Authors: Ryota Katsumi, Jeffrey B Stambough, Simon C. Mears, Paul Edwards, C.Lowry Barnes, Erin M.Mannen

Abstract:

INTRODUCTION: Abnormal spinopelvic alignment in the sagittal plane is thought to contribute to the sagittal imbalance and the pathogenesis of chronic low back pain. Knee flexion is proposed as a compensatory mechanism in cases of sagittal imbalance. In contrast, the malalignment of the osteoarthritic knee might contribute to abnormal spinopelvic alignment in the sagittal plane. The purpose of this retrospective study was to assess the relationship between knee flexion angle (KFA) and sagittal spinopelvic alignment parameters of patients with end-stage knee osteoarthritis in a weight-bearing standing position using a low-dose biplanar imaging system.

METHODS: According to a priori power analysis (G*Power 3.1; Institut fur Experimentaelle Psychologie, Dusseldorf, Germany), 84 patients with end-stage knee osteoarthritis and no history of severe spinal deformity, spinal fracture, or spinal surgery (33 male, 51 female, average age 65) underwent anteroposterior and lateral standing x-rays (EOS imaging). Sagittal alignment parameters were measured: thoracic kyphosis (TK), lumbar lordosis (LL), sagittal pelvic tilt (PT), sagittal vertical axis (SVA) and KFA (Figure 1). TK and LL were the angles between the superior endplate of T4 and the inferior endplate of T12, and the superior endplate of L1 and the endplate of S1, respectively. PT was the angle between the vertical and the line through the midpoint of the sacral plate to femoral head axis. SVA was the distance between C7 plumb line and posterior edge of sacral plate. KFA was the angle between the femoral axis and the tibial axis. The correlations between KFA and TK, LL, PT, SVA were evaluated using the Spearman’s rank-order correlation coefficient (rs). The probability level accepted for statistical significance was set to p < 0.05 (SPSS version 24; SPSS, Inc., Chicago, IL, USA).

RESULTS: The mean value, standard deviation, and range of each parameter are shown in Table 1. TK, LL, PT, SVA, KFA were 43.1°±13.5°, 52.2°±10.7°, 16.1°±8.6°, 31.3±34.1 mm, and 10.0°±9.4°, respectively. Significant correlations between KFA and LL (rs = -0.222, p = 0.042), and KFA and SVA (rs = 0.417, p < 0.001) were found. There were no significant correlations between KFA and TK or PT.

DISCUSSION AND CONCLUSION: The sagittal spinopelvic alignment was significantly influenced by KFA in patients with end-stage knee osteoarthritis. The more flexed knee led to reduced LL and larger SVA. According to Murata et al., LL was significantly reduced in patients whose limitation of extension of the knee was more than 5°. Patients with larger SVA are reported to be usually imbalanced and have higher disability scores. The correction of the sagittal malalignment of the knee by realignment surgery such as total knee arthroplasty may improve the sagittal imbalance.

Conference/Symposium/Course name, dates and location where the work was supposed to be presented:
American Academy of Orthopaedic Surgeons, 2020 Annual meeting

Authors: Alicja Urbaniak, Megan R. Reed, Michał Antoszczak, Michał Sulik, Adam Huczyński, Robert L. Eoff, Melanie C. MacNicol, Angus M. MacNicol, Timothy C. Chambers

Abstract

Breast cancer tumor metastasis is the leading cause of mortality among women. Cancer stem cells (CSCs) are the tumor-initiating cells which drive initiation, progression, metastasis, and tumor reoccurrence. Their resistance to conventional chemo- and radiotherapies and their ability to survive such treatment enables tumor reestablishment. Thus, therapeutic strategies targeting CSCs hold great potential for novel advances in cancer treatment. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic with anti-cancer activity towards various types of tumor cells, but its toxicity towards normal cells limits broad application. A library of 21 novel SAL analogs was screened to identify compounds with improved selectivity especially against breast cancer stem cells. SAL analogs were either single modified with ester or amide in the C1 position or double-modified C20-oxo derivatives. Eight single- and two double-modified derivatives were more potent (IC50 range of 1.13 ± 0.19 to 3.93 ± 0.39 μM) towards the breast cancer cell line MDA- MB-231 compared to SAL (IC50 of 5.81 ± 1.50). These derivatives induced DNA fragmentation suggestive of apoptotic cell death. Further, most of these derivatives had improved selectivity toward MDA-MB-231 cells compared to SAL when also tested against normal breast epithelial MCF10A cells. In addition, a butyl ester derivative of SAL, chosen based on increased potency and selectivity versus SAL, significantly reduced the colony-forming efficiency of MDA-MB-231 cells in association with selective loss of the CD44+/CD24-/low stem-cell-like subpopulation. Select derivatives were next screened against the NCI-60 Human Tumor Cell Line Panel. A double- modified analog of C20-oxo-SAL with hydroxamic acid was found to be more potent than SAL towards all 6 breast cancer cell lines in the panel as well as other tumor types especially leukemia. Studies are underway to test the analogs in three dimensional culture using breast cancer organoids derived from both cell lines and patients. The present findings highlight the therapeutic potential of SAL analogs towards breast cancer and breast cancer stem cells and support further research and clinical development of these compounds.

Funding: The present study was funded by grants (to AM and TCC) from the Arkansas Breast Cancer Research Program.
Testing was performed by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, http://dtp.cancer.gov.

Conference/Symposium/Course name, dates and location where the work was supposed to be presented:
Experimental Biology 2020, April 4-7 2020, San Diego