Notes

Synthesis regarding thiocolchicine amine derivatives and evaluation of their particular antiproliferative activity.
Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight due to species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologues were developed. The aim of this work was to investigate the utility of mouse model expressing human orthologues of PXR, CAR and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz and pioglitazone, which were employed to represent strong, moderate and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. Following the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction ical induction and to differentiate tissue dependent induction observed with rifampin, but not with efavirenz. SCH66336 These results not only foreshadow the potential application of such transgenic models in assessing clinical induction, but also in further investigating the mechanism of drug disposition.
Pediatric health care encounters declined during the coronavirus disease 2019 (COVID-19) pandemic, and pediatric residency programs have adapted trainee schedules to meet the needs of this changing clinical environment. We sought to evaluate the impact of the pandemic on pediatric interns' clinical exposure.

In this retrospective cohort study, we quantified patient exposure among pediatric interns from a single large pediatric residency program at a freestanding children's hospital. Patient encounters and shifts per pediatric intern in the inpatient and emergency department settings were evaluated during the COVID-19 pandemic, from March to June 2020, as compared with these 3 months in 2019. Patient encounters by diagnosis were also evaluated.

The median number of patient encounters per intern per 2-week block declined on the pediatric hospital medicine service (37.5 vs 27.0;
< .001) and intensive care step-down unit (29.0 vs 18.8;
= .004) during the pandemic. No significant difference in emergency department encounters was observed (63.0 vs 40.5;
= .06). The median number of shifts worked per intern per 2-week block also decreased on the pediatric hospital medicine service (10.5 vs 9.5,
< .001). Across all settings, there were more encounters for screening for infectious disease and fewer encounters for respiratory illnesses.

Pediatric interns at the onset of the COVID-19 pandemic were exposed to fewer patients and had reduced clinical schedules. Careful consideration is needed to track and supplement missed clinical experiences during the pandemic.
Pediatric interns at the onset of the COVID-19 pandemic were exposed to fewer patients and had reduced clinical schedules. Careful consideration is needed to track and supplement missed clinical experiences during the pandemic.Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. IMPLICATIONS This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies, including decrease of NF-κB in circulating leuchemic blasts. Here, we report that activation of NF-κB/p65 by castration in mouse and human prostate cancer models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT-sensitizing prostate cancer cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function. IMPLICATIONS Our study shows that DMAPT, an oral NF-κB inhibitor in clinical development, inhibits phosphorylated-p65 upregulation of AR-V7 and delays prostate cancer castration resistance. This provides rationale for the development of DMAPT as a novel therapeutic strategy to increase durable response in patients receiving AR-targeted therapy.
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