Huabin Yin

MiR-126-5p regulates osteoclast differentiation and bone resorption in giant cell tumor through inhibition of MMP-13

Giant cell tumor (GCT) of bone is an aggressive skeletal tumor characterized by localized bone resorption. Matrix metalloproteinase-13 (MMP-13) is the principal proteinase expressed by the stromal cells of GCT (GCTSCs) and also considered to play a crucial role in formation of the osteolytic lesion in GCT. However, the exact mechanism of the regulation of MMP-13 expression in GCTSCs was unknown. In this study, we identified miR-126-5p was significantly downregulated in GCTSCs and affect osteoclast (OC) differentiation and bone resorption by repressing MMP-13 expression at the post-transcriptional level. Thus, our studies show that miR-126-5p plays an important physiological role in multinucleated giant cell formation and osteolytic lesion in GCT.

MiR-126-5p regulates osteolysis formation and stromal cell proliferation in giant cell tumor through inhibition of PTHrP

Parathyroid hormone-related protein (PTHrP) has been identified to play a crucial role in osteolysis formation and stromal cell (GCTSC) proliferation in giant cell tumor (GCT). MiR-126-5p is an intronic miRNA identified as tumor suppressor in many tumors, but its role in GCT is poorly understood. We found that miR-126-5p was decreased in GCT and could directly regulate PTHrP expression. Furthermore, miR-126-5p could control osteoclast (OC) differentiation, GCTSC proliferation and osteolysis formation in GCT through negative regulation of PTHrP. Thus, these results suggest that miR-126-5p could directly target PTHrP and have a tumor suppressor function in GCT.

Surgery and prognostic factors of patients with epidural spinal cord compression caused by hepatocellular carcinoma metastases: retrospective study of 36 patients in a single center.

Study Design. A retrospective study of 36 patients with metastatic hepatocellular carcinoma (HCC) of the mobile spine was performed by survival analysis. Objective. To discuss the factors that may affect outcomes of patients with HCC spinal metastases. Summary of Background Data. HCC is a rare tumor in Western countries. However, HCC is common in Far East (Taiwan, Korea, mainland China), where the hepatitis B virus is epidemic. As the mean survival time of patients with HCC has largely increased in recent years, it is now more common to encounter a patient with epidural spinal cord compression caused by HCC spinal metastases in clinic. Methods. The univariate and multivariate analyses of various clinical factors were performed to identify independent variables that could predict prognosis. The survival rate was estimated by the Kaplan-Meier method, and differences were analyzed by the log-rank test. Factors with P values of 0.1 or less were subjected to multivariate analysis for survival rate by multivariate Cox proportional hazards analysis. Results. A total of 36 patients with metastatic HCC of the mobile spine were included in the study. Age (⩽45 yr/>45 yr), duration of preoperative symptoms (<6 mo/≥6 mo), preoperative Frankel score (A–C/D–E), Tomita score (5–7/8–10), and bisphosphonate treatment were suggested as the potential prognostic factors through univariate analysis. However, as they were submitted to the multivariate Cox regression model, only Tomita score was found as an independent prognostic factor. Conclusion. Tomita score no more than 7 is a favorable prognostic factor for HCC metastases in the mobile spine. Level of Evidence: 4

Breastfeeding and Risk of Rheumatoid Arthritis: A Systematic Review and Metaanalysis.

Objective. Previous studies have examined the association between breastfeeding and rheumatoid arthritis (RA), but their results were inconsistent. The aim of this study was to perform a metaanalysis to clarify the effect of breastfeeding on RA risk. Methods. The PubMed, EMBASE, Chinese National Knowledge Infrastructure, and Wanfang databases were searched for relevant studies published up to September 10, 2014. Data were extracted, and multivariable-adjusted OR with 95% CI were pooled in the random-effects model. Results. A total of 6 studies were included in the metaanalysis (RA cases: 1672, sample size: 143,670). Overall, an inverse association between breastfeeding and RA was observed (OR 0.675, 95% CI 0.493–0.924, p = 0.014). In the subgroup analysis, decreased RA risk was also found in both breastfeeding 1–12 months (OR 0.783, 95% CI 0.641–0.957, p = 0.015) and breastfeeding > 12 months (OR 0.579, 95% CI 0.462–0.726, p < 0.0005). Sensitivity analysis and cumulative analysis further strengthened the validity of the results. No publication bias was found in this metaanalysis. Conclusion. This metaanalysis suggests that breastfeeding is associated with a lower risk of RA, no matter if breastfeeding time is longer or shorter than 12 months.

Therapeutic strategy and outcome of spine tumors in pregnancy: a report of 21 cases and literature review.

Study Design. A retrospective study was performed. Objective. To illustrate the characteristics of spine tumors during pregnancy and obtain better insight into therapeutic strategies of such tumors by analyzing 21 cases treated in Changzheng Hospital and reviewing previous reports in the literature. Summary of Background Data. The concurrence of spine tumors and pregnancy is relatively rare. There are controversies over the treatment options for this disease, which increase the difficulty of the clinical treatment. Methods. Between 2002 and 2013, 21 pregnant patients were identified with spine tumors. Clinical data including symptoms, signs, treatment options, and obstetrical and neonatal outcomes were recorded and preserved. Clinical data and treatment efficacy were analyzed via medical record review. Results. The median age of the 21 patients was 28.87 years (interquartile range, 6.00 yr). Tumor types in this series were giant cell tumor (5 cases), hemangioma (5 cases), schwannoma (4 cases), eosinophilic granuloma (2 cases), neurofibroma (1 case), multiple myeloma (1 case), and with metastatic tumor (3 cases). Two patients underwent spine surgery during pregnancy and 8 patients accepted tumor resection immediately after delivery. Pregnancy termination occurred in 5 patients, whereas the rest of the patients smoothly gave birth to healthy babies including 3 premature infants. Two patients died and 2 patients experienced local recurrence during follow-up. Conclusion. With close observation, it was found that most of pregnant patients with benign spine tumors could postpone surgery after delivery. Surgical treatment should be adopted during pregnancy when patients are with highly malignant tumor or experience a sharp deterioration and the guard of it is safer than radiotherapy and chemotherapy during pregnancy. Level of Evidence: 4

Characterization of Nuclear Localization Signal in the N Terminus of Integrin-linked Kinase-associated Phosphatase (ILKAP) and Its Essential Role in the Down-regulation of RSK2 Protein Signaling

Background: As a phosphatase belonging to the PP2C family, ILKAP plays key roles in the regulation of cell survival and apoptosis. Results: ILKAP interacts with importin α proteins; nuclear ILKAP interacts with RSK2 and induces apoptosis by inhibiting RSK2 activity. Conclusion: ILKAP contains a functional NLS and induces apoptosis by regulating RSK2 signaling. Significance: ILKAP may regulate cell survival and apoptosis through the activation of nuclear pathways. Integrin-linked kinase-associated phosphatase (ILKAP) is a serine/threonine (S/T) phosphatase that belongs to the protein phosphatase 2C (PP2C) family. Many previous studies have demonstrated that ILKAP plays key roles in the regulation of cell survival and apoptosis. Researchers have thus far considered ILKAP a cytoplasmic protein that negatively regulates integrin signaling by interacting with and phosphorylating integrin-linked kinase 1 (ILK1). In this study, we found that both endogenous and tagged ILKAP mainly localize to the nucleus and that the nuclear transport of ILKAP is nuclear localization signal (NLS) importin-mediated. The ILKAP protein interacts directly with importin α1, α3, and α5. The NLS in ILKAP is located in the N-terminal region between amino acids 71 and 86, and the NLS-deleted ILKAP protein was distributed in the cytoplasm. In addition, we show that Lys-78 and Arg-79 are critical for the binding of ILKAP to importin α. We also found that nuclear ILKAP interacts with ribosomal protein S6 kinase-2 (RSK2) and induces apoptosis by inhibiting RSK2 activity and down-regulating the expression level of the RSK2 downstream substrate cyclin D1. These results indicate that ILKAP is a nuclear protein that regulates cell survival and apoptosis through the regulation of RSK2 signaling.

En bloc resection for treatment of tumor-induced osteomalacia: a case presentation and a systematic review

BackgroundTumor-induced osteomalacia (TIO) is a rare disorder, which is commonly found in craniofacial locations and in the extremities. To the best of our knowledge, only 16 cases have been described in the spine, and this is the first report to describe a case of patient with TIO in the thoracic spine combined with a mesenchymal hamartoma which had confused the therapeutic strategies to date.Case descriptionWe report the case of a 60-year-old patient with hypophosphatemia and presented with limb weakness. Treating with phosphate did not correct the hypophosphatemia and an 111In pentetreotide scintigraphy (octreotide scan) revealed an increased uptake at the right forearm. The tumor was resected totally, and the histopathology revealed a mesenchymal hamartoma, but we noticed that hypophosphatemia was not corrected after the tumor resection. Then a whole-body magnetic resonance imaging (WB-MRI) was performed and the results revealed tumorous tissues at the right T1 vertebral pedicle. The tumor was removed with an en bloc method, and the pathology showed phosphaturic mesenchymal tumor. Follow-up at 1 year after surgery revealed no recurrence, and the serum phosphorus level of the patient was normal.ConclusionsTumor-induced osteomalacia is exceedingly rare with only 16 cases in spine published in the literature. It is difficult to find and leads to years of suffering debilitating complications. In this regard, the WB-MRI is a better method to locate the real tumor. Treating with phosphate can only relieve symptoms, and a complete surgical removal remains the gold standard treatment.

Surgery for plasma cell neoplasia patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation

PurposeMultiple myeloma (MM) and solitary plasmacytoma of bone (SPB) are two independent subtypes of plasma cell dyscrasias which often occur in spine. However, little is known about the surgical treatment of patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation. The present study aimed to investigate the surgical outcome of these patients.MethodsWe retrospectively reviewed the data of a total of 64 patients receiving spinal surgery in our center, in which 30 were diagnosed as MM and 34 as SPB. Univariate and multivariate analyses were used to identify factors associated with overall survival (OS) and progression-free survival (PFS) of patients.ResultsSurgical treatment led to favorable results including pain relief, resumption of ambulatory ability as well as improvement of neurological function and life quality. Univariate analysis suggested that the potential prognostic factors for OS of MM patients were bisphosphonate treatment, post-surgical ambulatory status, Karnofsky Performance Score (KPS) and Frankel scale, and for PFS of MM patients were age at surgery, resection mode, postoperative ambulation status, KPS and Frankel scale, while the PFS of SPB patients was only significantly related to postoperative adjuvant therapies. Multivariate analysis indicated that postoperative ambulation status was the only independent risk factor for both OS and PFS of MM patients.ConclusionsSurgery may be beneficial to patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation, in which MM patients with postoperative ambulatory ability display better prognosis.

AURKA upregulation plays a role in fibroblast-reduced gefitinib sensitivity in the NSCLC cell line HCC827

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat non-small cell lung carcinoma (NSCLC) patients that have EGFR-activating mutations. EGFR-TKI monotherapy in most NSCLC patients with EGFR mutations who initially respond to EGFR-TKIs results in the development of acquired resistance. We investigated the role of fibroblasts in stromal cell-mediated resistance to gefitinib-induced apoptosis in EGFR-mutant NSCLC cells. While gefitinib induced apoptosis in EGFR-mutant NSCLC cells, apoptosis induction was diminished under stromal co-culture conditions. Protection appeared to be mediated in part by Aurora-A kinase (AURKA) upregulation. The protective effect of stromal cells was significantly reduced by pre-exposure to AURKA-shRNA. We suggest that combinations of AURKA antagonists and EGFR inhibitors may be effective in clinical trials targeting mutant EGFR NSCLCs.

5-Fluoruracil blocked giant cell tumor progression by suppressing osteoclastogenesis through NF-kappaB signals and blocking angiogenesis☆☆☆

Giant cell tumor of bone (GCTB) is a bone destroying tumor comprised of spindle-like stromal cells and monocytes of myeloid lineage that are differentiated into osteoclast-like multinucleated giant cells. Nuclear factor-Kappa B (NF-κB) has been identified to be essential for GCT progression. Herein, we found that 5-Fluorouracil (5-FU), a widely used chemotherapeutics, is a promising anticancer agent for GCT both targeting spindle-like stromal cells and osteoclast giant cells through NF-κB pathway. In this study, in vitro 5-FU not only directly blocked both stromal cell- and RANKL-induced osteoclastogenesis through NF-κB pathway, but also indirectly inhibited osteoclast formation and angiogenesis by suppressing the expression of osteoclast-activating factors including IL-1β, MCP-1 and tumor angiogenesis factor VEGF in stromal cells. In vivo, we found that 5-FU blocked GCT progression through NF-κB pathway by utilizing our chick embryo chorioallantoic membrane (CAM) model. Taken together, our results suggest that 5-FU can inhibit GCT development by suppressing osteoclast formation through NF-κB pathway and blocking angiogenesis, and may serve as a novel agent in the treatment of GCT.