Repeatability of Inertial Measurement Units for Measuring Pelvic Mobility in Patients Undergoing Total Hip Arthroplasty.

Consideration of pelvic mobility when positioning implants for total hip arthroplasty (THA) has been shown to reduce the risk of complications such as dislocation, squeaking and excessive wear. We aim to test the repeatability of pelvic tilt measurements taken between three positions (standing, flexed-seated and step-up) by an inertial measurement unit (IMU) and hence, evaluate their reliability in screening for high pelvic mobility in patients undergoing THA. The repeated IMU measurements of pelvic tilt were analysed for consistency and compared with measures taken by x-ray analysis. Our study showed greater variation in measures taken by the IMU particularly in the flexed-seated position. The patient's pelvic tilt in this position negatively correlated with their mid-back angle, suggesting the posture of the patient is a source of variation in the flexed-seated position if not kept consistent during assessments. IMUs were overall able to produce accurate and reliable measurements of pelvic tilt; however, protocols will need to be adjusted to factor in a patient's mid-back angle when taking future readings.

A Sensor-Based Screening Tool for Identifying High Pelvic Mobility in Patients Due to Undergo Total Hip Arthroplasty.

There is increasing evidence that pelvic mobility is a critical factor to consider in implant alignment during total hip arthroplasty (THA). Here, we test the feasibility of using an inertial sensor fitted across the sacrum to measure change in pelvic tilt, and hence screen for patients with high pelvic mobility. Patients (n = 32, mean age: 57.4 years) due to receive THA surgery participated in the study. Measures of pelvic tilt were captured simultaneously using the device and radiograph in three functional positions: Standing, flexed-seated, and step-up. We found a strong correlation between the device and radiograph measures for the change in pelvic tilt measure from standing to flexed-seated position (R2 = 0.911); 75% of absolute errors were under 5 degrees. We demonstrated that the device can be used as a screening tool to rapidly identify patients who would benefit from more detailed surgical planning of implant positioning to reduce future risks of impingement and dislocation.

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer.

Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.

BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

Bilateral closed flexor pollicis longus musculotendinous junction ruptures.

We present a case of bilateral closed flexor pollicis longus musculotendinous junction ruptures. Our case suggests multifactorial aetiology and provides further evidence for genetic influences in musculotendinous junction injuries.