., Tessari R., Zandona E., Zanoni G., Senna G., Crivellaro M.A., Cancian M., Venturini F., Ferri M., Leonardi L., Orzetti S., Caccin E., Baldo P., Capuano A., Rafaniello C., Ferrajolo C., Pagliaro C., Mercaldo M., di Giorgio A., Tari M., Manna S., Farina G., Di Mauro C., De Carlo I., Senesi I., Pileggi C., Palleria C., Gallelli L., De Sarro G., de Sarro C., Verduci C., Papadopoli R., Trabace L., Morgese M., Schiavone S., Tucci P., Bove M., Lapi F., Cricelli C., Racagni G., Tonolo S., Fava G., Giuffrida S., Amato V., Gambera M., Montresor V., and Mastropasqua D.

Subjects
COVID-19 Vaccines, safety, Surveillance Systems, Pivotal Clinical Trials
Abstract

Background and Objectives: The European Medicine Agency extended the use of Comirnaty, Spikevax, and Nuvaxovid in paediatrics; thus, these vaccines require additional real-world safety evidence. Herein, we aimed to monitor the safety of COVID-19 vaccines through Covid-19 Vaccine Monitor (CVM) and EudraVigilance surveillance systems and the published pivotal clinical trials. Methods: In a prospective cohort of vaccinees aged between 5 and 17 years, we measured the frequency of commonly reported (local/systemic solicited) and serious adverse drug events (ADRs) following the first and second doses of COVID-19 vaccines in Europe using data from the CVM cohort until April 2022. The results of previous pivotal clinical trials and data in the EudraVigilance were also analysed. Results: The CVM study enrolled 658 first-dose vaccinees (children aged 5–11 years; n = 250 and adolescents aged 12–17 years; n = 408). Local/systemic solicited ADRs were common, whereas serious ADRs were uncommon. Among Comirnaty first and second dose recipients, 28.8% and 17.1% of children and 54.2% and 52.2% of adolescents experienced at least one ADR, respectively; injection-site pain (29.2% and 20.7%), fatigue (16.1% and 12.8%), and headache (22.1% and 19.3%) were the most frequent local and systemic ADRs. Results were consistent but slightly lower than in pivotal clinical trials. Reporting rates in Eudravigilance were lower by a factor of 1000. Conclusions: The CVM study showed high frequencies of local solicited reactions after vaccination but lower rates than in pivotal clinical trials. Injection-site pain, fatigue, and headache were the most commonly reported ADRs for clinical trials, but higher than spontaneously reported data.

Published
2023

6. Elevation of Arginase-II in Podocytes Contributes to Age-Associated Albuminuria in Male Mice.

Author

Ajalbert, Guillaume, Brenna, Andrea, Ming, Xiu-Fen, Yang, Zhihong, and Potenza, Duilio M.

Subjects
MICE, KNOCKOUT mice, ALBUMINURIA, CHRONIC kidney failure, KIDNEY diseases, MALES
Abstract

One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3–4 months) and old (20–22 months) male and female mice of wt and arginase-II knockout (arg-ii−/−) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii−/− but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging. [ABSTRACT FROM AUTHOR]

Published
2023
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8. COVID-19 Vaccination in Pregnancy, Paediatrics, Immunocompromised Patients, and Persons with History of Allergy or Prior SARS-CoV-2 Infection: Overview of Current Recommendations and Pre- and Post-Marketing Evidence for Vaccine Efficacy and Safety

Author

Luxi N., Giovanazzi A., Capuano A., Crisafulli S., Cutroneo P. M., Fantini M. P., Ferrajolo C., Moretti U., Poluzzi E., Raschi E., Ravaldi C., Reno C., Tuccori M., Vannacci A., Zanoni G., Trifiro G., Petrelli G., Girotti S., Arzenton E., Magro L., Lora R., Bellantuono D., Sabaini A., Firenze A., Zodda D., Guidotti F., Zappone M., Alagna B., Spina E., Minore C., Costantino C., Conforto A., Vitale F., Morreale I., Marsala L., Farinella D., Bavetta S., Sapigni E., Potenza A. M., Podetti D., Nikitina V., Ricciardelli R., Mogheiseh N., Croce S., Paltrinieri B., Castellani S., Sangiorgi E., Selleri M., Lucchesi S., Catucci G., Savini D., Sacripanti C., Faccioli M., Romio M. S., Rossi L., Radici S., Negri G., Fares L., Ajolfi C., Fadda A., Chiarello A., Pieraccini F., Pappalardo F., Bonaiuti R., Lombardi N., Crescioli G., Tessari R., Zandona E., Marchiori F., Chiamulera C., Senna G., Crivellaro M. A., Cancian M., Venturini F., Ferri M., Leonardi L., Orzetti S., Caccin E., Baldo P., Rafaniello C., Pagliaro C., Mercaldo M., Fucile A., di Giorgio A., Tari M., Manna S., Farina G., Di Mauro C., De Carlo I., Senesi I., Pileggi C., Palleria C., Gallelli L., De Sarro G., Trabace L., Morgese M., Schiavone S., Tucci P., Bove M., Lapi F., Cricelli C., Racagni G., Tonolo S., Leopardi E., Fava G., Giuffrida S., Amato V., Gambera M., Montresor V., Luxi N., Giovanazzi A., Capuano A., Crisafulli S., Cutroneo P.M., Fantini M.P., Ferrajolo C., Moretti U., Poluzzi E., Raschi E., Ravaldi C., Reno C., Tuccori M., Vannacci A., Zanoni G., Trifiro G., Luxi, N., Giovanazzi, A., Capuano, A., Crisafulli, S., Cutroneo, P. M., Fantini, M. P., Ferrajolo, C., Moretti, U., Poluzzi, E., Raschi, E., Ravaldi, C., Reno, C., Tuccori, M., Vannacci, A., Zanoni, G., Trifiro, G., Petrelli G., Girotti S., Arzenton E., Magro L., Lora R., Bellantuono D., Sabaini A., Firenze A., Zodda D., Guidotti F., Zappone M., Alagna B., Spina E., Minore C., Costantino C., Conforto A., Vitale F., Morreale I., Marsala L., Farinella D., Bavetta S., Sapigni E., Potenza A.M., Podetti D., Nikitina V., Ricciardelli R., Mogheiseh N., Croce S., Paltrinieri B., Castellani S., Sangiorgi E., Selleri M., Lucchesi S., Catucci G., Savini D., Sacripanti C., Faccioli M., Romio M.S., Rossi L., Radici S., Negri G., Fares L., Ajolfi C., Fadda A., Chiarello A., Pieraccini F., Pappalardo F., Bonaiuti R., Lombardi N., Crescioli G., Tessari R., Zandona E., Marchiori F., Chiamulera C., Senna G., Crivellaro M.A., Cancian M., Venturini F., Ferri M., Leonardi L., Orzetti S., Caccin E., Baldo P., Rafaniello C., Pagliaro C., Mercaldo M., Fucile A., di Giorgio A., Tari M., Manna S., Farina G., Di Mauro C., De Carlo I., Senesi I., Pileggi C., Palleria C., Gallelli L., De Sarro G., Trabace L., Morgese M., Schiavone S., Tucci P., Bove M., Lapi F., Cricelli C., Racagni G., Tonolo S., Leopardi E., Fava G., Giuffrida S., Amato V., Gambera M., and Montresor V.

Subjects
Allergy, IMPACT, COVID-19 Vaccine, Breastfeeding, Review Article, Toxicology, Settore MED/42 - Igiene Generale E Applicata, CLINICAL CHARACTERISTICS, Pregnancy, Pharmacology (medical), Pregnancy Complications, Infectious, Child, OUTCOMES, education.field_of_study, CANCER, Vaccination, Europe, CORONAVIRUS DISEASE 2019, CLINICAL CHARACTERISTICS, CANCER, RECIPIENTS, SEVERITY, OUTCOMES, IMPACT, RATES, Breast Feeding, Child, Preschool, Practice Guidelines as Topic, Female, 2019-nCoV Vaccine mRNA-1273, Human, Adult, medicine.medical_specialty, COVID-19 Vaccines, Adolescent, BNT162 Vaccine, COVID-19, ChAdOx1 nCoV-19, Humans, Infant, SARS-CoV-2, Hypersensitivity, Immunocompromised Host, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, MEDLINE, CORONAVIRUS DISEASE 2019, medicine, RATES, education, Pharmacology, business.industry, medicine.disease, Vaccine efficacy, RECIPIENTS, SEVERITY, Family medicine, Pregnancy Complications, Infectiou, business
Abstract

To date, four vaccines have been authorised for emergency use and under conditional approval by the European Medicines Agency to prevent COVID-19: Comirnaty, COVID-19 Vaccine Janssen, Spikevax (previously COVID-19 Vaccine Moderna) and Vaxzevria (previously COVID-19 Vaccine AstraZeneca). Although the benefit–risk profile of these vaccines was proven to be largely favourable in the general population, evidence in special cohorts initially excluded from the pivotal trials, such as pregnant and breastfeeding women, children/adolescents, immunocompromised people and persons with a history of allergy or previous SARS-CoV-2 infection, is still limited. In this narrative review, we critically overview pre- and post-marketing evidence on the potential benefits and risks of marketed COVID-19 vaccines in the above-mentioned special cohorts. In addition, we summarise the recommendations of the scientific societies and regulatory agencies about COVID-19 primary prevention in the same vaccinee categories. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01131-6.

Published
2021

11. Phosphorylation of the ryanodine receptor 2 at serine 2030 is required for a complete β-adrenergic response.

Author

Potenza, Duilio M., Janicek, Radoslav, Fernandez-Tenorio, Miguel, Camors, Emmanuel, Ramos-Mondragón, Roberto, Valdivia, Héctor H., and Niggli, Ernst

Subjects
*HEART diseases, *PROTEIN kinases, *HEART cells, *RYANODINE receptors, *HEART failure, *EXERCISE
Abstract

During physical exercise or stress, the sympathetic system stimulates cardiac contractility via β-adrenergic receptor (β-AR) activation, resulting in protein kinase A (PKA)--mediated phosphorylation of the cardiac ryanodine receptor RyR2. PKAdependent "hyperphosphorylation" of the RyR2 channel has been proposed as a major impairment that contributes to progression of heart failure. However, the sites of PKA phosphorylation and their phosphorylation status in cardiac diseases are not well defined. Among the known RyR2 phosphorylation sites, serine 2030 (S2030) remains highly controversial as a site of functional impact. We examined the contribution of RyR2-S2030 to Ca2+ signaling and excitation--contraction coupling (ECC) in a transgenic mouse with an ablated RyR2-S2030 phosphorylation site (RyR2-S2030A+/+). We assessed ECC gain by using whole-cell patch--clamp recordings and confocal Ca2+ imaging during β-ARs stimulation with isoproterenol (Iso) and consistent SR Ca2+ loading and L-type Ca2+ current (ICa) triggering. Under these conditions, ECC gain is diminished in mutant compared with WT cardiomyocytes. Resting Ca2+ spark frequency (CaSpF) with Iso is also reduced by mutation of S2030. In permeabilized cells, when SR Ca2+ pump activity is kept constant (using 2D12 antibody against phospholamban), cAMP does not change CaSpF in S2030A+/+ myocytes. Using Ca2+ spark recovery analysis, we found that mutant RyR Ca2+ sensitivity is not enhanced by Iso application, contrary to WT RyRs. Furthermore, ablation of RyR2-S2030 prevents acceleration of Ca2+ waves and increases latency to the first spontaneous Ca2+ release after a train of stimulations during Iso treatment. Together, these results suggest that phosphorylation at S2030 may represent an important step in the modulation of RyR2 activity during β-adrenergic stimulation and a potential target for the development of new antiarrhythmic drugs. [ABSTRACT FROM AUTHOR]

Published
2019
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13. War in cyberspace: battling it out on the e-commerce frontier

Author

WRIGHT, BRADLEY C. and POTENZA, JOSEPH M.

Subjects
United States. Patent and Trademark Office -- Laws, regulations and rules, Trademarks -- Laws, regulations and rules, Domain names -- Laws, regulations and rules, Internet -- Laws, regulations and rules, Digital Millennium Copyright Act of 1998, General interest, News, opinion and commentary, Government regulation, Internet address/domain name, Internet, Laws, regulations and rules
Abstract

With the Internet have come new attacks on corporate identity. Time will tell whether companies can adapt to the changes faster than the interlopers. FED UP with your health club? [...]

Published
1999

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