Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases.Adverse reactions to these agents are one of the main causes of treatment discontinuation or inter...Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases.Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption.Myelosuppression is the most frequent adverse effect;however,approximately 5%-20%of patients develop gastrointestinal toxicity.The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy.In this editorial,we discuss evidence supporting the use of PACSIN2,RAC1,and ITPA genes,in addition to TPMT and NUDT15,as possible biomarkers for thiopurine-related gastrointestinal toxicity.展开更多
Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,in...Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.展开更多
The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various mem-brane deformations,such as actin reorganization,vesicle transport and microtubule movement.Our previous study shows ...The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various mem-brane deformations,such as actin reorganization,vesicle transport and microtubule movement.Our previous study shows that all PACSINs are composed of crescent shaped dimers with two wedge loops,and the wedge loop-mediated lateral interaction between neighboring dimers is important for protein packing and tubulation activity.Here,from the crystal packing of PACSIN 2,we observed a tight tip-to-tip interaction,in addition to the wedge loop-mediated lateral interaction.With this tip-to-tip interaction,the whole packing of PACSIN 2 shows a spiral-like assem-bly with a central hole from the top view.Elimination of this tip-to-tip connection inhibited the tubulation function of PACSIN 2,indicating that tip-to-tip interaction plays an important role in membrane deformation activity.Together with our previous study,we proposed a packing model for the assembly of PACSIN 2 on membrane,where the pro-teins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to gener-ate various diameter tubules.展开更多
文摘Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases.Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption.Myelosuppression is the most frequent adverse effect;however,approximately 5%-20%of patients develop gastrointestinal toxicity.The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy.In this editorial,we discuss evidence supporting the use of PACSIN2,RAC1,and ITPA genes,in addition to TPMT and NUDT15,as possible biomarkers for thiopurine-related gastrointestinal toxicity.
基金This project is supported by the Italian Ministry of Health(Progetto Ricerca Corrente 5/2012).
文摘Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.
基金the National High Technology and Develop-ment Program of China(973 Programs)(No.2010CB911800)the National Natural Science Foundation of China(Grant No.30930020).
文摘The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various mem-brane deformations,such as actin reorganization,vesicle transport and microtubule movement.Our previous study shows that all PACSINs are composed of crescent shaped dimers with two wedge loops,and the wedge loop-mediated lateral interaction between neighboring dimers is important for protein packing and tubulation activity.Here,from the crystal packing of PACSIN 2,we observed a tight tip-to-tip interaction,in addition to the wedge loop-mediated lateral interaction.With this tip-to-tip interaction,the whole packing of PACSIN 2 shows a spiral-like assem-bly with a central hole from the top view.Elimination of this tip-to-tip connection inhibited the tubulation function of PACSIN 2,indicating that tip-to-tip interaction plays an important role in membrane deformation activity.Together with our previous study,we proposed a packing model for the assembly of PACSIN 2 on membrane,where the pro-teins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to gener-ate various diameter tubules.
