CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis. © 2019, Park et al.1

Volume and Distribution of Periprosthetic Bone Cysts in the Distal Tibia and Talus before Early Revision of Total Ankle Arthroplasty

Periprosthetic osteolysis is a common complication following total ankle arthroplasty (TAA). However, understanding of osteolysis volume and distribution is still evolving, undermining efforts to reduce the incidence of osteolysis via bone remodeling. We obtained data on the characteristics of osteolysis developing within the distal tibia and talus after TAA. Three-dimensional computed tomography (3D-CT) reconstructions of 12 patients who underwent HINTEGRA TAA were performed. We identified 27 volumes of interest (VOIs) in the tibia and talus and used statistical methods to identify the characteristics of osteolysis in the VOIs. The osteolysis volume was significantly larger in the talus than in the tibia (162.1 ± 13.6 and 54.9 ± 6.1 mm3, respectively, p = 0.00). The extent of osteolysis within the peri-prosthetic region was greater than within other regions (p < 0.05). Particularly, in the talus, the region around the talar pegs exhibited 24.2 ± 4.5% more osteolysis than any other talar region (p = 0.00). Our results may suggest that extensive osteolysis within the peri-prosthetic region reflects changes in stress flow and distribution, which vary according to the design and placement of the fixation components. This is the first study to report 3D osteolysis patterns after TAA. Careful planning of TAA design improvements may reduce the incidence of osteolysis. Our results will facilitate the further development of TAA systems

Performance on the APACHE II, SAPS II, SOFA and the OHCA score of post-cardiac arrest patients treated with therapeutic hypothermia

<div><p>Objective</p><p>This study assessed the ability of the Acute Physiologic and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, and out-of-hospital cardiac arrest (OHCA) score to predict the outcome of OHCA patients who underwent therapeutic hypothermia (TH).</p><p>Methods</p><p>This study included OHCA patients treated with TH between January 2010 and December 2013. The APACHE II score, SAPS II, and SOFA score were calculated at the time of admission and 24 h and 48 h after intensive care unit admission. The OHCA score was calculated at the time of admission. The area under the curve (AUC) of the receiver operating characteristic curve and logistic regression analysis were used to evaluate outcome predictability.</p><p>Results</p><p>Data from a total of 173 patients were included in the analysis. The APACHE II score at 0 h and 48 h, SAPS II at 48 h, and OHCA score had moderate discrimination for mortality (AUC: 0.715, 0.750, 0.720, 0.740). For neurologic outcomes, the APACHE II score at 0 h and 48 h, SAPS II at 0 h and 48 h, and OHCA score showed moderate discrimination (AUC: 0.752, 0.738, 0.771, 0.771, 0.764). The APACHE II score, SAPS II and SOFA score at various time points, in addition to the OHCA score, were independent predictors of mortality and a poor neurologic outcome.</p><p>Conclusions</p><p>The APACHE II score, SAPS II, SOFA score, and OHCA score have different capabilities in discriminating and estimating hospital mortality and neurologic outcomes. The OHCA score, APACHE II score and SAPS II at time zero and 48 h offer moderate predictive accuracy. Other scores at 0 h and 48 h, except for the SOFA score, are independently associated with 30-day mortality and poor cerebral performance.</p></div

The ROC curves for severity scores and OHCA score over time.

<p>The ROC curves for severity scores and OHCA score over time.</p

The ROC curves for severity scores and OHCA score over time.

<p>The ROC curves for severity scores and OHCA score over time.</p

AUC values for each scoring system to predict 30-day mortality and neurologic outcomes.

<p>AUC values for each scoring system to predict 30-day mortality and neurologic outcomes.</p

Multivariate analysis of severity scoring systems with 30-day mortality and poor neurologic outcome.

<p>Multivariate analysis of severity scoring systems with 30-day mortality and poor neurologic outcome.</p

APACHE II score, SAPS II, SOFA score, and OHCA score according to time the period with 30-day mortality and neurologic outcome.

<p>APACHE II score, SAPS II, SOFA score, and OHCA score according to time the period with 30-day mortality and neurologic outcome.</p

Comparison of characteristics of survivors/non-survivors and good/poor CPC groups.

<p>Comparison of characteristics of survivors/non-survivors and good/poor CPC groups.</p