Affective instability across the lifespan in borderline personality disorder - a cross-sectional e-diary study.

OBJECTIVE: Longitudinal and cross-sectional studies suggest that affective instability is inversely related to greater age in borderline personality disorder (BPD). However, existing studies relied on retrospective self-reports of perceived instability. We examined affective instability in everyday life in patients with BPD and healthy controls (HCs) by age in a cross-sectional e-diary study. METHODS: Two hundred and sixty female participants between 14 and 53 years of age (130 patients with BPD and 130 HCs) carried an e-diary over 4 days. The e-diaries emitted a prompting signal in approximately hourly intervals asking participants to rate their current affective state, that is valence (ranging from pleasant to unpleasant) and tense arousal (ranging from calm/relaxed to restless/under tension). RESULTS: Multilevel analyses revealed a significant interaction of age and group predicting affective instability (valence: F(1,255.6)  = 7.59; P < 0.01; tense arousal: F(1,252)  = 6.08; P < 0.01), suggesting that affective instability significantly declines with greater age in patients with BPD. Controlling for the number of comorbid disorders and BPD severity did not change the results, illustrating an inverse relationship between age and affective instability in BPD (significant interaction of age*group for valence: F(1,238.7)  = 5.74; P < 0.02 and tense arousal: F(1,235.2)  = 5.28; P < 0.02). CONCLUSION: Affective instability during daily life declines with greater age in BPD. This decline is irrespective of comorbidity and BPD severity.

RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia.

Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.