Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo

Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20–40%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X_L, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicletreated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.     

The effect of patellar thickness on gait biomechanics following total knee arthroplasty

BackgroundPatella resurfacing is commonly performed during total knee arthroplasty; however, determining the appropriate patellar thickness remains a challenge. The purpose of this study was to evaluate the role of post-TKA patellar thickness on knee extensor strength and biomechanical joint loading forces during walking and stair negotiation.MethodsFifteen patients (21 knees) underwent gait analysis prior to TKA and post-TKA at six weeks, three months, six months, and one year. Knee extensor strength and biomechanics were collected during level walking and stair negotiation and analyzed using Pearson correlation coefficients.ResultsKnee extensor strength was positively correlated to patellar thickness at three months and one year post-TKA (p ≤ .05). During walking, no significant correlations were present. During stair ascent, there was a positive correlation between patellar thickness and peak knee flexion angle one year post-TKA (p ≤ .05). During stair descent, there was a positive correlation between patellar thickness and maximum vertical ground reaction forces at one year post-TKA (p ≤ .01).ConclusionsThe loss of patellar thickness when compared to measured pre-resurfacing thickness was correlated with a decrease in knee extensor strength; however, changes in patellar thickness were not significantly correlated to biomechanical loading forces during walking. Increases in demand of activity increase the torque to the knee joint, which elicit increases in compensatory motions, likely reducing the extent to which differences in joint loading during stair negotiation may be attributable to changes in patellar thickness. Therefore, the effect of post-patellar thickness on patient function in primary TKA is limited.     

Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.