Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats

Intensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the Notch2 signalling pathway in MTX chemotherapy-induced bone micro-vasculature impairment. Gene expression, histological and micro-computed tomography (micro-CT) analyses revealed that MTX-induced micro-vasculature dilation and regression is associated with the induction of Notch2 activity in endothelial cells and increased production of inflammatory cytokine tumour necrosis factor alpha (TNFα) from osteoblasts (bone forming cells) and bone marrow cells. Blockade of Notch2 by a neutralising antibody ameliorated MTX adverse effects on bone micro-vasculature, both directly by supressing Notch2 signalling in endothelial cells and indirectly via reducing TNFα production. Furthermore, in vitro studies using rat bone marrow-derived endothelial cell revealed that MTX treatment induces Notch2/Hey1 pathway and negatively affects their ability in migration and tube formation, and Notch2 blockade can partially protect endothelial cell functions from MTX damage.Yaser Peymanfar, Yu-Wen Su, Mohammadhossein Hassanshahi and Cory J. Xia

Regular supplementation with resveratrol improves bone mineral density in postmenopausal women: a randomised, placebo-controlled trial

Abstract not available.Rachel HX Wong, Jay Jay Thaung Zaw, Cory J Xian, and Peter RC How

Roles of microRNAs in osteogenesis or adipogenesis differentiation of bone marrow stromal progenitor cells

Bone marrow stromal cells (BMSCs) are multipotent cells which can differentiate into chondrocytes, osteoblasts, and fat cells. Under pathological stress, reduced bone formation in favour of fat formation in the bone marrow has been observed through a switch in the differentiation of BMSCs. The bone/fat switch causes bone growth defects and disordered bone metabolism in bone marrow, for which the mechanisms remain unclear, and treatments are lacking. Studies suggest that small non-coding RNAs (microRNAs) could participate in regulating BMSC differentiation by disrupting the post-transcription of target genes, leading to bone/fat formation changes. This review presents an emerging concept of microRNA regulation in the bone/fat formation switch in bone marrow, the evidence for which is assembled mainly from in vivo and in vitro human or animal models. Characterization of changes to microRNAs reveals novel networks that mediate signalling and factors in regulating bone/fat switch and homeostasis. Recent advances in our understanding of microRNAs in their control in BMSC differentiation have provided valuable insights into underlying mechanisms and may have significant potential in development of new therapeutics.Ya-Li Zhang, Liang Liu, Yaser Peymanfar, Paul Anderson and Cory J. Xia

Phase transition in the transverse Ising model using the extended coupled-cluster method

The phase transition present in the linear-chain and square-lattice cases of the transverse Ising model is examined. The extended coupled cluster method (ECCM) can describe both sides of the phase transition with a unified approach. The correlation length and the excitation energy are determined. We demonstrate the ability of the ECCM to use both the weak- and the strong-coupling starting state in a unified approach for the study of critical behavior.Comment: 10 pages, 7 eps-figure

FGF-2 gene polymorphism in osteoporosis among Guangxi’s Zhuang Chinese

Osteoporosis is a complex multifactorial disorder of gradual bone loss and increased fracture risk. While previous studies have shown the importance of many genetic factors in determining peak bone mass and fragility fractures and in suggesting involvement of fibroblast growth factor-2 (FGF-2) in bone metabolism and bone mass, the relationship of FGF-2 genetic diversity with bone mass/osteoporosis has not yet been revealed. The current study investigated the potential relevance of FGF-2 gene polymorphism in osteoporosis among a Zhuang ethnic Chinese cohort of 623, including 237 normal bone mass controls, 227 osteopenia, and 159 osteoporosis of different ages. Bone density was examined by calcaneus ultrasound attenuation measurement, and single nucleotide polymorphisms (SNPs) and linkage disequilibrium analyses were performed on five SNP loci of FGF-2 gene. Significant differences were found in bone mass in males between the 45-year-old and ≥70-year-old groups (p 0.8, and r² > 0.33). Thus, the rs308442 locus of FGF-2 gene is closely correlated to osteoporosis in this Zhuang ethnic Chinese cohort, and the TA may be the risk genotype of osteoporosis.Xiaoyun Bin, Chaowen Lin, Xiufeng Huang, Qinghui Zhou, Liping Wang and Cory J. Xia

Analyses of fracture line distribution in intra-articular distal radius fractures

PURPOSE:To assess the association between the fracture line distribution and the location of comminution in intra-articular distal radius fractures by building fracture mapping. PATIENTS/METHODS:Forty cases with intra-articular fractures of distal radius were enrolled in the current prospective clinical study. Fracture lines and comminution zones were identified by reduced three-dimensional computed tomography reconstructions and then graphically superimposed onto a standard template to create two-dimensional fracture maps, followed by the conversion into heating maps. Based on qualitative descriptive fracture mapping analyses, the patterns of intra-articular distal radius fractures were determined. RESULTS:It was observed that the highest fracture line intensity was located as an inverted "T" shape zone in the dorsal aspect of the joint with high incidence of fractures and the prominently intense color in heat mapping. The keystone projected area, the radial styloid process and the metacarpal radial side articular surface were found to be the least involved parts of the fracture. According to the mapping of the number and distribution of fracture lines, a new classification method for intra-articular fractures of the distal radius was redefined. Different surgical approaches and internal fixation techniques were proposed for different types. In this paper, we retrospectively compared the preoperative X-ray findings between different types. Based on the preoperative X-ray prediction, the distal intra-articular radius fractures were classified, so as to develop effective surgical strategies. In this study, a new surgical approach was attempted, but due to the lack of evidence-based evidence, long-term postoperative complications and hand function should be further evaluated. CONCLUSION:This study redefines a new method for the classification of intra-articular fractures of the distal radius, which allows doctors to have a clearer understanding of the characteristics of distal radius fractures. Moreover, the application value in fracture diagnosis is more significant, and the best surgical approach is selected for different types.Xin Zhang, Yinqi Zhang, Jian Fan, Feng Yuan, Qian Tang, Cory J. Xia

Tumor necrosis factor superfamily 15 promotes lymphatic metastasis via upregulation of vascular endothelial growth factor-C in a mouse model of lung cancer

Lymphatic metastasis is facilitated by lymphangiogenic growth factor vascular endothelial growth factor-C (VEGFC) that is secreted by some primary tumors. We previously identified tumor necrosis factor superfamily 15 (TNFSF15), a blood vascular endothelium-derived cytokine, in lymphatic endothelial cells, as a key molecular modulator during lymphangiogenesis. However, the effect of TNFSF15 on tumor lymphatic metastasis and the underlying molecular mechanisms remain unclear. We report here that TNFSF15, which is known to inhibit primary tumor growth by suppressing angiogenesis, can promote lymphatic metastasis through facilitating lymphangiogenesis in tumors. Mice bearing tumors induced by A549 cells stably overexpressing TNFSF15 exhibited a significant increase in densities of lymphatic vessels and a marked enhancement of A549 tumor cells in newly formed lymphatic vessels in the primary tumors as well as in lymph nodes. Treatment of A549 cells with TNFSF15 results in upregulation of VEGFC expression, which can be inhibited by siRNA gene silencing of death domain-containing receptor-3 (DR3), a cell surface receptor for TNFSF15. In addition, TNFSF15/DR3 signaling pathways in A549 cells include activation of NF-κB during tumor lymphangiogenesis. Our data indicate that TNFSF15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor-bearing mice. This finding also suggests that TNFSF15 may have potential as an indicator for prognosis evaluation.Tingting Qin, Dingzhi Huang, Zhujun Liu, Xiaoling Zhang, Yanan Jia, Cory J. Xian, Kai L

Short-term hypoxia accelerates bone loss in ovariectomized rats by suppressing osteoblastogenesis but enhancing osteoclastogenesis

BACKGROUND: Although it has been reported that hypoxic exposure can attenuate hypertension, heart disease, diabetes, and some other diseases, effects of hypoxia on osteoporosis are still unknown. MATERIAL AND METHODS: The current study investigated whether short-term hypoxic exposure (in comparison with normoxic conditions) affects bone metabolism in normal or ovariectomized (OVX) adult female rats in an vivo study. Micro-computed tomography bone volume/structural analyses, histological examination, and serum bone turnover biochemical assays were used. In addition, the expressions of some associated major regulatory molecules were measured in osteoblastic cultures. RESULTS: While the 14-day hypoxic exposure did not change the bone-remodeling process in normal adult female rats, it decreased bone volume, osteoclast density, and serum bone formation marker (alkaline phosphatase) level, but increased osteoclast density and serum bone resorption marker (C-telopeptide of collagen) level in OVX rats. The bone marrow adipocyte number and serum fatty acid binding protein-4 level were increased in OVX-hypoxic rats compared with OVX-normoxic rats. Consistently, in human MG-63 osteoblastic cultures, the hypoxic condition suppressed protein expression of osteogenic transcriptional factors Runx2 and osterix, elevated protein expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand, but reduced that of osteoclastogenic inhibitor osteoprotegerin. CONCLUSIONS: Our results suggest that, although no change occurred in the bone-remodeling process in normal adult female rats after hypoxic exposure, under the estrogen-deficient osteoporotic condition, the hypoxic condition can alter the bone microenvironment so that it may further impair osteoblastic differentiation and enhance osteoclastic formation, and thus reduce bone formation, enhance bone resorption, and accelerate bone loss.Guixin Wang, Jia Wang, Dawei Sun, Jingyi Xin, Liping Wang, Dong Huang, Weichi Wu, Cory J. Xia

An enhanced staining method K-B-2R staining for three-dimensional nerve reconstruction

BACKGROUND:Three-dimensional (3D) reconstruction of human peripheral nerves, as a useful tool to understand the nerve internal information and functional basis, has become an important area of research in the peripheral nerve field. METHODS:In this study, we proposed a two-dimensional (2D) Karnovsky-Roots toluidine blue ponceau 2R (K-B-2R) staining method based upon conventional Karnovsky-Roots staining. It significantly improved the ability to display nerve fascicles, motor and sensory nerve fiber textures. In this method, Karnovsky-Roots staining was carried out, followed by toluidine blue counterstain and ponceau 2R counterstain. RESULTS:Comparisons were conducted between the three methods in staining of median nerve sections, which showed similar distribution characters in acetylcholinesterase-positive sites. The additional counterstaining did not change the basis of Karnovsky-Roots staining. However, the resulting images from this new method significantly facilitated the subsequent 3D nerve reconstruction and 3D printing. CONCLUSIONS:These results show that the new staining method significantly enhanced the display qualities of nerve fascicle edges and fiber textures of motor and sensory nerves and facilitated 3D nerve reconstruction.Peng Luo, Jianghui Dong, Jian Qi, Yi Zhang, Xiaolin Liu, Yingchun Zhong, Cory J. Xian and Liping Wan

Tidal Dwarf Galaxies at Intermediate Redshifts

We present the first attempt at measuring the production rate of tidal dwarf galaxies (TDGs) and estimating their contribution to the overall dwarf population. Using HST/ACS deep imaging data from GOODS and GEMS surveys in conjunction with photometric redshifts from COMBO-17 survey, we performed a morphological analysis for a sample of merging/interacting galaxies in the Extended Chandra Deep Field South and identified tidal dwarf candidates in the rest-frame optical bands. We estimated a production rate about 1.4 {\times} 10^{-5} per Gyr per comoving volume for long-lived TDGs with stellar mass 3 {\times} 10^{8-9} solar mass at 0.5<z<1.1. Together with galaxy merger rates and TDG survival rate from the literature, our results suggest that only a marginal fraction (less than 10%) of dwarf galaxies in the local universe could be tidally-originated. TDGs in our sample are on average bluer than their host galaxies in the optical. Stellar population modelling of optical to near-infrared spectral energy distributions (SEDs) for two TDGs favors a burst component with age 400/200 Myr and stellar mass 40%/26% of the total, indicating that a young stellar population newly formed in TDGs. This is consistent with the episodic star formation histories found for nearby TDGs.Comment: 9 pages, 5 figures, Accepted for publication in Astrophysics & Space Scienc