Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer

Heart rate variability in critical care medicine: a systematic review.

BACKGROUND: Heart rate variability (HRV) has been used to assess cardiac autonomic activity in critically ill patients, driven by translational and biomarker research agendas. Several clinical and technical factors can interfere with the measurement and/or interpretation of HRV. We systematically evaluated how HRV parameters are acquired/processed in critical care medicine. METHODS: PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (1996-2016) were searched for cohort or case-control clinical studies of adult (>18 years) critically ill patients using heart variability analysis. Duplicate independent review and data abstraction. Study quality was assessed using two independent approaches: Newcastle-Ottowa scale and Downs and Black instrument. Conduct of studies was assessed in three categories: (1) study design and objectives, (2) procedures for measurement, processing and reporting of HRV, and (3) reporting of relevant confounding factors. RESULTS: Our search identified 31/271 eligible studies that enrolled 2090 critically ill patients. A minority of studies (15; 48%) reported both frequency and time domain HRV data, with non-normally distributed, wide ranges of values that were indistinguishable from other (non-critically ill) disease states. Significant heterogeneity in HRV measurement protocols was observed between studies; lack of adjustment for various confounders known to affect cardiac autonomic regulation was common. Comparator groups were often omitted (n = 12; 39%). This precluded meaningful meta-analysis. CONCLUSIONS: Marked differences in methodology prevent meaningful comparisons of HRV parameters between studies. A standardised set of consensus criteria relevant to critical care medicine are required to exploit advances in translational autonomic physiology.GLA is supported by a British Journal of Anaesthesia and Royal College of Anaesthetists Basic Science fellowship, British Oxygen Company grant from the Royal College of Anaesthetists and British Heart Foundation programme grant (RG/14/4/3073

Influence of the sagittal balance of the spine on the anterior pelvic plane and on the acetabular orientation

The Anterior Pelvic Plane (APP), defined by the anterior superior iliac spines and the pubic tubercle, was commonly used as reference for positioning and postoperative evaluation of the orientation of the acetabular cup in total hip arthroplasty. APP was assumed to be vertical, but was not observed always so, mostly because of associated spinal diseases inducing perturbations in the harmony of the sagittal balance of the pelvi-spinal unit. Consequently a sagittal rotation of the pelvis occurs, and so a tilt of the APP which alters directly the orientation of the cup in upright position. An analysis of the APP tilt related to the sagittal balance of the spine was provided and its implication on the cup orientation. It appeared essential for an individual adjustment of the cup positioning to avoid a functional mal-position which can lead to an increased risk of dislocation and impingement