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1.
J Pediatr Hematol Oncol ; 45(6): e695-e701, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37053507

RESUMEN

Approximately 4% to 35% of pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy) develop drug-induced hyperglycemia. Though hyperglycemia is associated with poor outcomes, no guidelines for identifying drug-induced hyperglycemia currently exist, and the time course for developing hyperglycemia remains relatively uncharacterized after induction therapy. The present study evaluated a hyperglycemia screening protocol that was implemented to identify hyperglycemia more promptly, examined predictors of hyperglycemia during ALL and LLy therapy, and described the timeline for developing hyperglycemia. A retrospective review of 154 patients diagnosed with ALL or LLy at Cook Children's Medical Center between March 2018 and April 2022 was performed. Predictors of hyperglycemia were examined with Cox regression. The hyperglycemia screening protocol was ordered for 88 (57%) patients. Fifty-four (35%) patients developed hyperglycemia. In multivariate analyses, age 10 years or older (hazard ratio = 2.50, P = 0.007) and weight loss (vs gain) during induction (hazard ratio = 3.39, P < 0.05) were associated with hyperglycemia. The present study identified a population of patients at risk of developing hyperglycemia and identifies strategies for hyperglycemia screening. In addition, the present study showed that some patients developed hyperglycemia after induction therapy, which highlights the importance of continued blood glucose monitoring in at-risk patients. Implications and suggestions for further research are discussed.


Asunto(s)
Hiperglucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Glucosa/efectos adversos , Automonitorización de la Glucosa Sanguínea , Glucemia , Detección Precoz del Cáncer , Hiperglucemia/inducido químicamente , Hiperglucemia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Retrospectivos
2.
J Biol Chem ; 292(35): 14438-14455, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28718450

RESUMEN

Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITPα, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITPα lipid exchange cycle: (i) interaction of PITPα with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITPα to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITPα; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITPα residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITPα PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.


Asunto(s)
Membrana Dobles de Lípidos/metabolismo , Modelos Moleculares , Fosfatidilcolinas/metabolismo , Fosfatidilinositoles/metabolismo , Proteínas de Transferencia de Fosfolípidos/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Apoproteínas/química , Apoproteínas/genética , Apoproteínas/metabolismo , Transporte Biológico , Biología Computacional , Secuencia Conservada , Transferencia de Energía , Enlace de Hidrógeno , Ligandos , Membrana Dobles de Lípidos/química , Simulación de Dinámica Molecular , Mutación Missense , Fosfatidilcolinas/química , Fosfatidilinositoles/química , Proteínas de Transferencia de Fosfolípidos/química , Proteínas de Transferencia de Fosfolípidos/genética , Polimorfismo de Nucleótido Simple , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
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