RESUMEN
BACKGROUND: Ixazomib citrate (IXA) in combination with lenalidomide and dexamethasone (IRD therapy) has been approved for the treatment of relapsed or refractory multiple myeloma. In Japan, as these three drugs have different dosing schedules, dosing instructions for patients have been prepared and distributed to patients via healthcare professionals to promote an understanding of the appropriate dosing regimen, as an additional risk minimization measure (aRMM). OBJECTIVES: This survey aimed to investigate whether the aRMM material is being utilized for the adequate use of IXA. METHODS: A web-based questionnaire survey was conducted among in-hospital pharmacists in Japan who instructed patients on IXA dosing for IRD therapy. The primary endpoint was the proportion of pharmacists who provided patients with the contents of the aRMM material (i.e., how to take IXA). The secondary endpoints were the proportion of pharmacists who had obtained the aRMM material and the proportion of pharmacists who understood the importance of explaining how to take IXA to patients. RESULTS: Of the 330 pharmacists who completed the questionnaire, 93.0% answered that they had explained how to take IXA to patients. Of those who answered that they had explained how to take IXA, 33.2% responded that they had experience in using the aRMM material. In addition, 37.6% of the pharmacists answered that they had obtained the aRMM material. Moreover, 95.8% stated that they knew how to take IXA, and 90.3, 9.1, 0.3, and 0.3% of pharmacists answered that the importance of explaining how to take IXA was "very important," "probably important," "less important" and "not important," respectively. CONCLUSIONS: How to take IXA was explained to patients by pharmacists and the aRMM material was utilized at the time of the explanation, indicating that the aRMM material contributes to the promotion of the appropriate use of IXA.
Asunto(s)
Alopecia/inducido químicamente , Antineoplásicos/efectos adversos , Enfermedades de la Piel/inducido químicamente , Edema/inducido químicamente , Extravasación de Materiales Terapéuticos y Diagnósticos , Síndrome Mano-Pie/etiología , Humanos , Hipersensibilidad/etiología , Terapia Molecular Dirigida/efectos adversos , Flebitis/inducido químicamente , Fotofobia/inducido químicamente , Trastornos de la Pigmentación/inducido químicamenteRESUMEN
The Rac-specific guanine nucleotide exchange factor (GEF) Asef is activated by binding to the tumor suppressor adenomatous polyposis coli mutant, which is found in sporadic and familial colorectal tumors. This activated Asef is involved in the migration of colorectal tumor cells. The GEFs for Rho family GTPases contain the Dbl homology (DH) domain and the pleckstrin homology (PH) domain. When Asef is in the resting state, the GEF activity of the DH-PH module is intramolecularly inhibited by an unidentified mechanism. Asef has a Src homology 3 (SH3) domain in addition to the DH-PH module. In the present study, the three-dimensional structure of Asef was solved in its autoinhibited state. The crystal structure revealed that the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site. Furthermore, the RT-loop and the C-terminal region of the SH3 domain interact with the DH domain in a manner completely different from those for the canonical binding to a polyproline-peptide motif. These results demonstrate that the blocking of the Rac-binding site by the SH3 domain is essential for Asef autoinhibition. This may be a common mechanism in other proteins that possess an SH3 domain adjacent to a DH-PH module.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/química , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Secuencias de Aminoácidos , Animales , Movimiento Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Cristalografía por Rayos X , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Mutación , Péptidos/química , Péptidos/genética , Péptidos/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho , Homología Estructural de Proteína , Factores de Intercambio de Guanina Nucleótido ras/metabolismo , Dominios Homologos srcRESUMEN
Protein TT0402 from Thermus thermophilus HB8 exhibits about 30-35% sequence identity with proteins belonging to subgroup IV in the aminotransferase family of the fold-type I pyridoxal 5'-phosphate (PLP)-dependent enzymes. In this study, we determined the crystal structure of TT0402 at 2.3 A resolution (R(factor) = 19.9%, R(free) = 23.6%). The overall structure of TT0402 exhibits the fold conserved in aminotransferases, and is most similar to that of the Escherichia coli phosphoserine aminotransferase, which belongs to subgroup IV but shares as little as 13% sequence identity with TT0402. Kinetic assays confirmed that TT0402 has higher transamination activities with the amino group donor, L-glutamate, and somewhat lower activities with L-aspartate. These results indicate that TT0402 is a subgroup IV aminotransferase for the synthesis/degradation of either L-aspartate or a similar compound.
