Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Paediatric arterial ischaemic stroke and cerebral sinovenous thrombosis: First report from the Italian registry of pediatric thrombosis (R. I. T. I., Registro Italiano Trombosi Infantili)

reserved55noData from large case series of children with cerebral thrombotic events are pivotal to improve prevention, early recognition and treatment of these conditions. The Italian Registry of Pediatric Thrombosis (R. I. T. I.) was established in 2007 by a multidisciplinary team, aiming for a better understanding of neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. We analysed data relative to the paediatric cerebral thrombotic events of the R. I. T. I. which occurred between January 2007 and June 2012. In the study period, 79 arterial ischaemic stroke (AIS) events (49 in males) and 91 cerebral sinovenous thrombosis (CSVT) events (65 in males) were enrolled in the R. I. T. I. Mean age at onset was 4.5 years in AIS, and 7.1 years in CSVT. Most common modes of presentation were hemiparesis, seizures and speech disturbances in AIS, and headache, seizures and lethargy in CSVT. Most common etiologies were underlying chronic diseases, vasculopathy and cardiopathy in AIS, and underlying chronic diseases and infection in CSVT. Time to diagnosis exceeded 24 hours in 46% AIS and 59% CSVT. Overall data from the Italian Registry are in substantial agreement with those from the literature, despite small differences. Among these, a longer time to diagnosis compared to other registries and case series poses the accent to the need of an earlier recognition of paediatric cerebrovascular events in Italy, in order to enable prompt and effective treatment strategies.mixedSuppiej A.; Gentilomo C.; Saracco P.; Sartori S.; Agostini M.; Bagna R.; Bassi B.; Giordano P.; Grassi M.; Guzzetta A.; Lasagni D.; Luciani M.; Molinari A.C.; Palmieri A.; Putti M.C.; Ramenghi L.A.; Rota L.L.; Sperli D.; Laverda A.M.; Simioni P.; Angriman M.; Aru A.B.; Barisone E.; Bartalena L.; Berta M.; Bertoni E.; Cancarini P.; Cavaliere E.; Celle M.E.; Cerbone A.M.; Cesaroni E.; Via L.D.; Dell'Oro M.G.; Di Rosa G.; Ferrari G.M.; Fiori S.; Gaffuri M.; Gallina M.R.; Gimmillaro A.; Grandone E.; Ladogana S.; Laforgia N.; La Piana R.; Maschio F.; Miniero R.; Nosadini M.; Panzeri D.; Petrucci A.; Piersigilli F.; Sala D.; Sangermani R.; Santoro N.; Tufano A.; Ventura G.; Vittorini R.Suppiej, A.; Gentilomo, C.; Saracco, P.; Sartori, S.; Agostini, M.; Bagna, R.; Bassi, B.; Giordano, P.; Grassi, M.; Guzzetta, A.; Lasagni, D.; Luciani, M.; Molinari, A. C.; Palmieri, A.; Putti, M. C.; Ramenghi, L. A.; Rota, L. L.; Sperli, D.; Laverda, A. M.; Simioni, P.; Angriman, M.; Aru, A. B.; Barisone, E.; Bartalena, L.; Berta, M.; Bertoni, E.; Cancarini, P.; Cavaliere, E.; Celle, M. E.; Cerbone, A. M.; Cesaroni, E.; Via, L. D.; Dell'Oro, M. G.; Di Rosa, G.; Ferrari, G. M.; Fiori, S.; Gaffuri, M.; Gallina, M. R.; Gimmillaro, A.; Grandone, E.; Ladogana, S.; Laforgia, N.; La Piana, R.; Maschio, F.; Miniero, R.; Nosadini, M.; Panzeri, D.; Petrucci, A.; Piersigilli, F.; Sala, D.; Sangermani, R.; Santoro, N.; Tufano, A.; Ventura, G.; Vittorini, R