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1. Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules

Author

Cipriani, F., Mastrorilli, C., Tripodi, S., Ricci, G., Perna, S., Panetta, V., Asero, R., Dondi, A., Bianchi, A., Maiello, N., Miraglia del Giudice, M., Frediani, T., Macrì, F., Lucarelli, S., Dello Iacono, I., Patria, M. F., Varin, E., Peroni, D., Chini, L., Moschese, V., Bernardini, R., Pingitore, G., Pelosi, U., Tosca, M., Paravati, F., Sfika, I., Businco, A. Di Rienzo, Povesi Dascola, C., Comberiati, P., Frediani, S., Lambiase, C., Verga, M. C., Faggian, D., Plebani, M., Calvani, M., Caffarelli, C., and Matricardi, P. M.

Published
2018
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8. Pollen-induced allergic rhinitis in 1360 Italian children: comorbidities and determinants of severity

Author

DONDI, ARIANNA, RICCI, GIAMPAOLO, BELLINI, FEDERICA, Tripodi S, Panetta V, Asero R, Businco AD, Bianchi A, Carlucci A, Maiello N, del Giudice MM, Frediani T, Sodano S, Dello Iacono I, Macrì F, Massaccesi V, Caffarelli C, Rinaldi L, Patria MF, Varin E, Peroni D, Chinellato I, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Tosca M, Paravati F, La Grutta S, Meglio P, Calvani M, Plebani M, Matricardi PM, Italian Pediatric Allergy Network, Dondi, A, Tripodi, S, Panetta, V, Asero, R, Businco, Ad, Bianchi, A, Carlucci, A, Ricci, G, Bellini, F, Maiello, N, MIRAGLIA DEL GIUDICE, Michele, Frediani, T, Sodano, S, Dello Iacono, I, Macrì, F, Massaccesi, V, Caffarelli, C, Rinaldi, L, Patria, Mf, Varin, E, Peroni, D, Chinellato, I, Chini, L, Moschese, V, Lucarelli, S, Bernardini, R, Pingitore, G, Pelosi, U, Tosca, M, Paravati, F, La Grutta, S, Meglio, P, Calvani, M, Plebani, M, Matricardi, Pm, Dondi A, Tripodi S, Panetta V, Asero R, Businco AD, Bianchi A, Carlucci A, Ricci G, Bellini F, Maiello N, del Giudice MM, Frediani T, Sodano S, Dello Iacono I, Macrì F, Massaccesi V, Caffarelli C, Rinaldi L, Patria MF, Varin E, Peroni D, Chinellato I, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Tosca M, Paravati F, La Grutta S, Meglio P, Calvani M, Plebani M, Matricardi PM, Italian Pediatric Allergy Network (I-PAN)., Businco, A, Miraglia del Giudice, M, Patria, M, and Matricardi, P

Subjects
Male, Questionnaires, Allergy, Pediatrics, multiple pollen sydrome, multiple pollen syndrome, Breastfeeding, Comorbidity, Airborne allergen, Surveys and Questionnaires, Epidemiology, Prevalence, Immunology and Allergy, Outpatient clinic, Age of Onset, Child, Conjunctivitis, Allergic, Rhinitis, pan-allergens, profilin, asthma, children, allergic rhinitis, epidemiology, italy, allergic conjunctivitis, Environmental exposure, Humans, Disease Progression, Italy, Allergens, Antigens, Plant, Skin Tests, Pollen, Child, Preschool, Rhinitis, Allergic, Seasonal, Early Diagnosis, Female, Allergic conjunctivitis, panallergen, allergic rhiniti, medicine.medical_specialty, Immunology, Allergic, medicine, allergic conjunctiviti, Antigens, Preschool, Asthma, Settore MED/38 - Pediatria Generale e Specialistica, Seasonal, business.industry, Plant, medicine.disease, Conjunctivitis, pan-allergen, Pediatrics, Perinatology and Child Health, business
Abstract

BACKGROUND: Pollen-induced allergic rhinoconjunctivitis (AR) is highly prevalent and rapidly evolving during childhood. General practitioners may not be fully aware of the nature and severity of symptoms experienced by patients and might underestimate the prevalence of moderate or severe disease. Thus, the relevance of early diagnosis and intervention may be overlooked. OBJECTIVES: To investigate the severity of pollen-induced AR and its determinants in Italian children referred to allergy specialists and who had never received specific immunotherapy (SIT). METHODS: Children (age 4-18 yr) affected by pollen-induced AR who had never undergone SIT were recruited between May 2009 and June 2011 in 16 pediatric outpatient clinics in 14 Italian cities. Recruited children's parents answered standardized questionnaires on atopic diseases (International Study of Allergy and Asthma in Childhood, Allergic Rhinitis and its Impact on Asthma, Global Initiative for Asthma). The children underwent skin-prick test (SPT) with several airborne allergens and six food allergens. Information on socio-demographic factors, parental history of allergic diseases, education, perinatal events, breastfeeding, nutrition and environmental exposure in early life was collected through an informatics platform shared by the whole network of clinical centers (AllergyCARD™). RESULTS: Among the 1360 recruited patients (68% males, age 10.5 ± 3.4 yr), 695 (51%) had moderate-to-severe AR, 533 (39%) asthma, and 325 (23.9%) oral allergy syndrome (OAS). Reported onset of pollen-induced AR was on average at 5.3 ± 2.8 yr, and its mean duration from onset was 5.2 ± 3.3 yr. Only 6.2% of the patients were pollen-monosensitized, and 84.9% were sensitized to ≥3 pollens. A longer AR duration was significantly associated with moderate-to-severe AR symptoms (p 0.004), asthma (p 0.030), and OAS comorbidities (p < 0.001). CONCLUSIONS: This nationwide study may raise awareness of the severity of pollen-induced AR among Italian children who have never received pollen SIT. The strong association between pollen-induced AR duration and several markers of disease severity needs replication in longitudinal studies, while suggesting that countrywide initiatives for earlier diagnosis and intervention should be planned.

Published
2013

9. Adherence issues related to sublingual immunotherapy as perceived by allergists

Author

Scurati, S., Frati, F., Passalacqua, G., Puccinelli, P., Hilaire, C., Incorvaia, C., D Avino, G., Comi, R., Lo Schiavo, M., Pezzuto, F., Montera, C., Pio, A., Teresa Ielpo, M., Cellini, F., Vicentini, L., Pecorari, R., Aresu, T., Capra, L., Benedictis, E., Bombi, C., Zauli, D., Vanzi, A., Alberto Paltrinieri, C., Bondioli, A., Paletta, I., Ventura, D., Mei, F., Paolini, F., Colangelo, C., Cavallucci, E., Cucinelli, F., Tinari, R., Ermini, G., Beltrami, V., Novembre, E., Begliomini, C., Marchese, E., Solito, E., Ammannati, V., Molino, G., Galli, E., Baldassini, M., Di Michele, L., Calvani, M., Gidaro, M., Venuti, A., Li Bianchi, E., Benassi, F., Pocobelli, D., Zangari, P., Rocco, M. G., Lo Vecchio, A., Pingitore, G., Grimaldi, O., Schiavino, D., Perrone, N., Antonietta Frieri, M., Di Rienzo, V., Tripodi, S., Scarpa, A., Tomsic, M., Bonaguro, R., Enrico Senna, G., Sirena, A., Turatello, F., Crescioli, S., Favero, E., Billeri, L., Chieco Bianchi, F., Gemignani, C., Zanforlin, M., Angiola Crivellaro, M., Hendrick, B., Maltauro, A., Masieri, S., Elisabetta Conte, M., Fama, M., Pozzan, M., Bonadonna, P., Casanova, S., Vallerani, E., Schiappoli, M., Borghesan, F., Giro, G., Casotto, S., Berardino, L., Zanoni, G., Ariano, R., Aquilina, R., Pellegrino, R., Marsico, P., Del Giudice, A., Narzisi, G., Tomaselli, V., Fornaca, G., Favro, M., Loperfido, B., Gallo, C., Buffoni, S., Gani, F., Raviolo, P., Faggionato, S., Truffelli, T., Vivalda, L., Albano, M., Enzo Rossi, R., Lattuada, G., Bona, F., Quaglio, L., Chiesa, A., Trapani, M., Seminara, R., Cucchi, B., Oderda, S., Borio, G., Galeasso, G., Garbaccio, P., Marco, A., Marengo, F., Cadario, G., Manzoni, S., Vinay, C., Curcio, A., Silvestri, A., Peduto, A., Riario-Sforza, G. G., Maria Forgnone, A., Barocelli, P., Tartaglia, N., Feyles, G., Giacone, A., Ricca, V., Guida, G., Nebiolo, F., Bommarito, L., Heffler, E., Vietti, F., Galimberti, M., Savi, E., Pappacoda, A., Bottero, P., Porcu, S., Felice, G., Berra, D., Francesca Spina, M., Pravettoni, V., Calamari, A. M., Varin, E., Iemoli, E., Lietti, D., Ghiglioni, D., Alessandro Fiocchi, Tosi, A., Poppa, M., Caviglia, A., Restuccia, M., Russello, M., Alciato, P., Manzotti, G., Ranghino, E., Luraschi, G., Rapetti, A., Rivolta, F., Allegri, F., Terracciano, L., Agostinis, F., Paolo Piras, P., Ronchi, G., Gaspardini, G., Caria, V., Tolu, F., Fantasia, D., Carta, P., Moraschini, A., Quilleri, R., Santelli, A., Prandini, P., Del Giudice, G., Apollonio, A., Bonazza, L., Teresa Franzini, M., Branchi, S., Zanca, M., Rinaldi, S., Catelli, L., Zanoletti, T., Cosentino, C., Della Torre, F., Cremonte, L., Musazzi, D., Suli, C., Rivolta, L., Ottolenghi, A., Marino, G., Sterza, G., Sambugaro, R., Orlandini, A., Minale, P., Voltolini, S., Bignardi, D., Omodeo, P., Tiri, A., Milani, S., Ronchi, B., Licardi, G., Bruni, P., Scibilia, J., Schroeder, J., Crosti, F., Maltagliati, A., Alesina, M. R., Mosca, M., Leone, G., Napolitano, G., Di Gruttola, G., Scala, G., Mascio, S., Valente, A., Marchetiello, I., Catello, R., Gazulli, A., Del Prete, A., Varricchio, A. M., Carbone, A., Forestieri, A., Stillitano, M., Leonetti, L., Tirroni, E., Castellano, F., Abbagnara, F., Romano, F., Levanti, C., Cilia, M., Longo, R., Ferrari, A., Merenda, R., Di Ponti, A., Guercio, E., Surace, L., Ammendola, G., Tansella, F., Peccarisi, L., Stragapede, L., Minenna, M., Granato, M., Fuiano, N., Pannofino, A., Ciuffreda, S., Giannotta, A., Morero, G., D Oronzio, L., Taddeo, G., Nettis, E., Cinquepalmi, G., Lamanna, C., Mastrandrea, F., Minelli, M., Salamino, F., Muratore, L., Latorre, F., Quarta, C., Ventura, M., D Ippolito, G., Giannoccaro, F., Dambra, P., Pinto, L., Triggiani, M., Munno, G., Manfredi, G., Lonero, G., Damiano, V., Errico, G., Di Leo, E., Manzari, F., Spagna, V., Arsieni, A., Matarrese, A., Mazzarella, G., Scarcia, G., Scarano, R., Ferrannini, A., Pastore, A., Maionchi, P., Filannino, L., Tria, M., Giuliano, G., Damiani, E., Scichilone, N., Marchese, M., Lucania, A., Marino, M., Strazzeri, L., Tumminello, S., Vitale, G. I., Gulotta, S., Gragotto, G., Zambito, M., Greco, D., Valenti, G., Licitra, G., Cannata, E., Filpi, R., Contraffatto, M., Sichili, S., Randazzo, S., Scarantino, G., Lo Porto, B., Pavone, F., Di Bartolo, C., Paternò, A., Rapisarda, F., Laudani, E., Leonardi, S., Padua, V., Cabibbo, G., Marino Guzzardi, G., Deluca, F., Agozzino, C., Pettinato, R., Ghini, M., Scurati S., Frati F., Passalacqua G., Puccinelli P., Hilaire C., Incorvaia C., D'Avino G., Comi R., Lo Schiavo M., Pezzuto F., Montera C., Pio A., Teresa Ielpo M., Cellini F., Vicentini L., Pecorari R., Aresu T., Capra L., De Benedictis E., Bombi C., Zauli D., Vanzi A., Alberto Paltrinieri C., Bondioli A., Paletta I., Ventura D., Mei F., Paolini F., Colangelo C., Cavallucci E., Cucinelli F., Tinari R., Ermini G., Beltrami V., Novembre E., Begliomini C., Marchese E., Solito E., Ammannati V., Molino G., Galli E., Baldassini M., Di Michele L., Calvani M., Gidaro M., Venuti A., Li Bianchi E., Benassi F., Pocobelli D., Zangari P., De Rocco M.G., Lo Vecchio A., Pingitore G., Grimaldi O., Schiavino D., Perrone N., Antonietta Frieri M., Di Rienzo V., Tripodi S., Scarpa A., Tomsic M., Bonaguro R., Enrico Senna G., Sirena A., Turatello F., Crescioli S., Favero E., Billeri L., Chieco Bianchi F., Gemignani C., Zanforlin M., Angiola Crivellaro M., Hendrick B., Maltauro A., Masieri S., Elisabetta Conte M., Fama M., Pozzan M., Bonadonna P., Casanova S., Vallerani E., Schiappoli M., Borghesan F., Giro G., Casotto S., Berardino L., Zanoni G., Ariano R., Aquilina R., Pellegrino R., Marsico P., Del Giudice A., Narzisi G., Tomaselli V., Fornaca G., Favro M., Loperfido B., Gallo C., Buffoni S., Gani F., Raviolo P., Faggionato S., Truffelli T., Vivalda L., Albano M., Enzo Rossi R., Lattuada G., Bona F., Quaglio L., Chiesa A., Trapani M., Seminara R., Cucchi B., Oderda S., Borio G., Galeasso G., Garbaccio P., De Marco A., Marengo F., Cadario G., Manzoni S., Vinay C., Curcio A., Silvestri A., Peduto A., Riario-Sforza G.G., Maria Forgnone A., Barocelli P., Tartaglia N., Feyles G., Giacone A., Ricca V., Guida G., Nebiolo F., Bommarito L., Heffler E., Vietti F., Galimberti M., Savi E., Pappacoda A., Bottero P., Porcu S., Felice G., Berra D., Francesca Spina M., Pravettoni V., Calamari A.M., Varin E., Iemoli E., Lietti D., Ghiglioni D., Fiocchi A., Tosi A., Poppa M., Caviglia A., Restuccia M., Russello M., Alciato P., Manzotti G., Ranghino E., Luraschi G., Rapetti A., Rivolta F., Allegri F., Terracciano L., Agostinis F., Paolo Piras P., Ronchi G., Gaspardini G., Caria V., Tolu F., Fantasia D., Carta P., Moraschini A., Quilleri R., Santelli A., Prandini P., Del Giudice G., Apollonio A., Bonazza L., Teresa Franzini M., Branchi S., Zanca M., Rinaldi S., Catelli L., Zanoletti T., Cosentino C., Della Torre F., Cremonte L., Musazzi D., Suli C., Rivolta L., Ottolenghi A., Marino G., Sterza G., Sambugaro R., Orlandini A., Minale P., Voltolini S., Bignardi D., Omodeo P., Tiri A., Milani S., Ronchi B., Licardi G., Bruni P., Scibilia J., Schroeder J., Crosti F., Maltagliati A., Alesina M.R., Mosca M., Leone G., Napolitano G., Di Gruttola G., Scala G., Mascio S., Valente A., Marchetiello I., Catello R., Gazulli A., Del Prete A., Varricchio A.M., Carbone A., Forestieri A., Stillitano M., Leonetti L., Tirroni E., Castellano F., Abbagnara F., Romano F., Levanti C., Cilia M., Longo R., Ferrari A., Merenda R., Di Ponti A., Guercio E., Surace L., Ammendola G., Tansella F., Peccarisi L., Stragapede L., Minenna M., Granato M., Fuiano N., Pannofino A., Ciuffreda S., Giannotta A., Morero G., D'Oronzio L., Taddeo G., Nettis E., Cinquepalmi G., Lamanna C., Mastrandrea F., Minelli M., Salamino F., Muratore L., Latorre F., Quarta C., Ventura M., D'Ippolito G., Giannoccaro F., Dambra P., Pinto L., Triggiani M., Munno G., Manfredi G., Lonero G., Damiano V., Errico G., Di Leo E., Manzari F., Spagna V., Arsieni A., Matarrese A., Mazzarella G., Scarcia G., Scarano R., Ferrannini A., Pastore A., Maionchi P., Filannino L., Tria M., Giuliano G., Damiani E., Scichilone N., Marchese M., Lucania A., Marino M., Strazzeri L., Tumminello S., Vitale G.I., Gulotta S., Gragotto G., Zambito M., Greco D., Valenti G., Licitra G., Cannata E., Filpi R., Contraffatto M., Sichili S., Randazzo S., Scarantino G., Lo Porto B., Pavone F., Di Bartolo C., Paterno A., Rapisarda F., Laudani E., Leonardi S., Padua V., Cabibbo G., Marino Guzzardi G., Deluca F., Agozzino C., Pettinato R., Ghini M., Scurati S, Frati F, Passalacqua G, Puccinelli P, Hilaire C, Incorvaia I, D'Avino G, Comi R, Lo Schiavio M, Pezzuto F, Montera C, Pio A, Ielpo MT, Cellini F, Vicentini L, Pecorari R, Aresu T, Capra L, De Benedictis E, Bombi C, Zauli D, and et al

Subjects
medicine.medical_specialty, Pathology, genetic structures, efficacy, Alternative medicine, Medicine (miscellaneous), Adherence, Cost, Efficacy, Side effects, Sublingual immunotherapy, Settore MED/10 - Malattie Dell'Apparato Respiratorio, sublingual immunotherapy, ALLERGEN, cost, medicine, Subcutaneous immunotherapy, Sublingual immunotherapy, adherence, Clinical efficacy, Intensive care medicine, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), sublingual immunoterapy, Original Research, Asthma, AEROALLERGENS, side effects, business.industry, Health Policy, medicine.disease, Slit, eye diseases, Clinical trial, Patient Preference and Adherence, immunotherapy, sense organs, Allergists, ADHERENCE TO TREATMENT, business, Social Sciences (miscellaneous)
Abstract

Silvia Scurati1, Franco Frati1, Gianni Passalacqua2, Paola Puccinelli1, Cecile Hilaire1, Cristoforo Incorvaia3, Italian Study Group on SLIT Compliance 1Scientific and Medical Department, Stallergenes, Milan, Italy; 2Allergy and Respiratory Diseases, Department of Internal Medicine, Genoa; 3Allergy/Pulmonary Rehabilitation, ICP Hospital, Milan, ItalyObjectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence.Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10.Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists.Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers.Keywords: adherence, sublingual immunotherapy, efficacy, cost, side effects

Published
2010

10. Diagnostic relevance of IgE sensitization profiles to eight recombinant <italic>Phleum pratense</italic> molecules.

Author

Cipriani, F., Mastrorilli, C., Tripodi, S., Ricci, G., Perna, S., Panetta, V., Asero, R., Dondi, A., Bianchi, A., Maiello, N., Miraglia del Giudice, M., Frediani, T., Macrì, F., Lucarelli, S., Dello Iacono, I., Patria, M. F., Varin, E., Peroni, D., Chini, L., and Moschese, V.

Subjects
CONJUNCTIVITIS, ATOPY, CONJUNCTIVA diseases, EYE inflammation, ALLERGIES, IMMUNOLOGIC diseases
Abstract

Abstract: Background: Grass pollen‐related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component‐resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. Methods: We examined 1120 children (age 4‐18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. Results: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass‐specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. Conclusions: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response. [ABSTRACT FROM AUTHOR]

Published
2018
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11. A parallel algorithm for the simultaneous solution of direct and adjoint multigroup diffusion problems.

Author

Goos, Gerhard, Hartmanis, Juris, Leeuwen, Jan, Alexandrov, Vassil, Dongarra, Jack, Varin, E., Roy, R., and Nkaoua, T.

Abstract

In this paper, an acceleration scheme for the inverse power method based on the stationary properties of the Rayleigh ratio will be presented. Its practical use will be demonstrated by simultaneously solving the direct and adjoint multigroup diffusion problems. A parallel algorithm is developed using a repartition of both problems over two processors with a minimal communication effort. Speed-ups are given for a variety of problems on different computer architectures. [ABSTRACT FROM AUTHOR]

Published
1998
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16. Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules

Author

Giuseppe Pingitore, Nunzia Maiello, Francesco Macrì, Mario Plebani, Pasquale Comberiati, Salvatore Tripodi, Francesca Cipriani, A Di Rienzo Businco, Valentina Panetta, Viviana Moschese, Maria Francesca Patria, Carla Mastrorilli, Diego Faggian, Tullio Frediani, P M Matricardi, Simone Frediani, M. Miraglia Del Giudice, Carlo Caffarelli, Mauro Calvani, Arianna Dondi, Diego Peroni, Umberto Pelosi, F. Paravati, C Lambiase, Mariangela Tosca, Maria Carmen Verga, Sandra Lucarelli, Loredana Chini, Serena Perna, I Dello Iacono, Roberto Bernardini, C. Povesi Dascola, Annamaria Bianchi, Riccardo Asero, Elena Varin, Ifigenia Sfika, Giampaolo Ricci, Cipriani, F., Mastrorilli, C., Tripodi, S., Ricci, G., Perna, S., Panetta, V., Asero, R., Dondi, A., Bianchi, A., Maiello, N., Miraglia del Giudice, M., Frediani, T., Macrì, F., Lucarelli, S., Dello Iacono, I., Patria, M.F., Varin, E., Peroni, D., Chini, L., Moschese, V., Bernardini, R., Pingitore, G., Pelosi, U., Tosca, M., Paravati, F., Sfika, I., Businco, A. Di Rienzo, Povesi Dascola, C., Comberiati, P., Frediani, S., Lambiase, C., Verga, M.C., Faggian, D., Plebani, M., Calvani, M., Caffarelli, C., Matricardi, P.M., Macrã¬, F., Patria, M. F., Verga, M. C., and Matricardi, P. M.

Subjects
Male, Allergy, grass pollen, Immunoglobulin E, Airborne allergen, component-resolved diagnostics, Atopy, 0302 clinical medicine, allergy, children, IgE sensitization profiles, Immunology and Allergy, Immunology, 030212 general & internal medicine, Child, Sensitization, Rhinitis, biology, Settore MED/38, Recombinant Proteins, Phleum pratense, medicine.anatomical_structure, Italy, Child, Preschool, Female, Adolescent, IgE sensitization profile, Phleum, 03 medical and health sciences, Allergic, Oral allergy syndrome, medicine, Humans, Preschool, Asthma, Settore MED/38 - Pediatria Generale e Specialistica, Seasonal, business.industry, Component-resolved diagnostic, Rhinitis, Allergic, Seasonal, Allergens, medicine.disease, biology.organism_classification, Cross-Sectional Studies, 030228 respiratory system, biology.protein, business, Biomarkers
Abstract

Background Grass pollen–related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. Methods We examined 1120 children (age 4–18y) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight Phleum pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. Results The analysis of IgE responses against eight Phleum pratense molecules showed 87profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SAR, and complex profiles were associated with longer disease duration. Conclusions In a large pediatric population, the complexity of IgE sensitization profiles against Phleum pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7 and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response. This article is protected by copyright. All rights reserved.

Published
2018

17. Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification

Author

Riccardo Asero, Diego Faggian, Roberta Olcese, Loredana Chini, Maria Francesca Patria, Francesco Macrì, Alessandro Travaglini, Serena Perna, Sandra Lucarelli, Carla Mastrorilli, Carlo Caffarelli, M. Miraglia Del Giudice, Viviana Moschese, Umberto Pelosi, Francesca Cipriani, Nunzia Maiello, Mario Plebani, Simone Frediani, A. Di Rienzo-Businco, Giuseppe Pingitore, Roberto Bernardini, I Dello Iacono, Elena Varin, Ifigenia Sfika, Annamaria Bianchi, Giampaolo Ricci, Salvatore Tripodi, Pasquale Comberiati, Anastasia Cirisano, C. Pistoletti, C. Povesi Dascola, Mauro Calvani, Matteo Moretti, Maria Carmen Verga, Tullio Frediani, P M Matricardi, Arianna Dondi, Diego Peroni, Paolo Giordani, Mastrorilli, C., Tripodi, S., Caffarelli, C., Perna, S., Di Rienzo Businco, A., Sfika, I., Asero, R., Dondi, Arianna, Bianchi, A., Povesi Dascola, C., Ricci, Giampaolo, Cipriani, Francesca, Maiello, N., Miraglia Del Giudice, M., Frediani, T., Frediani, S., Macrì, F., Pistoletti, C., Dello Iacono, I., Patria, M. F., Varin, E., Peroni, D., Comberiati, P., Chini, L., Moschese, V., Lucarelli, S., Bernardini, R., Pingitore, G., Pelosi, U., Olcese, R., Moretti, M., Cirisano, A., Faggian, D., Travaglini, A., Plebani, M., Verga, M. C., Calvani, M., Giordani, P., Matricardi, P. M., Dondi, A., Ricci, G., Cipriani, F., Maiello, Nunzia, and MIRAGLIA DEL GIUDICE, Michele

Subjects
Male, pollen-food syndrome, Allergy, Comorbidity, Immunoglobulin E, 0302 clinical medicine, Risk Factors, Immunology and Allergy, 030212 general & internal medicine, Age of Onset, endotype, Child, Prospective cohort study, Sensitization, Conjunctivitis, Allergic, education.field_of_study, panallergens, biology, Syndrome, medicine.anatomical_structure, Italy, classification, endotypes, Child, Preschool, Population Surveillance, panallergen, Pollen, Female, Seasons, oral allergy syndrome, Food Hypersensitivity, Adolescent, Population, Immunology, pollen food syndrome, 03 medical and health sciences, Oral allergy syndrome, children, medicine, cluster analysi, Humans, molecules, education, neoplasms, Skin Tests, Settore MED/38 - Pediatria Generale e Specialistica, molecule, business.industry, allergic rhinoconjunctiviti, Rhinitis, Allergic, Seasonal, allergic rhinoconjunctivitis, Allergens, medicine.disease, cluster analysis, 030228 respiratory system, Food, biology.protein, Age of onset, business
Abstract

Background Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. Methods We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. Results PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. Conclusions In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

Published
2016

18. Comparison of ammoniated and nonammoniated extracts in children with latex allergy

Author

S. La Grutta, Gianni Mistrello, G. B. Pajno, G. Passalacqua, Elena Varin, La Grutta, S, Mistrello, G, Varin, E, Pajno, G, and Passalacqua, G

Subjects
Male, Allergy, Latex Hypersensitivity, Adolescent, Latex, Immunology, Provocation test, Immunoblotting, medicine.disease_cause, Immunoglobulin E, Sensitivity and Specificity, Ige reactivity, Allergen, Radioallergosorbent Test, Ammonia, medicine, Immunology and Allergy, Humans, Child, Electrophoresis, Polyacrylamide Gel, Skin Tests, Allergens, Female, ammoniated extract, diagnosis, immunoblotting, latex allergy, nonammoniated extract, RAST, biology, medicine.diagnostic_test, Skin Test, Chemistry, Radioallergosorbent test, medicine.disease, Latex allergy, biology.protein, Human
Abstract

Background: The use of ammoniated or nonammoniated latex extracts for the diagnosis of latex allergy is still a matter of debate. The aim of our study was to compare the characteristics of the two types of extracts by immunoblotting and RAST techniques in children with ascertained latex allergy. Methods: Ammoniated (AL) and nonammoniated latex (NAL) extracts were prepared and blotted on SDS-PAGE to resolve their components. Also a solid phase for RAST assays was prepared with the two extracts. The sera from 18 children (mean age 11.4 years, range 6–15 years), with ascertained latex allergy (clinical history, skin test, CAP-RAST and provocation) were used for the experiments. Results: The NAL extract is resolved in many bands (5–100 kDa), whereas AL showed only few components, likely Hev b 4, 6 and 7. IgE reactivity against AL was observed only in 5/18 patients, whereas 12/18 were positive with NAL. The blotting profile against NAL was complex and the IgE recognition pattern involved different bands. Conclusion: The extract obtained from NAL is able to detect specific IgE against a greater number of allergenic determinants, and therefore a greater diagnostic accuracy can be expected.

Published
2003

19. Inverse association between the molecular spreading of IgE to grass pollen and the IgE response to Dermatophagoides pteronyssinus among children with seasonal allergic rhinitis.

Author

Brindisi G, Cipriani F, Potapova E, Tripodi S, Panetta V, Bernardini R, Caffarelli C, Casani A, Cervone R, Chini L, Comberiati P, Castro G, Del Giudice MM, Iacono ID, Businco ADR, Dramburg S, Gallucci M, Giannetti A, Moschese V, Sfika I, Varin E, Ricci G, Reese G, Zicari AM, and Matricardi PM

Abstract

Background: Seasonal allergic rhinoconjunctivitis (SAR) is a worldwide health problem, especially in Westernized countries. Previous studies of the "Panallergens in Pediatrics" (PAN-PED) cohort found that molecular spreading (ie, the progressive increase in serum specific IgE antibody levels) of the IgE response to the grass pollen, Phleum pratense , molecules is directly associated with polysensitization to pollen in general.The research question is aimed at verifying whether this association can also be detected for non-pollen allergens, specifically Dermatophagoides pteronyssinnus ( D.pt ), to better understand the relationship between a perennial allergen ( D.pt ) and a seasonal allergen ( Phleum pratense ).To this end, our first objective was to analyze the biobank of the PAN-PED cohort serum by measuring the IgE levels to D.pt and its major recombinant molecules (Der p1, Der p2, Der p23); subsequently we investigated their correlation towards Phleum pratense IgE response, studying also the relationship between the molecular spreading of these 2 different allergens., Methods: Among 1120 patients positive to Phleum pratense , 638 were also sensitized to D.pt . Patients underwent skin prick tests (SPT) for inhalant extracts, and their serum was tested for total IgE (tIgE), and sIgE to pollen and perennial allergens. Considering the molecular allergen detection through the component resolved diagnosis (CRD), out of 638 patients, 146 were further investigated by performing IgE tests of the 3 major D.pt. molecules: Der p1, Der p2, and Der p23., Results: We found that a broader molecular response to Phleum pratense molecules, assessed by CRD, was associated with higher tIgE levels, polysensitization to pollens, and higher IgE levels to pollens, but also to lower IgE levels to D.pt and lower degree of sensitization to rDer p1, r Der p2, and rDer p23. In a multivariate linear model, the number of Phleum pratense molecules recognized by IgE was still inversely associated with the IgE level to D.pt extract., Conclusions: The main finding of this study was the detection of an inverse association, never described in the literature, between the molecular spreading of the IgE response to Phleum pratense and the IgE response to D.pt . This led us to speculate on the etiopathogenetic hypothesis according to which, among the majority of pollen allergic patients, a strong and molecularly diversified IgE response may be limited to pollen allergens and may be preventing or contrasting the development of an equally strong and diversified IgE sensitization to D.pt molecules. The biological mechanisms underlying this phenomenon deserve to be investigated., Competing Interests: Dr. P. Matricardi reports grants and personal fees from Euroimmun AG; grants and personal fees from Thermo Fisher Scientific, personal fees from Hycor Biomedical Inc, outside the submitted work. Dr S. Tripodi is cofounder of TPS Production. All other authors declared no conflicts of interest., (© 2024 The Authors.)

Published
2024
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20. Incidence and clinical impact of bile ducts changes after multibipolar radiofrequency ablation for hepatocellular carcinoma.

Author

Varin E, Beunon P, N'Kontchou G, Petit A, Pescatori LC, Ganne-Carrié N, Nault JC, Seror O, and Sutter O

Subjects
Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Aged, 80 and over, Adult, Bile Ducts diagnostic imaging, Bile Ducts surgery, Incidence, Risk Factors, Treatment Outcome, Liver Cirrhosis diagnostic imaging, Postoperative Complications epidemiology, Carcinoma, Hepatocellular surgery, Carcinoma, Hepatocellular diagnostic imaging, Liver Neoplasms surgery, Liver Neoplasms diagnostic imaging, Radiofrequency Ablation methods
Abstract

Objectives: This study aimed to evaluate the incidence and clinical implications of bile duct changes following multibipolar radiofrequency ablation (mbpRFA) for hepatocellular carcinoma (HCC)., Materials and Methods: Radiological, clinical, and biological data from consecutive cirrhotic patients who underwent first-line mbpRFA between 2007 and 2014 for uninodular HCC ≤ 5 cm were retrospectively collected. Follow-up imaging was reviewed to identify bile duct changes and factors associated with biliary changes were assessed using multivariable analysis. Baseline and 6-month liver function tests were compared in patients with and without bile duct changes. Complications, cirrhosis decompensation, and survival rates were compared in both groups., Results: A total of 231 patients (mean age 68 years [39-85], 187 men) underwent 266 mbpRFA sessions for uninodular HCC (mean size 26 mm). Of these, 76 (33%) developed bile duct changes (upstream bile duct dilatations and/or bilomas) with a mean onset time of 3 months. Identified risk factors for these changes were the infiltrative aspect of the tumor (p = 0.035) and its location in segment VIII (p < 0.01). The average increase in bilirubin at 6 months was higher in the group with biliary changes (+2.9 vs. +0.4 µg/mL; p = 0.03). There were no significant differences in terms of complications, cirrhosis decompensation at 1 year (p = 0.95), local and distant tumor progression (p = 0.91 and 0.14 respectively), and overall survival (p = 0.4) between the two groups., Conclusion: Bile duct changes are common after mbpRFA for HCC, especially in tumors with an infiltrative aspect or those located in segment VIII. These changes do not appear to negatively impact the course of cirrhosis at 1 year or overall survival., Clinical Relevance Statement: Bile duct changes following mbpRFA for HCC are relatively common. Nevertheless, they do not raise clinical concerns in terms of complications, deterioration in liver function, or survival rates. Consequently, specific monitoring or interventions for these bile duct changes are not warranted., Key Points: • Bile duct changes are frequently observed after multibipolar radiofrequency ablation for hepatocellular carcinoma, occurring in 33% of cases in our study. • Patients with bile duct changes exhibited a higher increase in bilirubin levels at 6 months but no more cirrhosis decompensation or liver abscesses. • Biliary changes following multibipolar radiofrequency ablation for hepatocellular carcinoma are not alarming and do not necessitate any specific monitoring or intervention., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Published
2024
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21. IgE to cyclophilins in pollen-allergic children: Epidemiologic, clinical, and diagnostic relevance of a neglected panallergen.

Author

Matricardi PM, Potapova E, Panetta V, Lidholm J, Mattsson L, Scala E, Bernardini R, Caffarelli C, Casani A, Cervone R, Chini L, Comberiati P, De Castro G, Miraglia Del Giudice M, Dello Iacono I, Di Rienzo Businco A, Gallucci M, Giannetti A, Moschese V, Varin E, Bianchi A, Calvani M, Frediani T, Macrì F, Maiello N, Paravati F, Pelosi U, Peroni D, Pingitore G, Tosca M, Zicari AM, Ricci G, Asero R, and Tripodi S

Subjects
Humans, Child, Male, Female, Adolescent, Child, Preschool, Antigens, Plant immunology, Italy epidemiology, Prevalence, Immunoglobulin E immunology, Immunoglobulin E blood, Rhinitis, Allergic, Seasonal immunology, Rhinitis, Allergic, Seasonal epidemiology, Rhinitis, Allergic, Seasonal diagnosis, Rhinitis, Allergic, Seasonal blood, Cyclophilins immunology, Allergens immunology, Pollen immunology
Abstract

Background: Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice., Objective: We investigated the epidemiologic, diagnostic, and clinical relevance of cyclophilins in seasonal allergic rhinitis and its comorbidities., Methods: We examined a random sample of 253 (25%) of 1263 Italian children with seasonal allergic rhinitis from the Panallergens in Pediatrics (PAN-PED) cohort with characterized disease phenotypes. Nested studies of sensitization prevalence, correlation, and allergen extract inhibition were performed in patients sensitized to birch pollen extract but lacking IgE to Bet v 1/2/4 (74/1263) or with highest serum level of IgE to Bet v 1 (26/1263); and in patients with sensitization to various extracts (ragweed, mugwort, pellitory, Plantago, and plane tree), but not to their respective major allergenic molecule, profilins, and polcalcins. IgE to cyclophilin was detected with recombinant Bet v 7, and extract inhibition tests were performed with the same rBet v 7., Results: IgE to rBet v 7 was detected in 43 (17%) of 253 patients. It was associated with asthma (P < .028) and oral allergy syndrome (P < .017) in univariate but not multivariate analysis adjusted for IgE to profilins (Phl p 12), PR-10s (Bet v 1), and lipid transfer proteins (Pru p 3). IgE to rBet v 7 was also highly prevalent (47/74, 63%) among patients with unexplained sensitization to birch pollen extract. In patients with unexplained sensitization to ragweed, mugwort, pellitory, Plantago and plane tree pollen, the levels of IgE to those extracts correlated with the levels of IgE to rBet v 7, and they were also significantly inhibited by rBet v 7 (inhibition range 45%-74%)., Conclusions: IgE sensitization to cyclophilin is frequent in pollen-allergic patients living in temperate areas and can produce "false" positive outcomes in skin prick and IgE tests to pollen extracts. Molecular diagnostic guidelines should include this panallergen family., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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22. IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins.

Author

Potapova E, Tripodi S, Panetta V, Dramburg S, Bernardini R, Caffarelli C, Casani A, Cervone R, Chini L, Comberiati P, De Castro G, Del Giudice MM, Dello Iacono I, Di Rienzo Businco A, Gallucci M, Giannetti A, Moschese V, Sfika I, Varin E, Asero R, Bianchi A, Calvani M, Frediani T, Macrì F, Maiello N, Paravati F, Pelosi U, Peroni D, Pingitore G, Tosca M, Zicari AM, Ricci G, Reese G, Grabenhenrich L, Icke K, Grübl A, Müller C, Zepp F, Schuster A, Wahn U, Lau S, Keil T, and Matricardi PM

Subjects
Adult, Humans, Child, Child, Preschool, Cohort Studies, Prevalence, Allergens, Carbohydrates, Risk Factors, Cross Reactions, Immunoglobulin E, Hypersensitivity
Abstract

Background: IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. Their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood., Methods: We examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (Panallergen in Paediatrics, PAN-PED), as well as with a longitudinal approach in 612 German children (Multicenter Allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. The presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA)., Results: IgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. Children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. Among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period., Conclusions: Our results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Published
2024
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23. Thermal ablation of ultrasound and non-contrast computed tomography invisible primary and secondary liver tumors: targeting by selective intra-arterial lipiodol injection.

Author

Kobe A, Tselikas L, Deschamps F, Roux C, Delpla A, Varin E, Hakime A, and de Baère T

Subjects
Humans, Male, Middle Aged, Aged, Female, Ethiodized Oil therapeutic use, Retrospective Studies, Tomography, X-Ray Computed, Liver Neoplasms diagnostic imaging, Liver Neoplasms surgery, Liver Neoplasms pathology, Carcinoma, Hepatocellular diagnostic imaging, Carcinoma, Hepatocellular surgery, Catheter Ablation methods
Abstract

Purpose: To evaluate the technical feasibility and outcomes of thermal ablation following selective intra-arterial lipiodol injection (SIALI) for targeting primary and secondary liver tumors invisible on ultrasound (US) and non-contrast computed tomography (CT)., Methods: This retrospective study included 18 patients with 20 tumors (67% male, mean age 60.8 ± 12.1 years). The 20 tumors included 15 liver metastases and 5 hepatocellular carcinomas. All patients underwent single-session SIALI and subsequent CT-guided thermal ablation. The primary outcome was a technical success, defined as visualization of the tumor after SIALI and successful thermal ablation. Secondary outcomes were local recurrence rate and procedure-related complications., Results: The median tumor size was 1.5 (1-2.5) cm. In addition, SIALI was performed with a median volume of 3 (1-10) mL of lipiodol resulting in intra-tumoral iodized oil accumulation in 19 tumors and negative imprint with iodized oil accumulation of the surrounding liver parenchyma in 1 tumor. The technical success rate was 100%. No local occurrence was observed at a mean follow-up time of 3 ± 2.5 years., Conclusion: SIALI to tag liver tumors not visible with US and non-contrast CT before percutaneous ablation is highly feasible and has a high success rate for the treatment of both primary and secondary liver tumors.

Published
2023
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24. Coil Embolization of Variant Hepatic Arteries During Percutaneous Arterial Port Catheter Placement for Intraarterial Chemotherapy: Analysis of Intrahepatic Perfusion Redistribution and Treatment Efficacy.

Author

Kobe A, Deschamps F, Meyblum L, Varin E, Delpla A, Hakime A, Teriitehau C, Roux C, Boileve A, Gelli M, de Baère T, and Tselikas L

Subjects
Male, Humans, Adult, Middle Aged, Aged, Female, Hepatic Artery diagnostic imaging, Retrospective Studies, Infusions, Intra-Arterial methods, Catheters, Indwelling, Perfusion, Treatment Outcome, Liver Neoplasms diagnostic imaging, Liver Neoplasms therapy, Liver Neoplasms blood supply, Vascular Access Devices, Antineoplastic Agents
Abstract

Purpose: The purpose of this study was to analyze the intrahepatic perfusion redistribution after embolization of hepatic arterial variants during percutaneous arterial port catheter placement as well as to investigate the treatment efficacy of intraarterial chemotherapy in perfusion redistribution-dependent compared to redistribution-independent liver areas., Materials and Methods: This retrospective study included 62 patients (67.7% males, mean age of 56 ± 12 years). A replaced left hepatic artery was encountered in 36/62 (58.1%), a replaced right hepatic artery in 19/62 (30.6%) and a replaced left and right hepatic artery in 7/62 of patients (11.3%), respectively. Subjective perfusion analysis was performed on digital subtracted angiography and computed tomography (CT)/cone-beam computed tomography (CBCT) images evaluating the visibility of the main, segmental and subsegmental branches of the embolized variant hepatic artery, re-perfused from intrahepatic arterial anastomoses. For objective perfusion analysis ROI measurements on CT/CBCT images were taken in the redistribution-dependent and redistribution-independent liver lobe. Response analysis according to RECIST 1.1 was separately calculated for the redistribution-dependent and redistribution-independent liver lobe., Results: Intrahepatic reperfusion of the embolized variant hepatic artery was observed immediately after embolization with visualization of the subsegmental branches in 95.2% of patients. ROI measurements on CT/CBCT images (right lobe mean 76 ± 30.2 HU, left lobe mean 74.4 ± 30.5, p-value 0.88) did not show any differences. Treatment response after intraarterial chemotherapy did not differ between the redistribution-dependent and redistribution-independent liver lobes., Conclusion: Embolization of hepatic arterial variants during percutaneous arterial port catheter placement results in effective intrahepatic perfusion redistribution and does not compromise treatment efficacy of intraarterial chemotherapy in the redistribution-dependent liver lobe., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Published
2023
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25. Single-session transarterial chemoembolization combined with percutaneous thermal ablation in liver metastases 3 cm or larger.

Author

Kobe A, Tselikas L, Deschamps F, Roux C, Delpla A, Varin E, Hakime A, and De Baère T

Subjects
Male, Humans, Female, Adult, Middle Aged, Aged, Retrospective Studies, Treatment Outcome, Disease Progression, Combined Modality Therapy, Liver Neoplasms pathology, Chemoembolization, Therapeutic methods, Carcinoma, Hepatocellular pathology, Catheter Ablation methods
Abstract

Purpose: The purpose of this study was to evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with percutaneous thermal ablation in patients with liver metastases 3 cm in diameter or larger., Materials and Methods: This retrospective study included 39 patients with a total of 46 liver metastases treated. There were 14 men and 25 women, with a mean age of 55 ± 13.3 (SD) (age range: 28-77 years). All patients were treated with a combination of TACE and thermal ablation in a single session. Primary outcome was local tumor progression. Secondary outcomes were procedure related complications and systemic disease progression., Results: Mean tumor size was 3.6 ± 0.6 (SD) cm (range: 3-5 cm). Conventional TACE was performed in 32 liver metastases (32/46; 70%) and drug-eluting beads-TACE in 14 liver metastases (14/46; 30%) followed by radiofrequency ablation in 34 (34/46; 74%), microwave ablation in 11 (11/46; 24%) and cryoablation in one (1/46; 2%) metastasis. Four grade 2 (4/39; 10%) complications were observed. After a mean follow up of 31.9 ± 26.1 (SD) months (range: 2-113 months) overall local tumor progression rate was 15% (7/46). Local tumor progression rate at 12 months was 13% (6/46). Overall systemic disease progression was seen in 29 patients (29/39; 74%) with a systemic disease progression rate at 12 months of 59% (23/39)., Conclusion: Treatment of large liver metastases with TACE and thermal ablation in a single session is safe and achieves high local control rate., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Published
2022
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26. Thermal ablation of the most challenging cases of liver metastases.

Author

de Baere T, Kobe A, Tselikas L, Dioguardi M, Varin E, and Deschamps F

Subjects
Humans, Patient Selection, Treatment Outcome, Ablation Techniques, Catheter Ablation methods, Liver Neoplasms diagnostic imaging, Liver Neoplasms pathology, Liver Neoplasms surgery, Surgery, Computer-Assisted methods
Abstract

Patient selection for image-guided thermal ablation of liver metastases has to be taken in a multidisciplinary tumor board given the extreme complexity of cancer metastatic disease, and the numerous treatment options offered to oligometastatic patient today.The role of image-guided thermal ablation increases over years in the treatment of liver metastases. In order to fulfill the expected outcomes which are to have a local control rate equivalent to surgery, interventional oncologist have to take every measure that will help when treating most challenging metastases including image guidance, anesthesia, respiration monitoring, ablation technique, confirmation software that can favor positive outcomes, and in some way to render challenging metastases easy to treat.

Published
2022
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27. Robotic assistance for percutaneous needle insertion in the kidney: preclinical proof on a swine animal model.

Author

de Baere T, Roux C, Noel G, Delpla A, Deschamps F, Varin E, and Tselikas L

Subjects
Animals, Disease Models, Animal, Kidney diagnostic imaging, Kidney surgery, Needles, Phantoms, Imaging, Swine, Robotic Surgical Procedures methods, Robotics
Abstract

Background: We evaluated the accuracy, safety, and feasibility of a computed tomography (CT)-guided robotic assistance system for percutaneous needle placement in the kidney., Methods: Fiducials surgically implanted into the kidneys of two pigs were used as targets for subsequent robotically-assisted needle insertion. Robotically-assisted needle insertions and CT acquisitions were coordinated using respiratory monitoring. An initial scan volume data set was used for needle insertion planning defining skin entry and target point. Then, needle insertion was performed according to robot positioning. The accuracy of needle placement was evaluated upon the distance between the needle tip and the predefined target on a post needle insertion scan. A delayed contrast-enhanced CT scan was acquired to assess safety., Results: Eight needle trajectories were performed with a median procedural time measured from turning on the robotic system to post needle insertion CT scan of 21 min (interquartile range 15.5-26.5 min). Blind review of needle placement accuracy was 2.3 ± 1.2 mm (mean ± standard deviation) in lateral deviation, 0.7 ± 1.7 mm in depth deviation, and 2.8 ± 1.3 mm in three-dimensional Euclidian deviation. All needles were inserted on the first attempt, which determined 100% feasibility, without needle readjustment. The angulation and length of the trajectory did not impact on the needle placement accuracy. Two minor procedure-related complications were encountered: 2 subcapsular haematomas (13 × 6 mm and 35 × 6 mm) in the same animal., Conclusions: Robotically-assisted needle insertion was shown feasible, safe and accurate in a swine kidney model. Further larger studies are needed., (© 2022. The Author(s) under exclusive licence to European Society of Radiology.)

Published
2022
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28. Thermal Ablation Combined with Selective Transarterial Embolization of Centrally Located Renal Cell Carcinomas Measuring 3 cm or Larger.

Author

Kobe A, Tselikas L, Deschamps F, Roux C, Delpla A, Varin E, Hakime A, and de Baère T

Subjects
Aged, Female, Humans, Male, Retrospective Studies, Treatment Outcome, Carcinoma, Renal Cell diagnostic imaging, Carcinoma, Renal Cell surgery, Catheter Ablation methods, Embolization, Therapeutic methods, Kidney Neoplasms diagnostic imaging, Kidney Neoplasms surgery
Abstract

Purpose: The purpose of this study was to evaluate the long-term outcomes of patients with centrally located renal cell carcinomas (RCC) measuring 3 cm or larger, treated by a standardized transarterial embolization protocol associated with percutaneous ablation., Materials and Methods: This retrospective study included 11 patients (73% male, mean age 73.4 ± 6.5 years) with RCC and contraindications for surgery. All patients underwent a single session combining transarterial embolization with iodized oil and subsequent thermal percutaneous ablation. Primary and secondary local tumor control were analyzed, defined as absence of any contrast enhancing nodular lesion in the treated area after a single or percutaneous re-treatment session, respectively., Results: Mean tumor size was 3.5 ± 0.3 cm (range 3-4 cm) with a mean R.E.N.A.L. nephrometry score ((R)adius; (E)xophytic, endophytic properties; (N)earness to the collecting system; (A)nterior, posterior; (L)ocation relative to the polar line) of 8 ± 0.9 (range 7-9). Nearness to the collecting system was 4-7 mm in two patients (18%) and ≤ 4 mm in nine patients (82%). After a mean follow-up of 5.2 ± 2.5 years primary and secondary local tumor control rate were 82% and 100%, respectively. No change in serum creatinine levels and glomerular filtration rate was observed compared to pre-treatment values., Conclusion: A combined treatment of selective transarterial embolization and percutaneous ablation of large centrally located RCC (> 3 cm) is safe, feasible and can achieve excellent oncological long-term results. Larger prospective studies are needed., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Published
2022
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29. Percutaneous Fixation of Impending Fracture of the Hip.

Author

Roux C, Tselikas L, Delpla A, Yevich S, Teriitehau C, Hakime A, Varin E, Kobe A, de Baère T, and Deschamps F

Subjects
Fracture Fixation, Internal adverse effects, Fracture Fixation, Internal methods, Humans, Treatment Outcome, Cementoplasty adverse effects, Cementoplasty methods, Fractures, Bone, Fractures, Spontaneous prevention & control, Fractures, Spontaneous surgery, Neoplasms
Abstract

According to the literature, prophylactic consolidation of proximal femur lytic metastasis the is recommended when the Mirels' score is above 8. Osteoplasty (cementoplasty of proximal femur) alone provides inadequate consolidation. Various mini-invasive technics, augmented osteoplasties, have been proposed for better long-term consolidation. The aim of this review is to detail the augmented osteoplasty techniques described in the literature and to report their safeties and efficacies to prevent pathological fracture of the proximal femur. A PubMed research found 8 studies that evaluated augmented osteoplasty of the proximal femur in cancer patients. All devices demonstrate adequate safety and low rate of secondary pathological fractures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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30. Thermal ablation in the management of oligometastatic colorectal cancer.

Author

De Baere T, Tselikas L, Delpla A, Roux C, Varin E, Kobe A, Yevich S, and Deschamps F

Subjects
Humans, Ablation Techniques, Catheter Ablation methods, Colorectal Neoplasms pathology, Hyperthermia, Induced, Liver Neoplasms therapy, Lung Neoplasms therapy
Abstract

Purpose: To review available evidence on thermal ablation of oligometastatic colorectal cancer., Methods: Technical and cancer specific considerations for percutaneous image-guided thermal ablation of oligometastatic colorectal metastases in the liver and lung were reviewed. Ablation outcomes are compared to surgical and radiation therapy literature., Results: The application of thermal ablation varies widely based on tumor burden, technical expertise, and local cancer triage algorithms. Ablation can be performed in combination or in lieu of other cancer treatments. For surgically non-resectable liver metastases, a randomized trial has demonstrated the superiority of thermal ablation combined with chemotherapy compared to systemic chemotherapy alone in term of progression-free survival and overall survival (OS), with 5-, and 8-year OS of 43.1% and 35.9% in the combined arm vs. 30.3% and 8.9% in the chemotherapy alone arm. As ablation techniques and technology improve, the role of percutaneous thermal ablation may expand even into surgically resectable disease. Many of the prognostic factors for better OS after local treatment of lung metastases are the same for surgery and thermal ablation, including size and number of metastases, disease-free interval, complete resection/ablation, negative carcinoembryonic antigen, neoadjuvant chemotherapy, and controlled extra-pulmonary metastases. When matched for these factors, thermal ablation for lung and liver metastases appears to provide equivalent overall survival as surgery, in the range of 50% at 5 years. Thermal ablation has limitations that should be respected to optimize patient outcomes and minimize complications including targets that are well-visualized by image guidance, measure <3cm in diameter, and be located at least 3mm distance from prominent vasculature or major bronchi., Conclusions: The routine incorporation of image-guided thermal ablation into the therapeutic armamentarium for the treatment of oligometastatic colorectal cancer can provide long survival and even cure.

Published
2022
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31. Role of Thermal Ablation in Colorectal Cancer Lung Metastases.

Author

Delpla A, de Baere T, Varin E, Deschamps F, Roux C, and Tselikas L

Abstract

Background : Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or stereotactic ablative radiotherapy (SABR). Methods : Indications, technical considerations, oncological outcomes such as survival (OS) or local control (LC), prognostic factors and complications of thermal ablation in colorectal cancer lung metastases were reviewed and put into perspective with results of surgery and SABR. Results : LC rates varied from 62 to 91%, with size of the metastasis (<2 cm), proximity to the bronchi or vessels, and size of ablation margins (>5 mm) as predictive factors of LC. Median OS varied between 33 and 68 months. Pulmonary free disease interval <12 months, positive carcinoembryonic antigen, absence of neoadjuvant chemotherapy and uncontrolled extra-pulmonary metastases were poor prognostic factors for OS. While chest drainage for less than 48 h was required in 13 to 47% of treatments, major complications were rare. Conclusions : Thermal ablation of a selected subpopulation of patients with colorectal cancer lung metastases is safe and can provide excellent LC and delay systemic chemotherapy.

Published
2021
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32. House dust mite allergy and shrimp allergy: a complex interaction.

Author

Celi G, Brusca I, Scala E, Villalta D, Pastorello E, Farioli L, Cortellini G, Deleonardi G, Galati P, Losappio L, Manzotti G, Pirovano B, Muratore L, Murzilli F, Cucinelli F, Musarra A, Cilia M, Nucera E, Aruanno A, Ria F, Patria MF, Varin E, Polillo BR, Sargentini V, Quercia O, Uasuf CG, Zampogna S, Carollo M, Graci S, and Asero R

Subjects
Adolescent, Adult, Animals, Cross Reactions, Female, Food Hypersensitivity immunology, Humans, Immunoglobulin E metabolism, Italy epidemiology, Male, Middle Aged, Penaeidae, Prevalence, Pyroglyphidae, Young Adult, Antigens, Dermatophagoides immunology, Arthropod Proteins immunology, Food Hypersensitivity epidemiology, Tropomyosin immunology
Abstract

Summary: Background and Objective. Sensitization and allergy to shrimp among Italian house dust mite allergic patients are not well defined and were investigated in a large multicenter study. Methods. Shrimp sensitization and allergy were assessed in 526 house dust mite (HDM)-allergic patients submitted to the detection of IgE to Der p 10 and 100 atopic control not sensitized to HDM. Results. Shrimp allergy occurred in 9% of patients (vs 0% of 100 atopic controls not sensitized to HDM; p minor 0.001). Shrimp-allergic patients were less frequently hypersensitive to airborne allergens other than HDM than crustacean-tolerant subjects (35% vs 58.8%; p minor 0.005). Only 51% of tropomyosin-sensitized patients had shrimp allergy, and these showed significantly higher Der p 10 IgE levels than shrimp-tolerant ones (mean 22.2 KU/l vs 6.2 KU/l; p minor 0.05). Altogether 53% of shrimp-allergic patients did not react against tropomyosin. Conclusions. Shrimp allergy seems to occur uniquely in association with hypersensitivity to HDM allergens and tropomyosin is the main shrimp allergen but not a major one, at least in Italy. Along with tropomyosin-specific IgE levels, monosensitization to HDM seems to represent a risk factor for the development of shrimp allergy among HDM allergic patients.

Published
2020
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33. No-Touch Multi-bipolar Radiofrequency Ablation for the Treatment of Subcapsular Hepatocellular Carcinoma ≤ 5 cm Not Puncturable via the Non-tumorous Liver Parenchyma.

Author

Petit A, Hocquelet A, N'kontchou G, Varin E, Sellier N, Seror O, and Sutter O

Subjects
Aged, Aged, 80 and over, Carcinoma, Hepatocellular diagnostic imaging, Disease Progression, Female, Follow-Up Studies, Humans, Liver diagnostic imaging, Liver surgery, Liver Neoplasms diagnostic imaging, Magnetic Resonance Imaging, Interventional methods, Male, Middle Aged, Punctures, Radiography, Interventional methods, Retrospective Studies, Survival Rate, Tomography, X-Ray Computed methods, Treatment Outcome, Carcinoma, Hepatocellular surgery, Catheter Ablation methods, Liver Neoplasms surgery
Abstract

Purpose: The percutaneous ablation of subcapsular hepatocellular carcinoma (S-HCC) may involve a risk of complications such as hemorrhage and tumor seeding, mainly linked to the direct tumor puncture often inevitable with mono-applicator ablation devices. The purpose of this study was to assess the efficacy and safety of no-touch multi-bipolar radiofrequency ablation (NTMBP-RFA) for the treatment of S-HCC ≤ 5 cm not puncturable via the non-tumorous liver parenchyma., Materials and Methods: Between September 2007 and December 2014, 58 consecutive patients (median age: 63 years [46-86], nine females) with 59 S-HCC ≤ 5 cm (median diameter: 25 mm [10-50 mm]), not puncturable via the non-tumorous liver parenchyma, were treated with NTMBP-RFA. Response and follow-up were assessed by CT or MRI. Complications were graded using the Cardiovascular and Interventional Radiological Society of Europe classification. Overall local tumor progression (OLTP)-free survival was assessed using the Kaplan-Meier method. A Cox proportional model evaluated the factors associated with OLTP. Signs of peritoneal or parietal tumor seeding were noted during follow-up imaging studies., Results: A complete ablation was achieved in 57/58 patients (98.3%) after one (n = 51) or two (n = 6) procedures. Three patients (5.2%) experienced complications (sepsis, cirrhosis decompensation; CIRSE grade 2 or 3). After a median follow-up period of 30.5 months [1-97], no patients had tumor seeding. The 1, 2 and 3-year OLTP-free survival rates were 98%, 94% and 91%, respectively. No factors were associated with OLTP., Conclusion: NTMBP-RFA is a safe and effective treatment for S-HCC not puncturable via the non-tumorous liver parenchyma.

Published
2020
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34. House dust mite allergy in Italy-Diagnostic and clinical relevance of Der p 23 (and of minor allergens): A real-life, multicenter study.

Author

Celi G, Brusca I, Scala E, Villalta D, Pastorello E, Farioli L, Cortellini G, Deleonardi G, Galati P, Losappio L, Manzotti G, Pirovano B, Muratore L, Murzilli F, Cucinelli F, Musarra A, Cilia M, Nucera E, Aruanno A, Ria F, Patria MF, Varin E, Polillo BR, Sargentini V, Quercia O, Gabriela Uasuf C, Zampogna S, Carollo M, Graci S, Amato S, Mistrello G, and Asero R

Subjects
Animals, Asthma diagnosis, Asthma immunology, Disease Progression, Humans, Italy, Allergens immunology, Antigens, Dermatophagoides immunology, Dermatophagoides pteronyssinus immunology, Hypersensitivity diagnosis, Hypersensitivity immunology
Published
2019
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35. Early molecular biomarkers predicting the evolution of allergic rhinitis and its comorbidities: A longitudinal multicenter study of a patient cohort.

Author

Cipriani F, Tripodi S, Panetta V, Perna S, Potapova E, Dondi A, Bernardini R, Caffarelli C, Casani A, Cervone R, Chini L, Comberiati P, De Castro G, Miraglia Del Giudice M, Dello Iacono I, Di Rienzo Businco A, Gallucci M, Giannetti A, Mastrorilli C, Moschese V, Pelosi S, Sfika I, Varin E, Villella V, Zicari AM, Brindisi G, Ricci G, and Matricardi PM

Subjects
Adolescent, Allergens immunology, Asthma epidemiology, Asthma etiology, Child, Disease Progression, Female, Follow-Up Studies, Humans, Italy epidemiology, Longitudinal Studies, Male, Prevalence, Prospective Studies, Rhinitis, Allergic complications, Rhinitis, Allergic diagnosis, Risk Factors, Skin Tests statistics & numerical data, Surveys and Questionnaires, Biomarkers blood, Immunoglobulin E blood, Rhinitis, Allergic blood, Skin Tests methods
Abstract

Background: Pollen-related seasonal allergic rhinoconjunctivitis (SAR) is a very frequent pediatric disease in Westernized countries. Risk factors and disease phenotypes have been thoroughly examined in several cross-sectional studies. By contrast, only a few studies have examined disease evolution in patient cohorts. We investigated predictive biomarkers of disease evolution in a large cohort of children with SAR., Methods: During 2015-2017 (follow-up), we re-examined 401 patients from those enrolled in 2009-2011 (baseline) by the "Panallergens in Pediatrics" study, a large multicenter survey of Italian children with SAR. Information on clinical history (standard questionnaire, AllergyCARD®; TPS, Italy) and skin prick tests for inhalant and foods extracts (ALK-Abelló, Hørsholm, Denmark) was acquired as at baseline visit. Evolution in clinical and sensitization data of patients was analyzed over time, as well as their association with the main baseline characteristics and atopy risk factors., Results: The average age of participants was 10.4 ± 3.4 years at baseline and 16.2 ± 3.6 years at follow-up. SAR persisted in 93.3% of patients at follow-up and became more frequently associated with asthma (from 36.7% at baseline to 48.6% at follow-up) and oral allergy syndrome (OAS, from 23.4% to 37.7%). Compared to baseline, the prevalence of skin sensitization to some pollens (Phleum pratense, Corylus avellana, Platanus acerifolia, Artemisia vulgaris) and vegetables (hazelnut, wheat, and apple) significantly decreased at follow-up. Earlier onset of SAR and polysensitization at baseline were associated with incident asthma at follow-up. The presence at baseline of serum IgE to the following allergen molecules was identified as biomarkers of clinical evolution: (a) Phl p 1, for persistence of SAR; (b) Phl p 5, for persistence of both rhinitis and asthma; (c) Pru p 3, for new onset of asthma; (d) Bet v 1, for persistence of OAS., Conclusions: Seasonal allergic rhinoconjunctivitis is clinically heterogeneous in its evolution from childhood to adolescence. The detection of serum IgE to specific molecules (Phl p 1, Phl p 5, Bet v 1, Pru p 3) may be useful as biomarkers to predict SAR persistence and future onset of comorbidities, such as asthma and/or OAS., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Published
2019
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36. Atelocollagen-mediated in vivo siRNA transfection in ovarian carcinoma is influenced by tumor site, siRNA target and administration route.

Author

Meryet-Figuière M, Lecerf C, Varin E, Coll JL, Louis MH, Dutoit S, Giffard F, Blanc-Fournier C, Hedir S, Vigneron N, Brotin E, Pelletier L, Josserand V, Denoyelle C, and Poulain L

Subjects
Animals, Carcinoma diagnostic imaging, Carcinoma genetics, Cell Line, Tumor, Female, Genetic Vectors administration & dosage, Genetic Vectors genetics, Humans, Luciferases genetics, Luminescent Measurements methods, Mice, Mice, Nude, Myeloid Cell Leukemia Sequence 1 Protein genetics, Ovarian Neoplasms diagnostic imaging, Ovarian Neoplasms genetics, Random Allocation, Transfection, Xenograft Model Antitumor Assays, bcl-X Protein genetics, Carcinoma therapy, Collagen administration & dosage, Ovarian Neoplasms therapy, RNA, Small Interfering administration & dosage
Abstract

Ovarian cancer is the leading cause of death from gynecological malignancies worldwide, and innate or acquired chemoresistance of ovarian cancer cells is the major cause of therapeutic failure. It has been demonstrated that the concomitant inhibition of Bcl-xL and Mcl-1 anti-apoptotic activities is able to trigger apoptosis in chemoresistant ovarian cancer cells. In this context, siRNA-mediated Bcl‑xL and Mcl-1 inhibition constitutes an appealing strategy by which to eliminate chemoresistant cancer cells. However, the safest and most efficient way to vectorize siRNAs in vivo is still under debate. In the present study, using in vivo bioluminescence imaging, we evaluated the interest of atelocollagen to vectorize siRNAs by intraperitoneal (i.p.) or intravenous (i.v.) administration in 2 xenografted ovarian cancer models (peritoneal carcinomatosis and subcutaneous tumors in nude mice). Whereas i.p. administration of atelocollagen-vectorized siRNA in the peritoneal carcinomatosis model did not induce any gene downregulation, a 70% transient downregulation of luciferase expression was achieved after i.v. injection of atelocollagen-vectorized siRNA in the subcutaneous (s.c.) model. However, the use of siRNA targeting Bcl-xL or Mcl-1 did not induce target-specific downregulation in vivo in nude mice. Our results therefore show that atelocollagen complex formulation, the administration route, tumor site and the identity of the siRNA target influence the efficiency of atelocollagen‑mediated siRNA delivery.

Published
2017
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37. Amino Acid-based Formula in Cow's Milk Allergy: Long-term Effects on Body Growth and Protein Metabolism.

Author

Canani RB, Nocerino R, Frediani T, Lucarelli S, Di Scala C, Varin E, Leone L, Muraro A, and Agostoni C

Subjects
Biomarkers blood, Blood Proteins metabolism, Body Height, Case-Control Studies, Female, Follow-Up Studies, Humans, Infant, Intention to Treat Analysis, Male, Milk Hypersensitivity blood, Treatment Outcome, Weight Gain, Amino Acids therapeutic use, Infant Formula, Milk Hypersensitivity diet therapy, Whey
Abstract

Objectives: The long-term effects of amino acid-based formula (AAF) in the treatment of cow's milk allergy (CMA) are largely unexplored. The present study comparatively evaluates body growth and protein metabolism in CMA children treated with AAF or with extensively hydrolyzed whey formula (eHWF), and healthy controls., Methods: A 12-month multicenter randomized control trial was conducted in outpatients with CMA (age 5-12 m) randomized in 2 groups, treated with AAF (group 1) and eHWF (group 2), and compared with healthy controls (group 3) fed with follow-on (if age <12 months) or growing-up formula (if age >12 months). At enrolment (T0), after 3 (T3), 6 (T6), and 12 months (T12) a clinical evaluation was performed. At T0 and T3, in subjects with CMA serum levels of albumin, urea, total protein, retinol-binding protein, and insulin-like growth factor 1 were measured., Results: Twenty-one subjects in group 1 (61.9% boys, age 6.5 ± 1.5 months), 19 in group 2 (57.9% boys, age 7 ± 1.7 months) and 25 subjects in group 3 (48% boys, age 5.5 ± 0.5 months) completed the study. At T0, the weight z score was similar in group 1 (-0.74) and 2 (-0.76), with differences compared to group 3 (-0.17, P < 0.05). At T12, the weight z score value was similar between the 3 groups without significant differences. There were no significant changes in protein metabolism in children in groups 1 and 2., Conclusion: Long-term treatment with AAF is safe and allows adequate body growth in children with CMA.

Published
2017
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38. Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

Author

Mastrorilli C, Tripodi S, Caffarelli C, Perna S, Di Rienzo-Businco A, Sfika I, Asero R, Dondi A, Bianchi A, Povesi Dascola C, Ricci G, Cipriani F, Maiello N, Miraglia Del Giudice M, Frediani T, Frediani S, Macrì F, Pistoletti C, Dello Iacono I, Patria MF, Varin E, Peroni D, Comberiati P, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Olcese R, Moretti M, Cirisano A, Faggian D, Travaglini A, Plebani M, Verga MC, Calvani M, Giordani P, and Matricardi PM

Subjects
Adolescent, Age of Onset, Child, Child, Preschool, Cluster Analysis, Comorbidity, Conjunctivitis, Allergic epidemiology, Conjunctivitis, Allergic immunology, Female, Food Hypersensitivity epidemiology, Food Hypersensitivity immunology, Humans, Immunoglobulin E blood, Immunoglobulin E immunology, Italy epidemiology, Male, Population Surveillance, Rhinitis, Allergic, Seasonal epidemiology, Rhinitis, Allergic, Seasonal immunology, Risk Factors, Seasons, Skin Tests, Syndrome, Allergens immunology, Conjunctivitis, Allergic diagnosis, Food adverse effects, Food Hypersensitivity diagnosis, Pollen immunology, Rhinitis, Allergic, Seasonal diagnosis
Abstract

Background: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens., Methods: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population., Results: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit., Conclusions: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2016
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39. Inhibition of the MAP3 kinase Tpl2 protects rodent and human β-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4.

Author

Varin EM, Wojtusciszyn A, Broca C, Muller D, Ravier MA, Ceppo F, Renard E, Tanti JF, and Dalle S

Subjects
Apoptosis, Chronic Disease, Cytokines, Diabetes Mellitus, Type 2 pathology, Exenatide, Humans, Inflammation, Diabetes Mellitus, Type 2 etiology, MAP Kinase Kinase Kinases metabolism, Peptides metabolism, Venoms metabolism
Abstract

Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-cells. Although the MAP3 kinase tumor progression locus 2 (Tpl2) is known to integrate signals from inflammatory stimuli in macrophages, fibroblasts and adipocytes, its role in β-cells is unknown. We demonstrate that Tpl2 is expressed in INS-1E β-cells, mouse and human islets, is activated and upregulated by cytokines and mediates ERK1/2, JNK and p38 activation. Tpl2 inhibition protects β-cells, mouse and human islets from cytokine-induced apoptosis and preserves glucose-induced insulin secretion in mouse and human islets exposed to cytokines. Moreover, Tpl2 inhibition does not affect survival or positive effects of glucose (i.e., ERK1/2 phosphorylation and basal insulin secretion). The protection against cytokine-induced β-cell apoptosis is strengthened when Tpl2 inhibition is combined with the glucagon-like peptide-1 (GLP-1) analog exendin-4 in INS-1E cells. Furthermore, when combined with exendin-4, Tpl2 inhibition prevents cytokine-induced death and dysfunction of human islets. This study proposes that Tpl2 inhibitors, used either alone or combined with a GLP-1 analog, represent potential novel and effective therapeutic strategies to protect diabetic β-cells.

Published
2016
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40. The Nutritional Value of Protein-hydrolyzed Formulae.

Author

Agostoni C, Terracciano L, Varin E, and Fiocchi A

Subjects
Animals, Cattle, Child Development, Dietary Proteins adverse effects, Dietary Proteins metabolism, Humans, Infant, Infant Formula metabolism, Infant Nutrition Disorders diet therapy, Infant Nutrition Disorders etiology, Infant, Newborn, Infant, Premature, Milk Hypersensitivity physiopathology, Milk Proteins adverse effects, Milk Proteins metabolism, Milk Proteins therapeutic use, Nutritive Value, Protein Hydrolysates adverse effects, Protein Hydrolysates metabolism, Term Birth, Dietary Proteins therapeutic use, Infant Formula chemistry, Infant Nutrition Disorders prevention & control, Milk Hypersensitivity diet therapy, Protein Hydrolysates therapeutic use
Abstract

Allergy to cow's milk proteins is a challenging condition in early infancy. Allergic infants may be predisposed to impairments of growth from either the disease itself or the nutritional constraints of the exclusion diet they should follow. Formulae based on extensively hydrolyzed cow's milk proteins are widely used, representing therapy, and constituting 100% nutrient source in the first four to six months of life and half the daily nutrient intake in the second semester of life. In some cases, these products are used also for preventive purposes. Some impairments in growth have been reported for infants using these products, even if mostly limited to the first year of life, with no apparent consequences in either the medium or long term. The macronutrient content of infant formulae based on protein hydrolysates, whichever the source, should carefully be tested not only as far as the optimal utilization of nitrogenous sources but also on the nature and metabolic fate of non-nitrogen caloric sources, represented by carbohydrates and fats, and micronutrients, particularly iron. It is recommended that studies aimed at the allergologic effects of these products also include an appropriate nutritional evaluation to determine their efficiency.

Published
2016
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41. Prevalence and Clinical Relevance of IgE Sensitization to Profilin in Childhood: A Multicenter Study.

Author

Asero R, Tripodi S, Dondi A, Di Rienzo Businco A, Sfika I, Bianchi A, Candelotti P, Caffarelli C, Povesi Dascola C, Ricci G, Calamelli E, Maiello N, Miraglia Del Giudice M, Frediani T, Frediani S, Macrì F, Moretti M, Dello Iacono I, Patria MF, Varin E, Peroni D, Comberiati P, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Tosca M, Cirisano A, Faggian D, Plebani M, Verga C, and Matricardi PM

Subjects
Carrier Proteins immunology, Child, Cross Reactions immunology, Cucumis sativus immunology, Female, Fruit immunology, Humans, Italy, Male, Poaceae immunology, Prevalence, Rhinitis, Allergic, Seasonal immunology, Risk Factors, Skin Tests methods, Allergens immunology, Antigens, Plant immunology, Hypersensitivity epidemiology, Hypersensitivity immunology, Immunoglobulin E immunology, Pollen immunology, Profilins immunology
Abstract

Background: Little is known about the prevalence and clinical relevance of hypersensitivity to the plant panallergen profilin in children., Objectives: The present study aimed to investigate prevalence, risk factors and clinical relevance of profilin sensitization in a large cohort of Italian children of different ages living in different geographic areas., Methods: Children with pollen allergy enrolled by 16 pediatric outpatient clinics sited in three main geographic areas of Italy were studied. SPT were carried out with commercial pollen extracts and a commercial purified date palm pollen profilin. IgE specific for allergenic pollen molecules, Phl p 12 (grass profilin) and Pru p 3 (peach lipid transfer protein) were tested by ImmunoCAP FEIA., Results: IgE to Phl p 12 (≥0.35 kU/l) was observed in 296 of the 1,271 participants (23%), including 17 of the 108 (16%) preschool children. Profilin SPT was positive (≥3 mm) in 320/1,271 (25%) participants. The two diagnostic methods were concordant in 1,151 (91%, p < 0.0001) cases. Phl p 12 IgE prevalence declined from northern to southern Italy and was directly associated with IgE to Phl p 1 and/or Phl p 5 and Ole e 1. Among children with IgE to Phl p 12, OAS was provoked by kiwi, melon, watermelon, banana, apricot and cucumber., Conclusions: Profilin sensitization is very frequent among pollen-allergic children, occurs at a very young age and contributes to the development of childhood OAS with a typical pattern of offending foods. Pediatricians should always consider IgE sensitization to profilin while examining pollen-allergic children, even if they are at preschool age., (© 2015 S. Karger AG, Basel.)

Published
2015
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43. The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever.

Author

Stringari G, Tripodi S, Caffarelli C, Dondi A, Asero R, Di Rienzo Businco A, Bianchi A, Candelotti P, Ricci G, Bellini F, Maiello N, Miraglia del Giudice M, Frediani T, Sodano S, Dello Iacono I, Macrì F, Peparini I, Povesi Dascola C, Patria MF, Varin E, Peroni D, Comberiati P, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Tosca M, Cirisano A, Faggian D, Travaglini A, Plebani M, and Matricardi PM

Subjects
Adolescent, Allergens chemistry, Child, Child, Preschool, Cross Reactions, Female, Gene Expression, Humans, Immunoglobulin E blood, Male, Plants immunology, Pollen chemistry, Profilins genetics, Profilins immunology, Rhinitis, Allergic, Seasonal immunology, Rhinitis, Allergic, Seasonal pathology, Skin Tests, Allergens immunology, Desensitization, Immunologic methods, Pollen immunology, Rhinitis, Allergic, Seasonal diagnosis, Rhinitis, Allergic, Seasonal therapy
Abstract

Background: Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component-resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources., Objectives: We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR., Methods: Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists., Results: No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists., Conclusions: In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Published
2014
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44. Proteasome dysfunction mediates high glucose-induced apoptosis in rodent beta cells and human islets.

Author

Broca C, Varin E, Armanet M, Tourrel-Cuzin C, Bosco D, Dalle S, and Wojtusciszyn A

Subjects
Animals, Apoptosis drug effects, Caspase 3 genetics, Caspase 3 metabolism, Cells, Cultured, Endoplasmic Reticulum Stress drug effects, Endoplasmic Reticulum Stress genetics, Exenatide, Gene Expression, Glucose metabolism, Humans, Hyperglycemia genetics, Hyperglycemia pathology, Hypoglycemic Agents pharmacology, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells pathology, Male, Peptides pharmacology, Poly(ADP-ribose) Polymerases genetics, Poly(ADP-ribose) Polymerases metabolism, Proteasome Endopeptidase Complex drug effects, Proteasome Inhibitors pharmacology, Proteolysis drug effects, Rats, Signal Transduction, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, Ubiquitin genetics, Ubiquitin metabolism, Venoms pharmacology, Apoptosis genetics, Glucose pharmacology, Hyperglycemia metabolism, Insulin-Secreting Cells metabolism, Proteasome Endopeptidase Complex metabolism
Abstract

The ubiquitin/proteasome system (UPS), a major cellular protein degradation machinery, plays key roles in the regulation of many cell functions. Glucotoxicity mediated by chronic hyperglycaemia is detrimental to the function and survival of pancreatic beta cells. The aim of our study was to determine whether proteasome dysfunction could be involved in beta cell apoptosis in glucotoxic conditions, and to evaluate whether such a dysfunction might be pharmacologically corrected. Therefore, UPS activity was measured in GK rats islets, INS-1E beta cells or human islets after high glucose and/or UPS inhibitor exposure. Immunoblotting was used to quantify polyubiquitinated proteins, endoplasmic reticulum (ER) stress through CHOP expression, and apoptosis through the cleavage of PARP and caspase-3, whereas total cell death was detected through histone-associated DNA fragments measurement. In vitro, we found that chronic exposure of INS-1E cells to high glucose concentrations significantly decreases the three proteasome activities by 20% and leads to caspase-3-dependent apoptosis. We showed that pharmacological blockade of UPS activity by 20% leads to apoptosis in a same way. Indeed, ER stress was involved in both conditions. These results were confirmed in human islets, and proteasome activities were also decreased in hyperglycemic GK rats islets. Moreover, we observed that a high glucose treatment hypersensitized beta cells to the apoptotic effect of proteasome inhibitors. Noteworthily, the decreased proteasome activity can be corrected with Exendin-4, which also protected against glucotoxicity-induced apoptosis. Taken together, our findings reveal an important role of proteasome activity in high glucose-induced beta cell apoptosis, potentially linking ER stress and glucotoxicity. These proteasome dysfunctions can be reversed by a GLP-1 analog. Thus, UPS may be a potent target to treat deleterious metabolic conditions leading to type 2 diabetes.

Published
2014
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45. Food allergy as defined by component resolved diagnosis.

Author

Incorvaia C, Rapetti A, Aliani M, Castagneto C, Corso N, Landi M, Lietti D, Murante N, Muratore L, Russello M, Varin E, Makrì E, Fuiano N, and Scala E

Subjects
Algorithms, Animals, Antigens, Plant immunology, Cross Reactions, Diagnosis, Differential, Food adverse effects, Humans, Pathology, Molecular trends, Plants, Precision Medicine, Skin Tests, Allergens adverse effects, Allergens immunology, Food Hypersensitivity diagnosis, Recombinant Proteins immunology
Abstract

The diagnosis of food allergy, as assessed by skin tests or in vitro tests with allergen extracts, has insufficient diagnostic performance and needs to be confirmed by food challenges. However, the availability of molecular allergens (recombinant or highly purified) for laboratory methods has profoundly changed the diagnostic approach to food allergy. In fact, the allergy diagnosis conducted at the molecular level, which is defined internationally as component resolved diagnosis (CRD), allows to characterize more precisely the sensitization profile of the individual patient, distinguishing the sensitizations to allergens that are strongly associated with a given source (genuine sensitizers) from those to molecules that are common to many sources (panallergens) or cross-react with other components from the same family or from other families. This review provides an update on the allergen molecules from foods, including plant foods and animal foods, and on the techniques to detect them, by means of a single reagent (singleplex) or an array of molecules tested at the same time (multiplex). Such testing offers detailed information on the sensitization profile of patients and enables the physician to suitably manage their allergy. Moreover, identifying the real causative allergens will be crucial when allergen immunotherapy for food allergy will be introduced in the near future. We also address patents concerning food allergens in this review.

Published
2014
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46. Pollen-induced allergic rhinitis in 1360 Italian children: comorbidities and determinants of severity.

Author

Dondi A, Tripodi S, Panetta V, Asero R, Businco AD, Bianchi A, Carlucci A, Ricci G, Bellini F, Maiello N, del Giudice MM, Frediani T, Sodano S, Dello Iacono I, Macrì F, Massaccesi V, Caffarelli C, Rinaldi L, Patria MF, Varin E, Peroni D, Chinellato I, Chini L, Moschese V, Lucarelli S, Bernardini R, Pingitore G, Pelosi U, Tosca M, Paravati F, La Grutta S, Meglio P, Calvani M, Plebani M, and Matricardi PM

Subjects
Age of Onset, Allergens immunology, Antigens, Plant immunology, Child, Child, Preschool, Comorbidity, Disease Progression, Early Diagnosis, Female, Humans, Italy, Male, Pollen adverse effects, Pollen immunology, Prevalence, Rhinitis, Allergic, Seasonal diagnosis, Skin Tests, Surveys and Questionnaires, Conjunctivitis, Allergic epidemiology, Rhinitis, Allergic, Seasonal epidemiology
Abstract

Background: Pollen-induced allergic rhinoconjunctivitis (AR) is highly prevalent and rapidly evolving during childhood. General practitioners may not be fully aware of the nature and severity of symptoms experienced by patients and might underestimate the prevalence of moderate or severe disease. Thus, the relevance of early diagnosis and intervention may be overlooked., Objectives: To investigate the severity of pollen-induced AR and its determinants in Italian children referred to allergy specialists and who had never received specific immunotherapy (SIT)., Methods: Children (age 4-18 yr) affected by pollen-induced AR who had never undergone SIT were recruited between May 2009 and June 2011 in 16 pediatric outpatient clinics in 14 Italian cities. Recruited children's parents answered standardized questionnaires on atopic diseases (International Study of Allergy and Asthma in Childhood, Allergic Rhinitis and its Impact on Asthma, Global Initiative for Asthma). The children underwent skin-prick test (SPT) with several airborne allergens and six food allergens. Information on socio-demographic factors, parental history of allergic diseases, education, perinatal events, breastfeeding, nutrition and environmental exposure in early life was collected through an informatics platform shared by the whole network of clinical centers (AllergyCARD™)., Results: Among the 1360 recruited patients (68% males, age 10.5 ± 3.4 yr), 695 (51%) had moderate-to-severe AR, 533 (39%) asthma, and 325 (23.9%) oral allergy syndrome (OAS). Reported onset of pollen-induced AR was on average at 5.3 ± 2.8 yr, and its mean duration from onset was 5.2 ± 3.3 yr. Only 6.2% of the patients were pollen-monosensitized, and 84.9% were sensitized to ≥3 pollens. A longer AR duration was significantly associated with moderate-to-severe AR symptoms (p 0.004), asthma (p 0.030), and OAS comorbidities (p < 0.001)., Conclusions: This nationwide study may raise awareness of the severity of pollen-induced AR among Italian children who have never received pollen SIT. The strong association between pollen-induced AR duration and several markers of disease severity needs replication in longitudinal studies, while suggesting that countrywide initiatives for earlier diagnosis and intervention should be planned., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2013
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47. Roles and regulation of the transcription factor CREB in pancreatic β -cells.

Author

Dalle S, Quoyer J, Varin E, and Costes S

Subjects
Cyclic AMP Response Element-Binding Protein chemistry, Cyclic AMP Response Element-Binding Protein genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Glucose metabolism, Humans, Insulin metabolism, Insulin Secretion, Receptor Protein-Tyrosine Kinases metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction, Transcription, Genetic, Cyclic AMP Response Element-Binding Protein metabolism, Insulin-Secreting Cells metabolism
Abstract

The preservation of a functional pancreatic β-cell mass has become a major point of research in type 2 diabetes (T2D) and the future therapies of T2D notably aim at protecting the β-cell from dysfunction and apoptotic death. β-cell proliferation, survival and insulin secretion are regulated by crucial transcription factors which are activated by signalling pathways engaged by nutrients, G-protein coupled receptors or tyrosine kinase receptors. Among these factors, the cAMP-responsive element-binding protein (CREB) has emerged as a key transcriptional element for the maintenance of an efficient glucose sensing, insulin exocytosis, insulin gene transcription and β-cell survival. CREB activates the transcription of target genes within the β-cells in response to a diverse array of stimuli including glucose, incretin hormones such as the glucagon-like peptide-1 (GLP-1) or the gastric inhibitory polypeptide (GIP), the pituitary adenylate cyclase-activating polypeptide (PACAP), or growth factors such as the insulin like growth factor-1 (IGF-1). All these stimuli phosphorylate CREB at a particular residue, serine 133, which is required for CREB-mediated transcription. However, the molecular mechanisms by which CREB activates gene transcription in β-cells vary according to the nature of the stimulus. These mechanisms involve different protein kinases, scaffold proteins and cofactors which allow CREB to specifically regulate the expression of crucial genes such as insulin, BCL-2, cyclin D1, cyclin A2 or IRS-2. In this review, we summarize the signalling pathways that lead to CREB phosphorylation in β-cells and the molecular features of each signalling pathway that rise specificity at the level of CREB activation and regulation.

Published
2011
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48. Citrate induces apoptotic cell death: a promising way to treat gastric carcinoma?

Author

Lu Y, Zhang X, Zhang H, Lan J, Huang G, Varin E, Lincet H, Poulain L, and Icard P

Subjects
Cell Line, Tumor, Cell Nucleus drug effects, Cell Nucleus pathology, Cell Nucleus Shape drug effects, Cell Proliferation drug effects, Cell Shape drug effects, Drug Screening Assays, Antitumor, Humans, Mitochondria drug effects, Mitochondria metabolism, Models, Biological, Signal Transduction drug effects, Apoptosis drug effects, Citric Acid pharmacology, Citric Acid therapeutic use, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology
Abstract

Unlabelled: Gastric carcinoma is frequent, particularly in China, and therapy is often inefficient. Because cancer cells are partly or mainly dependent on glycolysis to generate adenosine triphosphate ATP (Warburg effect) and/or to produce precursors (of lipid, nucleotides, etc.) for building new cells, any inhibition of glycolysis may slow down the cell proliferation and/or may kill cells. The antitumor effect of citrate, an anti-glycolytic agent inhibiting phosphofructokinase (PFK) was tested on two human gastric carcinoma cell lines., Materials and Methods: Cell viability and morphology were assessed after 24-72 h exposure to citrate (5, 10, 220 mM). Apoptosis was assessed by annexin V-FITC/PI staining and Western immunobloting., Results: A 3-day continuous exposure to citrate led to near destruction of the cell population in both cell lines, apoptotic cell death occurred through the mitochondrial pathway in a dose- and time-dependent manner, associated with the reduction of the anti-apoptotic Mcl-1 protein in both lines., Conclusion: Citrate demonstrates strong cytotoxic activity against two gastric cancer lines, leading to an early diminution of expression of Mcl-1 and to massive apoptotic cell death involving the mitochondrial pathway.

Published
2011

49. Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy.

Author

Varin E, Denoyelle C, Brotin E, Meryet-Figuière M, Giffard F, Abeilard E, Goux D, Gauduchon P, Icard P, and Poulain L

Subjects
Blotting, Western, Cell Line, Tumor, Humans, Mesothelioma drug therapy, Mesothelioma metabolism, Microscopy, Electron, Transmission, Myeloid Cell Leukemia Sequence 1 Protein, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cisplatin pharmacology, Down-Regulation, Mesothelioma pathology, Proto-Oncogene Proteins c-bcl-2 metabolism, bcl-X Protein metabolism
Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited response to platinum-based chemotherapy. Several lines of evidence support a role for the anti-apoptotic protein Bcl-x(L) in MPM chemoresistance. Since it has been recently suggested that Mcl-1 cooperates with Bcl-x(L) for protection against cell death, we investigated the response of mesothelioma cell lines to the downregulation of Bcl-x(L) (alone or in combination with cisplatin) and the potential interest of its concomitant inhibition with that of Mcl-1. Using RNA interference, we showed that Bcl-x(L) depletion sensitized two highly chemoresistant mesothelioma cell lines to cisplatin and that under this treatment, one cell line, MSTO-211H, displayed an apoptotic type of cell death, whereas the other, NCI-H28, evidenced mainly necrotic-type cell death. Otherwise, the inhibition of Mcl-1 by cisplatin may contribute to this induction of cell death observed after Bcl-x(L) downregulation. Strikingly, we observed that the simultaneous inhibition of Bcl-x(L) and Mcl-1 using small interfering RNA (siRNA) induced a massive cell death in the absence of chemotherapy and was sufficient to avoid escape to treatment in MSTO-211H cells. In NCI-H28, the addition of a low cisplatin concentration allowed to impede the long-term recovery observed after treatment by the siRNA combination. Together, these findings provide a strong molecular basis for the clinical evaluation of therapies targeting both Bcl-x(L) and Mcl-1, alone or in combination with conventional chemotherapy, for the treatment of MPM.

Published
2010
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50. GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a beta-arrestin 1-mediated ERK1/2 activation in pancreatic beta-cells.

Author

Quoyer J, Longuet C, Broca C, Linck N, Costes S, Varin E, Bockaert J, Bertrand G, and Dalle S

Subjects
14-3-3 Proteins metabolism, Animals, Cell Line, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Cytosol drug effects, Cytosol metabolism, Enzyme Activation drug effects, Insulin-Secreting Cells drug effects, Mice, Phosphorylation drug effects, Ribosomal Protein S6 Kinases, 90-kDa metabolism, Serine, Signal Transduction drug effects, Time Factors, bcl-Associated Death Protein chemistry, beta-Arrestin 1, beta-Arrestins, Apoptosis drug effects, Arrestins metabolism, Glucagon-Like Peptide 1 pharmacology, Insulin-Secreting Cells metabolism, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, bcl-Associated Death Protein metabolism
Abstract

Strategies based on activating GLP-1 receptor (GLP-1R) are intensively developed for the treatment of type 2 diabetes. The exhaustive knowledge of the signaling pathways linked to activated GLP-1R within the beta-cells is of major importance. In beta-cells, GLP-1 activates the ERK1/2 cascade by diverse pathways dependent on either Galpha(s)/cAMP/cAMP-dependent protein kinase (PKA) or beta-arrestin 1, a scaffold protein. Using pharmacological inhibitors, beta-arrestin 1 small interfering RNA, and islets isolated from beta-arrestin 1 knock-out mice, we demonstrate that GLP-1 stimulates ERK1/2 by two temporally distinct pathways. The PKA-dependent pathway mediates rapid and transient ERK1/2 phosphorylation that leads to nuclear translocation of the activated kinases. In contrast, the beta-arrestin 1-dependent pathway produces a late ERK1/2 activity that is restricted to the beta-cell cytoplasm. We further observe that GLP-1 phosphorylates the cytoplasmic proapoptotic protein Bad at Ser-112 but not at Ser-155. We find that the beta-arrestin 1-dependent ERK1/2 activation engaged by GLP-1 mediates the Ser-112 phosphorylation of Bad, through p90RSK activation, allowing the association of Bad with the scaffold protein 14-3-3, leading to its inactivation. beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. This new regulatory mechanism engaged by activated GLP-1R involving a beta-arrestin 1-dependent spatiotemporal regulation of the ERK1/2-p90RSK activity is now suspected to participate in the protection of beta-cells against apoptosis. Such signaling mechanism may serve as a prototype to generate new therapeutic GLP-1R ligands.

Published
2010
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