MicroRNA-631 Resensitizes Doxorubicin-Resistant Chondrosarcoma Cells by Targeting Apelin.

Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.

Double-blind parallel comparison of multiple doses of apraclonidine, clonidine, and placebo administered intra-articularly to patients undergoing arthroscopic knee surgery.

OBJECTIVE: This clinical study assessed and compared the potential analgesic and adverse effect of IA apraclonidine with IA clonidine. METHODS: Eighty patients scheduled for arthroscopic knee surgery under general anesthesia were randomized to receive, in a double-blind manner, either IA normal saline (group 1), 50 microg IA apraclonidine (group 2), 150 microg IA apraclonidine (group 3), or 150 microg IA clonidine (group 4), all in a volume of 20 mL subsequent to surgery. Visual analog pain scores (VAS), the duration of analgesia as defined by the time to first demand for supplemental analgesics, the subsequent 24-hour consumption of postoperative supplementary analgesics, and patient adverse effects were evaluated. RESULTS: The patients from groups 3 and 4 demonstrated a longer duration of analgesia and used fewer analgesics in the first postoperative 24 hour period compared with group 1 and 2 patients (P < 0.05). The VAS scores corresponding to the periods 1, 2, and 4 hours postoperatively were significantly lower for group 3 than for group 1 patients. The VAS scores at 1 and 4 hours postoperatively were also lower for group 3 than for group 2 patients (P < 0.05). There was no significant difference in the incidence of side effects among the 4 groups. DISCUSSION: The IA application of 150 microg apraclonidine and 150 microg clonidine provide similar degree of postoperative analgesia following knee arthroscopic surgery without any difference in adverse events.

Intrathecal spinal progenitor cell transplantation for the treatment of neuropathic pain.

Injury to, or dysfunction of, the nervous system can lead to spontaneous pain, hyperalgesia, and/or allodynia. It is believed that the number and activity of GABAergic neurons gradually decreases over the dorsal horn. Glutamic acid decarboxylase (GAD) immunocompetence has been demonstrated on spinal progenitor cells (SPCs) cultivated in vitro. The intrathecal implantation of these cultivated progenitor cells may provide a means of alleviating neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve was used to induce chronic neuropathic pain in the hind paw of rats. SPCs (1 x 10(6)) were implanted intrathecally on the third day after the CCI surgery. The behavioral response to thermal hyperalgesia was observed and recorded during the 14 days postsurgery. Various techniques were utilized to trace the progenitor cells, confirm the differentiation, and identify the neurotransmitters involved. GAD immunoactivity was revealed for 65% of the cultivated spinal progenitor cells in our study. We also determined that transplanted cells could survive more than 3 weeks postintrathecal implantation. Significant reductions were demonstrated for responses to thermal stimuli for the CCI rats that had received intrathecal SPC transplantation. A novel intrathecal delivery with SPCs reduced CCI-induced neuropathic pain.