HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma.

Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-ß stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-ß-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression.

Kinematic and clinical analyses of upper-extremity movements after constraint-induced movement therapy in patients with stroke: a randomized controlled trial.

OBJECTIVE: To study the effects of constraint-induced movement therapy (CIMT) relative to traditional intervention on motor-control strategies for upper-arm reaching and motor performance at the impairment and functional levels in stroke patients. DESIGN: Two-group randomized controlled trial (RCT); pretreatment and posttreatment measures. SETTING: Rehabilitation clinics. PARTICIPANTS: Forty-seven stroke patients (mean age, 55y) 3 weeks to 37 months postonset of a first-ever cerebrovascular accident. INTERVENTIONS: Forty-seven patients received either CIMT (restraint of the less affected hand combined with intensive training of the more affected upper extremity) or traditional intervention (control treatment) during the study. The treatment intensity was matched between the 2 groups (2h/d, 5d/wk for 3wk). MAIN OUTCOME MEASURES: Outcomes were evaluated using (1) kinematic variables of reaching movement used to describe the control strategies for reaching, (2) the Fugl-Meyer Assessment (FMA) of motor-impairment severity, and (3) the Motor Activity Log (MAL) evaluating the functional ability of the upper extremity. RESULTS: After treatment, the CIMT group showed better strategies of reaching control than the control group (P<.03). The CIMT group also showed less motor impairment on the FMA (P=.019) and higher functional ability on the MAL (P<.001). CONCLUSIONS: This study is the first RCT to show differences in motor-control strategies as measured by kinematic variables after CIMT versus traditional intervention. In addition to improving motor performance at the impairment and functional levels, CIMT conferred therapeutic benefits on control strategies determined by kinematic analysis.