Phosphorylation of ribosomal protein L13a is essential for translational repression of inflammatory genes by the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex. Here we show IFN-γ activates a kinase cascade in which death-associated protein kinase-1 (DAPK) activates zipper-interacting protein kinase (ZIPK), culminating in L13a phosphorylation on Ser77, L13a release from the ribosome, and translational silencing of GAIT element-bearing target mRNAs. Remarkably, both kinase mRNAs contain functional 3’UTR GAIT elements and thus the same inhibitory pathway activated by the kinases is co-opted to suppress their expression. Inhibition of DAPK and ZIPK facilitates cell restoration to the basal state and allows renewed induction of GAIT target transcripts by repeated stimulation. Thus, the DAPK-ZIPK-L13a axis forms a unique regulatory module that first represses, then re-permits inflammatory gene expression. We propose the module presents an important checkpoint in the macrophage “resolution of inflammation” program, and that pathway defects may contribute to chronic inflammatory disorders.

No abstract

The coronavirus disease (COVID-19) pandemic has disrupted not only clinical care but also medical education. Physical distancing and shift rearrangements for both trainees and faculty have led to abrupt cancelation of many in-person didactics. These have been replaced by distance learning options, which include both synchronous and asynchronous curricula. Unfortunately, many medical educators have been forced to quickly create distance-learning options for trainees with little prior experience. In this perspective, we review the evidence base for distance learning and discuss practical considerations for transitioning traditional in-person curricula to distance platforms. We review technical aspects of distance learning as well as educational principles essential for success. The goal is for medical educators to optimize distance learning not just during this COVID-19 pandemic but beyond this crisis as well.

No abstract

No abstract

IntroductionMutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear.MethodsWe undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods.ResultsAll patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01).ConclusionsKRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.

Background Constitutive activation of STAT5 (by phosphorylation) has been identified in a number of malignancies, including acute myeloid leukemia (AML). Objectives We investigated whether the level of phosphorylated STAT5 (pSTAT5) expression correlates with clinical outcome in AML. Methods Adult patients with newly diagnosed AML receiving induction chemotherapy and with an available diagnostic bone marrow were evaluated. Results Forty‐two percent of patients had pSTAT5 expression >0 on immunohistochemical analysis of fixed bone marrow core biopsies. In multivariable analyses, controlling for age, history of antecedent hematologic disorder, cytogenetic risk, and WBC at diagnosis, pSTAT5 expression was significantly associated with an increased risk of death (HR 1.96, 95% CI 1.19–3.23, P  = 0.008) and of relapse after achieving complete remission (HR 2.31, 95% CI 1.16–4.63, P = 0.018). Conclusions Validation of pSTAT5's prognostic value requires additional study in a larger group of uniformly treated patients. However, our data suggests that targeting this signaling pathway in AML may improve the outcome of patients.

No abstract