Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.

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This manuscript demonstrates that β-arrestin2 mediates thoracic aortic aneurysm formation in a murine model of Marfan syndrome (MFS) by regulating proaneurysmal signaling. This work identifies a novel signaling cascade that contributes to aortic aneurysm formation as well as several potential, previously unappreciated therapeutic targets in MFS.

Cereblon (CRBN) is a substrate recruiter element of the E3 cullin 4‐RING ubiquitin ligase complex, and a binding target of immunomodulatory agents (IMiDs). CRBN is responsible for the pleiotropic effects of IMiDs, yet its function in angiogenesis and in mediating the antiangiogenic effects of IMiDs remains unclear. We investigated the role of CRBN in the angiogenic process and in propagating the antiangiogenic effects of IMiDs in vitro. siRNA‐mediated CRBN knock down in human endothelial cells (HUVEC and HMVEC‐L), did not affect endothelial cell proliferation, migration, or tube formation. Using CRBN‐deficient mice, we further demonstrated that microvessal formation can occur independently of cereblon in the ex vivo mouse aortic ring model. The cereblon E3 ubiquitin ligase complex can recruit endothelial cell‐specific factors, AGO2 (associated with angiogenesis), and SALL4 (associated with embryogenesis/angiogenesis), for ubiquitin‐mediated degradation. Knockdown of CRBN caused a corresponding increase in AGO2 and SALL4 protein expression and IMiD treatment was able to rescue the siCRBN effect to increase the CRBN expression. These findings suggest one potential mechanism of action that likely involves a tightly coordinated regulation of CRBN with endothelial cell targets and highlight the need to further elucidate the mechanism(s), which could include cereblon‐independent pathways, through which IMiDs exert their antiangiogenic effects.

Vaso-occlusive episodes (VOEs) are a common complication of sickle cell disease (SCD) and a significant cause of morbidity. Managing VOE pain can be difficult and complex.Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been used to manage VOE pain. This systematic literature review synthesizes research published from 2010 to 2020 on the use of ketamine infusion to decrease VOE pain. The review demonstrates that ketamine, a safe and effective treatment for VOE pain, could be considered more widely. However, the significant variability among published clinical studies with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation highlights the need for standardized ketamine infusion protocols for the management of VOE pain. We conclude with a brief discussion of key components of a potential standardized protocol supported by the literature reviewed as well as areas for future investigation.

Introduction: Transporters comprising the blood-brain barrier complicate delivery of many therapeutics to the central nervous system. The present study ascertained whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. Methods: Wild-type and Mdr1a/Mdr1b (-/-) mice were treated with botryllamide G and lapatinib ("doublet therapy"), and while a separate cohort of wild-type mice was treated with botryllamide, tariquidar and lapatinib ("triplet therapy"). Results: Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the in vitro IC 50 of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In Mdr1a/ Mdr1b (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 h*ng/mL vs 4007 h*ng/mL; P = .031), but not plasma exposure (P = .15). No significant differences were observed after 24 h. Lapatinib brain exposure was greater through 1 h when wild-type mice were administered triplet therapy (298 h*pg/mg vs 120 h*pg/mg; P < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 h*pg/mg vs 4461hr*ng/mL; P < .001) and did not alter the brain:plasma ratio. Conclusions: In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking Abcb1, although the combination of botryllamide G and tariquidar increases brain exposure in wild-type mice only briefly (1 h). Additional research is needed to find analogs of this compound that have better pharmacokinetics and pharmacodynamic effects on ABCG2 inhibition.

Background Rituximab is a monoclonal anti‐CD20 antibody used as a second‐line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy. Objectives The purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response. Methods This is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers. Results A total of 64 patients met criteria for inclusion. Complete rituximab response (56%) was not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP. Conclusions Pre‐rituximab immunologic evaluation varied significantly between adults and children, which could represent institution‐specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre‐rituximab immunologic evaluation is needed.

Background Typical sickle cell disease (SCD) vaso‐occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. Objectives This study aimed to characterize ketamine use for VOE management in pediatric SCD. Method This retrospective case series summarizes a single‐center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. Results Continuous low‐dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0 μg/kg/min; median maximum dose 3.0 μg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days. In most encounters, ketamine infusion was discontinued prior to opioid patient‐controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low‐dose ketamine infusion was associated with side effects noted in 21.8% (n = 34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. Conclusion Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.