RESUMO
IKZF1-deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1-loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.
RESUMO
Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.
Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Aminoácidos/metabolismo , Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Piperidinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adenina/farmacologia , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Asparaginase/farmacologia , Linhagem Celular Tumoral , Humanos , Camundongos , Piperidinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Trainees develop surgical technical skills by learning from experts who provide context for successful task completion, identify potential risks, and guide correct instrument handling. This expert-guided training faces significant limitations in objectively assessing skills in real-time and tracking learning. It is unknown whether AI systems can effectively replicate nuanced real-time feedback, risk identification, and guidance in mastering surgical technical skills that expert instructors offer. This randomized controlled trial compared real-time AI feedback to in-person expert instruction. Ninety-seven medical trainees completed a 90-min simulation training with five practice tumor resections followed by a realistic brain tumor resection. They were randomly assigned into 1-real-time AI feedback, 2-in-person expert instruction, and 3-no real-time feedback. Performance was assessed using a composite-score and Objective Structured Assessment of Technical Skills rating, rated by blinded experts. Training with real-time AI feedback (n = 33) resulted in significantly better performance outcomes compared to no real-time feedback (n = 32) and in-person instruction (n = 32), .266, [95% CI .107 .425], p < .001; .332, [95% CI .173 .491], p = .005, respectively. Learning from AI resulted in similar OSATS ratings (4.30 vs 4.11, p = 1) compared to in-person training with expert instruction. Intelligent systems may refine the way operating skills are taught, providing tailored, quantifiable feedback and actionable instructions in real-time.
Assuntos
Inteligência Artificial , Competência Clínica , Humanos , Feminino , Masculino , Adulto , Treinamento por Simulação/métodosRESUMO
BACKGROUND AND OBJECTIVES: Subpial corticectomy involving complete lesion resection while preserving pial membranes and avoiding injury to adjacent normal tissues is an essential bimanual task necessary for neurosurgical trainees to master. We sought to develop an ex vivo calf brain corticectomy simulation model with continuous assessment of surgical instrument movement during the simulation. A case series study of skilled participants was performed to assess face and content validity to gain insights into the utility of this training platform, along with determining if skilled and less skilled participants had statistical differences in validity assessment. METHODS: An ex vivo calf brain simulation model was developed in which trainees performed a subpial corticectomy of three defined areas. A case series study assessed face and content validity of the model using 7-point Likert scale questionnaires. RESULTS: Twelve skilled and 11 less skilled participants were included in this investigation. Overall median scores of 6.0 (range 4.0-6.0) for face validity and 6.0 (range 3.5-7.0) for content validity were determined on the 7-point Likert scale, with no statistical differences between skilled and less skilled groups identified. CONCLUSION: A novel ex vivo calf brain simulator was developed to replicate the subpial resection procedure and demonstrated face and content validity.
RESUMO
The current therapeutic options for acute decompensated heart failure are limited to afterload reducers and positive inotropes. The latter increases myocardial contractility through changes in myocyte calcium (Ca²âº) handling (mostly through stimulation of the ß-adrenergic pathways [ß-ADR]) and is associated with paradoxical effects of arrhythmias, cell death, and subsequently increased mortality. We have previously demonstrated that probenecid can increase cytosolic Ca²âº levels in the cardiomyocyte resulting in an improved inotropic response in vitro and in vivo without activating the ß-ADR system. We hypothesize that, in contrast to other commonly used inotropes, probenecid functions through a system separate from that of ß-ADR and hence will increase contractility and improve function without damaging the heart. Furthermore, our goal was to evaluate the effect of probenecid on cell death in vitro and its use in vivo as a positive inotrope in a mouse model of ischemic cardiomyopathy. Herein, we demonstrate that probenecid induced an influx of Ca²âº similar to isoproterenol, but does not induce cell death in vitro. Through a series of in vivo experiments we also demonstrate that probenecid can be used at various time points and with various methods of administration in vivo in mice with myocardial ischemia, resulting in improved contractility and no significant difference in infarct size. In conclusion, we provide novel data that probenecid, through its activity on cellular Ca²âº levels, induces an inotropic effect without causing or exacerbating injury. This discovery may be translatable if this mechanism is preserved in man.