Insulin Receptor Isoforms in Cancer

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy

Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2–3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage

Long-term proactive management of psoriasis with calcipotriol and betamethasone dipropionate foam: an Italian consensus through a combined nominal group technique and Delphi approach

none85Background: Although long-term management of psoriasis is paramount, this approach is challenging in clinical practice. In the recent PSO-LONG trial, a fixed-dose combination of betamethasone dipropionate (BD) and calcipotriol (Cal) foam applied twice a week on non-consecutive days for 52 weeks (proactive treatment) reduced the risk of relapse. However, the role of Cal/BD foam in the long-term management of psoriasis needs further clarifications. The ProActive Management (PAM) program, a nationwide Italian project, aims at reaching a consensus on the role of proactive management of psoriasis. Methods: A steering committee generated some statements through the nominal group technique (NGT). The statements were voted by an expert panel in an adapted Delphi voting process. Results: Eighteen statements were proposed, and the majority of them (14/18) reached a consensus during the Delphi voting. The need to provide long-term proactive topical treatment to reduce the risk of relapse for the treatment of challenging diseases sites or in patients where phototherapy or systemic therapies are contraindicated/ineffective was widely recognized. A consensus was reached about the possibility to associate the proactive treatment with systemic and biological therapies, without the need for dose intensification, thus favoring a prolonged remission. Moreover, the proactive treatment was recognized as more effective than weekend therapy in increasing time free from relapses. Approaches to improve adherence, on the other hand, need further investigation. Conclusions: The inclusion in guidelines of a proactive strategy among the effective treatment options will be a fundamental step in the evolution of a mild-moderate psoriasis therapeutic approach.noneDe Simone, Clara; Dapavo, Paolo; Malagoli, Piergiorgio; Martella, Alessandro; Campanati, Anna; Campione, Elena; Errichetti, Enzo; Franchi, Chiara; Gambardella, Alessio; Megna, Matteo; Osti, Federica; Ribero, Simone; Zagni, Giovanni; Calzavara-Pinton, Piergiacomo; Fabbrocini, Gabriella; Amoruso, Giuseppe Fabrizio; Baglieri, Francesco; Biamonte, Anna Silvia; Bianchelli, Tommaso; Bigi, Laura; Bortoli, Jarno; Brunetti, Bruno; Buligan, Cinzia; Cagni, Elisabetta; Calderoni, Ombretta; Calzavara-Pinton, Piergiacomo; Campanati, Anna; Caputo, Alighiero; Carrera, Carlo Giovanni; Carugno, Andrea; Chersi, Karin; Cicchelli, Stefano; De Natale, Flora; De Simone, Clara; Dapavo, Paolo; Di Maria, Domenico; Errichetti, Enzo; Fabbrocini, Gabriella; Ferrari, Angelo Salvatore; Fogli, Emanuela; Forconi, Riccardo; Franchi, Chiara; Galeazzi, Augusto; Gambardella, Alessio; Giovannini, Andrea; Giura, Maria Teresa; Iuculano, Massimo; Lazzaretti, Giuseppe; Leporati, Claudia; Magnanini, Massimiliano; Malagoli, Piergiorgio; Marconi, Barbara; Martella, Alessandro; Maruccia, Adriana; Megna, Matteo; Miglietta, Roberta; Minuti, Anna; Mocci, Luigi; Modica, Sonia; Narcisi, Alessandra; Odorici, Giulia; Osti, Federica; Pazzaglia, Massimiliano; Peila, Rossana; Pertusi, Ginevra; Pezza, Michele; Pezzullo, Elio; Puccia, Nunzio; Raulo, Umberto; Ribero, Simone; Rossi, Mariateresa; Rusignuolo, Sergio; Sapienza, Giada; Savarese, Catello; Scalisi, Mariaelena; Strippoli, Davide; Stroppiana, Elena; Tiberio, Rossana; Trischitta, Antonino; Tucci, Maria Giovanna; Vaira, Fabrizio; Verrone, Anna; Villa, Lucia; Zagni, Fabio; Zoccali, AndreaDe Simone, Clara; Dapavo, Paolo; Malagoli, Piergiorgio; Martella, Alessandro; Campanati, Anna; Campione, Elena; Errichetti, Enzo; Franchi, Chiara; Gambardella, Alessio; Megna, Matteo; Osti, Federica; Ribero, Simone; Zagni, Giovanni; Calzavara-Pinton, Piergiacomo; Fabbrocini, Gabriella; Amoruso, Giuseppe Fabrizio; Baglieri, Francesco; Biamonte, Anna Silvia; Bianchelli, Tommaso; Bigi, Laura; Bortoli, Jarno; Brunetti, Bruno; Buligan, Cinzia; Cagni, Elisabetta; Calderoni, Ombretta; Calzavara-Pinton, Piergiacomo; Campanati, Anna; Caputo, Alighiero; Carrera, Carlo Giovanni; Carugno, Andrea; Chersi, Karin; Cicchelli, Stefano; De Natale, Flora; De Simone, Clara; Dapavo, Paolo; Di Maria, Domenico; Errichetti, Enzo; Fabbrocini, Gabriella; Ferrari, Angelo Salvatore; Fogli, Emanuela; Forconi, Riccardo; Franchi, Chiara; Galeazzi, Augusto; Gambardella, Alessio; Giovannini, Andrea; Giura, Maria Teresa; Iuculano, Massimo; Lazzaretti, Giuseppe; Leporati, Claudia; Magnanini, Massimiliano; Malagoli, Piergiorgio; Marconi, Barbara; Martella, Alessandro; Maruccia, Adriana; Megna, Matteo; Miglietta, Roberta; Minuti, Anna; Mocci, Luigi; Modica, Sonia; Narcisi, Alessandra; Odorici, Giulia; Osti, Federica; Pazzaglia, Massimiliano; Peila, Rossana; Pertusi, Ginevra; Pezza, Michele; Pezzullo, Elio; Puccia, Nunzio; Raulo, Umberto; Ribero, Simone; Rossi, Mariateresa; Rusignuolo, Sergio; Sapienza, Giada; Savarese, Catello; Scalisi, Mariaelena; Strippoli, Davide; Stroppiana, Elena; Tiberio, Rossana; Trischitta, Antonino; Tucci, Maria Giovanna; Vaira, Fabrizio; Verrone, Anna; Villa, Lucia; Zagni, Fabio; Zoccali, Andre