AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.

AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.

Case Management in Primary Care for Frequent Users of Health Care Services: A Realist Synthesis.

PURPOSE: Case management (CM) is a promising intervention for frequent users of health care services. Our research question was how and under what circumstances does CM in primary care work to improve outcomes among frequent users with chronic conditions? METHODS: We conducted a realist synthesis, searching MEDLINE, CINAHL, Embase, and PsycINFO (1996 to September 2017) for articles meeting the following criteria: (1) population: adult frequent users with chronic disease, (2) intervention: CM in a primary care setting with a postintervention evaluation, and (3) primary outcomes: integration of services, health care system use, cost, and patient outcome measures. Academic and gray literature were evaluated for relevance and robustness. Independent reviewers extracted data to identify context, mechanism, and outcome (CMO) configurations. Analysis of CMO configurations allowed for the modification of an initial program theory toward a refined program theory. RESULTS: Of the 9,295 records retrieved, 21 peer-reviewed articles and an additional 89 documents were retained. We evaluated 19 CM interventions and identified 11 CMO configurations. The development of a trusting relationship fostering patient and clinician engagement in the CM intervention was recurrent in many CMO configurations. CONCLUSION: Our refined program theory proposes that in the context of easy access to an experienced and trusted case manager who provides comprehensive care while maintaining positive interactions with patients, the development of this relationship fosters the engagement of both individuals and yields positive outcomes when the following mechanisms are triggered: patients and clinicians feel supported, respected, accepted, engaged, and committed; and patients feel less anxious, more secure, and empowered to self-manage.

Homoassociation of VE-cadherin follows a mechanism common to "classical" cadherins.

Vascular endothelial cadherin (VE-cadherin/cadherin5) is specifically expressed in adherens junctions of endothelial cells and exerts important functions in cell-cell adhesion as well as signal transduction. To analyze the mechanism of VE-cadherin homoassociation, the ectodomains CAD1-5 were connected by linker sequences to the N terminus of the coiled-coil domain of cartilage matrix protein (CMP). The chimera VECADCMP were expressed in mammalian cells. The trimeric coiled-coil domain leads to high intrinsic domain concentrations and multivalency promoting self-association. Ca(2+)-dependent homophilic association of VECADCMP was detected in solid phase assays and cross-linking experiments. A striking analogy to homoassociation of type I ("classical") cadherins like E, N or P-cadherin was observed when interactions in VECADCMP and between these trimeric proteins were analyzed by electron microscopy. Ca(2+)-dependent ring-like and double ring-like arrangements suggest interactions between domains 1 and 2 of the ectodomains, which may be correlated with lateral and adhesive contacts in the adhesion process. Association to complexes composed of two VECADCMP molecules was also demonstrated by chemical cross-linking. No indication for an antiparallel association of VECAD ectodomains to hexameric complexes as proposed by Legrand et al. was found. Instead the data suggest that homoassociation of VE-cadherin follows the conserved mechanism of type I cadherins.

Complementary expression and regulation of cadherins 6 and 11 during specific steps of motoneuron differentiation.

Cadherins constitute one of the major classes of adhesion receptors participating in the architectural organization of embryonic tissues. We previously identified type II cadherins 6 and 11, whose mRNA expression was tightly regulated during mouse neuromuscular development. Here we determine the regulation of expression and the localization of the corresponding proteins in relation to spinal neuron differentiation and peripheral nerve outgrowth. Cadherin-11 expression initially appeared in motor columns before extending to the whole spinal cord, dorsal root ganglia, and sensory-motor peripheral nerves. Then, its expression decreased in nervous tissues and became predominant in mesenchymes. Cadherin-6 was exclusively expressed in floor and roof plates, motor columns, and motor peripheral nerves, including motor axons and Schwann cell precursors. Compared to cadherin-11, its expression in motor columns was delayed and restricted to certain subpopulations of motoneurons. These results strongly implicate cadherins 6 and 11 in the control of spinal motoneuron differentiation and segregation and in axoaxonal, axoglial, and glio-glial interactions during sensory-motor nerve progression.