Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Early Intervention Strategies For Acute Cartilage Injury Ex-vivo Porcine Knee Model

Objectives: Traumatic injury to cartilage has been shown to lead to Post-Traumatic Osteoarthritis (PTOA). The acute phase of PTOA is characterized with increased expression of aggrecanases and inflammatory cytokines in the injured cartilage. Early intervention therapies aim to be administered during the acute phase for the prevention of PTOA development. Our objective was to determine the effect of Interleukin Receptor Antagonist Protein (IRAP), Hyaluronan (HA), and Mesenchymal Stem Cell (MSC) treatment as early intervention strategies by examining the changes in microRNA (miRNA) and mRNA expression in cartilage at 8 hours after impact injury. Methods: Custom impact device was used to create replicable injury ex-vivo to intact porcine knee joint. Injury was caused by dropping a 10kg weight one time from 1m directly above the knee in extension. One hour after impact 20µg/mL IRAP, 15mg/mL HA (MW 1.9 MDa), or 5x106 P4 MSCs in 1mL saline was intra-articularly injected. Control legs (no injury) and injury legs (injury, no treatment) received saline injection. At 8 hours post-injury, cartilage samples were harvested for genetic expression analysis. Genetic expression of miR-140 (regulates ADAMTS-5) miR-125b (regulates ADAMTS-4), ADAMTS-4, ADAMTS-5, MMP-3, IL-1β, and TNF-α were analyzed by RT-PCR. Groups were compared by one-way analysis of variance followed by Tukey's post-hoc test. A P-value <0.05 was considered significant (N=3 pigs/group). Results: After IRAP treatment, expressions of ADAMTS-4, ADAMTS-5, IL-1β, and TNF-α in cartilage were significantly down-regulated from injury group (all P<0.001) (Figure 1A). Expressions of miR-140 and miR-125b were significantly up-regulated after IRAP treatment as compared to control and injury (both P<0.05 to control, P<0.001 to injury) (Figure 1B). MiR-27b expression was significantly up-regulated after treatment as compared to control (P<0.001). After HA treatment, expressions of ADAMTS-4, ADAMTS-5, MMP-3, and TNF-α were significantly up-regulated from control (all P<0.05) (Figure 1C). Expression of IL-1β after HA treatment tended for up-regulation (P=0.15). Expressions of miR-125b, miR-140, and miR-27b were significantly up-regulated after HA treatment as compared to control and injury groups (all P<0.05) (Figure 1D). After MSC treatment, relative expressions of ADAMTS-4, ADAMTS-5, and IL-1β were significantly up-regulated (all P<0.01) as compared to controls (Figure 1E). Expression of TNF-α after treatment tended for up-regulation (P=0.14). No significant differences were found in miRNA expressions after MSC treatment (Figure 1F). Conclusion: The results show that IRAP, HA, and MSC treatment administered during acute phase of cartilage injury each have a distinct effect on catabolic and inflammatory regulation. HA and MSC treatment did not have significant effect on the inflammatory and catabolic response of injured cartilage within the first 8 hours of injury. However, the beneficial effects of HA may take place beyond the acute time frame as suggested by increased miR-125b and miR-140 expressions after treatment. IRAP treatment increased expressions of miR-140, -125b, and -27b in cartilage, indicating increased inhibition of their respective enzymes, as shown by reduced aggrecanase and inflammatory genetic expressions. Clinically, these findings support the potential of IRAP and HA treatment as early intervention strategies for the prevention of cartilage degeneration after impact injury

Cyclic compression maintains viability and induces chondrogenesis of human mesenchymal stem cells in fibrin gel scaffolds

Mechanical loading has long been shown to modulate cartilage-specific extracellular matrix synthesis. With joint motion, cartilage can experience mechanical loading in the form of compressive, tensile or shearing load, and hydrostatic pressure. Recent studies have demonstrated the capacity of unconfined cyclic compression to induce chondrogenic differentiation of human mesenchymal stem cell (hMSC) in agarose culture. However, the use of a nonbiodegradable material such as agarose limits the applicability of these constructs. Of the possible biocompatible materials available for tissue engineering, fibrin is a natural regenerative scaffold, which possesses several desired characteristics including a controllable degradation rate and low immunogenicity. The objective of the present study was to determine the capability of fibrin gels for supporting chondrogenesis of hMSCs under cyclic compression. To optimize the system, three concentrations of fibrin gel (40, 60, and 80 mg/mL) and three different stimulus frequencies (0.1, 0.5, and 1.0 Hz) were used to examine the effects of cyclic compression on viability, proliferation and chondrogenic differentiation of hMSCs. Our results show that cyclic compression (10% strain) at frequencies >0.5 Hz and gel concentration of 40 mg/mL fibrinogen appears to maintain cellular viability within scaffolds. Similarly, variations in gel component concentration and stimulus frequency can be modified such that a significant chondrogenic response can be achieved by hMSC in fibrin constructs after 8 h of compression spread out over 2 days. This study demonstrates the suitability of fibrin gel for supporting the cyclic compression-induced chondrogenesis of mesenchymal stem cells

Isolation of Pluripotent Neural Crest-Derived Stem Cells from Adult Human Tissues by Connexin-43 Enrichment

Identification and isolation of pluripotent stem cells in adult tissues represent an important advancement in the fields of stem cell biology and regenerative medicine. For several years, research has been performed on the identification of biomarkers that can isolate stem cells residing in neural crest (NC)-derived adult tissues. The NC is considered a good model in stem cell biology as cells from it migrate extensively and contribute to the formation of diverse tissues in the body during organogenesis. Migration of these cells is modulated, in part, by gap junction communication among the cell sheets. Here we present a study in which, selection of connexin 43 (Cx43) expressing cells from human adult periodontal ligament yields a novel pluripotent stem cell population. Cx43 + periodontal ligament stem cells express pluripotency-associated transcription factors OCT4, Nanog, and Sox2, as well as NC-specific markers Sox10, p75, and Nestin. When injected in vivo into an immunodeficient mouse model, these cells were capable of generating teratomas with tissues from the three embryological germ layers: endoderm, mesoderm, and ectoderm. Furthermore, the cells formed mature structures of tissues normally arising from the NC during embryogenesis such as eccrine sweat glands of the human skin, muscle, neuronal tissues, cartilage, and bone. Immunohistochemical analysis confirmed the human origin of the neoplastic cells as well as the ectodermal and endodermal nature of some of the structures found in the tumors. These results suggest that Cx43 may be used as a biomarker to select and isolate the remnant NC pluripotent stem cells from adult human tissues arising from this embryological structure. The isolation of these cells through routine medical procedures such as wisdom teeth extraction further enhances their applicability to the regenerative medicine field

Measurement of ATP-Induced Membrane Potential Changes in IVD cells

Extracellular adenosine-5'-triphosphate (ATP) triggers biological responses in a wide variety of cells and tissues and activates signaling cascades that affect cell membrane potential and excitability. It has been demonstrated that compressive loading promotes ATP production and release by intervertebral disc (IVD) cells, while a high level of extracellular ATP accumulates in the nucleus pulposus (NP) of the IVD. In this study, a noninvasive system was developed to measure ATP-induced changes in the membrane potential of porcine IVD cells using the potential sensitive dye di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate (di-8-ANEPPS).The responses of NP and annulus fibrosus (AF) cells to ATP were examined in monolayer and 3-dimensional cultures. It was found that the pattern and magnitude of membrane potential change in IVD cells induced by extracellular ATP depended on cell type, culture condition, and ATP dose. In addition, gene expression of P2X purinergic receptor was found in both cell types. Inhibition of the ATP-induced response by pyridoxalphosphate-6-azophenyl-2', 4'-disulfonate (PPADS), a non-competitive inhibitor of P2 receptors, suggests that ATP may modulate the biological activities of IVD cells via P2 purinergic receptors

Characterization and Therapeutic Uses of Exosomes: A New Potential Tool in Orthopedics

In recent years, regenerative medicine has directed its interests onto the use of stem cells to heal human tissues. One specific class of cells that has been used in this field of research is mesenchymal stem cells (MSCs). Because of difficulties with the usage of whole stem cells, researchers have turned to an alternative, the secretome of the MSCs. In recent years, research has explored numerous aspects of the MSC secretome, especially the most promising aspect, exosomes. This review explores a variety of interests in exosomes including the classification and molecular composition of exosomes, mechanisms for exosome isolation, and the various biological functions of exosomes. As more is discovered about the exosomes, their different diagnostic and therapeutic uses in the medical field have also been explored. A new field attempting to exploit the exosomes in clinical practice is orthopedics. Although a significant deal of research has been carried out, even more is being discovered to allow utilization of the exosomes in clinical practice

Mechanical loading affects the energy metabolism of intervertebral disc cells

Research has shown that mechanical loading affects matrix biosynthesis of intervertebral disc (IVD) cells; however, the pathway(s) to this effect is currently unknown. Cellular matrix biosynthesis is an energy demanding process. The objective of this study was to investigate the effects of static and dynamic compressive loading on energy metabolism of IVD cells. Porcine annulus fibrosus (AF) and nucleus pulposus (NP) cells seeded in 2% agarose were used in this experiment. Experimental groups included 15% static compression and 0.1 and 1 Hz dynamic compression at 15% strain magnitude for 4 h. ATP, lactate, glucose, and nitric oxide (NO) contents in culture media, and ATP content in cell-agarose construct were measured using biochemical assays. While the total ATP content of AF cells was promoted by static and dynamic loading, only 1 Hz dynamic loading increased total ATP content of NP cells. Increases in lactate production and glucose consumption of AF cells suggest that ATP production via glycolysis is promoted by dynamic compression. ATP release and NO production of AF and NP cells were significantly increased by dynamic loading. Thus, this study clearly illustrates that static and dynamic compressive loading affect IVD cell energy production while cellular responses to mechanical loading were both cell type and compression type dependent

Osteogenic differentiation of stem cells derived from human periodontal ligaments and pulp of human exfoliated deciduous teeth

Multipotent stem cells derived from periodontal ligaments (PDLSC) and pulp of human exfoliated deciduous teeth (SHED) represent promising cell sources for bone regeneration. Recent studies have demonstrated that retinoic acid (RA) and dexamethasone (Dex) induce osteogenesis of postnatal stem cells. The objective of this study was to examine the effects of RA and Dex on the proliferation and osteogenic differentiation of SHED and PDLSC and to compare the osteogenic characteristics of SHED and PDLSC under RA treatment. SHED and PDLSC were treated with serum-free medium either alone or supplemented with RA or Dex for 21 days. The proliferation of SHED and PDLSC was significantly inhibited by both RA and Dex. RA significantly upregulated gene expression and the activity of alkaline phosphatase in SHED and PDLSC. Positive Alizarin red and von Kossa staining of calcium deposition was seen on the RA-treated SHED and PDLSC after 21 days of culture. The influences of RA on the osteogenic differentiation of SHED and PDLSC were significantly stronger than with Dex. Supplementation with insulin enhanced RA-induced osteogenic differentiation of SHED. Thus, RA is an effective inducer of osteogenic differentiation of SHED and PDLSC, whereas RA treatment in combination with insulin supplementation might be a better option for inducing osteogenic differentiation. Significantly higher cell proliferation of PDLSC results in greater calcium deposition after 3-week culture, suggesting that PDLSC is a better osteogenic stem cell source. This study provides valuable information for efficiently producing osteogenically differentiated SHED or PDLSC for in vivo bone regeneration