Functional independence measure for elderly patients undergoing aortic valve replacement.

OBJECTIVE: This study aimed to evaluate the efficacy of the Functional Independence Measure to assess preoperative frailty for elderly patients undergoing surgical aortic valve replacement. METHODS: Eighty-five patients >65 years who survived elective isolated aortic valve replacement from January 2008 to October 2015 were included. The mean age at the operation was 78 ± 6 years old (n = 28 males, n = 57 females). The patients were divided into two groups according to their status at discharge: impossible to discharge home or hospitalization for >30 days (compromised group, n = 8), or unaffected (unaffected group, n = 77). Preoperative frailty was evaluated with the Functional Independence Measure, which comprises 18 items divided into six domains: self-care, sphincter control, mobility, locomotion, communication, and social cognition. RESULTS: The preoperative total Functional Independence Measure score was significantly lower in the compromised group (79 ± 32) than in the unaffected group (120 ± 9, p < 0.01). The preoperative motor Functional Independence Measure score was significantly lower in the compromised group (45 ± 24) than in the unaffected group (85 ± 9, p = <0.01). The duration of postoperative intubation, intensive care unit stay, and postoperative hospitalization were significantly longer in the compromised group than in the unaffected group (48 ± 67 vs 16 ± 12 h, p < 0.01; 6.7 ± 5.3 vs 3.4 ± 2.0 days, p < 0.01; 34 ± 27 vs 23 ± 11 days, p = 0.02, respectively). CONCLUSIONS: The preoperative Functional Independence Measure is effective for assessing preoperative frailty in elderly patients undergoing aortic valve replacement in terms of predicting operative morbidity.

PCTK1 regulates integrin-dependent spindle orientation via protein kinase A regulatory subunit KAP0 and myosin X.

Integrin-dependent cell-extracellular matrix (ECM) adhesion is a determinant of spindle orientation. However, the signaling pathways that couple integrins to spindle orientation remain elusive. Here, we show that PCTAIRE-1 kinase (PCTK1), a member of the cyclin-dependent kinases (CDKs) whose function is poorly characterized, plays an essential role in this process. PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA). This phosphorylation is dispensable for KAP0 dimerization and for PKA binding but is necessary for its interaction with myosin X, a regulator of spindle orientation. KAP0 binds to the FERM domain of myosin X and enhances the association of myosin X-FERM with ß1 integrin. This interaction between myosin X-FERM and ß1 integrin appeared to be crucial for spindle orientation control. We propose that PCTK1-KAP0-myosin X-ß1 integrin is a functional module providing a link between ECM and the actin cytoskeleton in the ECM-dependent control of spindle orientation.

Pregnenolone functions in centriole cohesion during mitosis.

Cell division is controlled by a multitude of protein enzymes, but little is known about roles of metabolites in this mechanism. Here, we show that pregnenolone (P5), a steroid that is produced from cholesterol by the steroidogenic enzyme Cyp11a1, has an essential role in centriole cohesion during mitosis. During prometa-metaphase, P5 is accumulated around the spindle poles. Depletion of P5 induces multipolar spindles that result from premature centriole disengagement, which are rescued by ectopic introduction of P5, but not its downstream metabolites, into the cells. Premature centriole disengagement, induced by loss of P5, is not a result of precocious activation of separase, a key factor for the centriole disengagement in anaphase. Rather, P5 directly binds to the N-terminal coiled-coil domain of short-form of shugoshin 1 (sSgo1), a protector for centriole cohesion and recruits it to spindle poles in mitosis. Our results thus reveal a steroid-mediated centriole protection mechanism.

Inhibition of endocytic vesicle fusion by Plk1-mediated phosphorylation of vimentin during mitosis.

Endocytic vesicle fusion is inhibited during mitosis, but the molecular pathways that mediate the inhibition remain unclear. Here we uncovered an essential role of Polo-like kinase 1 (Plk1) in this mechanism. Phosphoproteomic analysis revealed that Plk1 phosphorylates the intermediate filament protein vimentin on Ser459, which is dispensable for its filament formation but is necessary for the inhibition of endocytic vesicle fusion in mitosis. Furthermore, this mechanism is required for integrin trafficking toward the cleavage furrow during cytokinesis. Our results thus identify a novel mechanism for fusion inhibition in mitosis and implicate its role in vesicle trafficking after anaphase onset.