Recovery of Tendon Characteristics by Inhibition of Aberrant Differentiation of Tendon-Derived Stem Cells from Degenerative Tendinopathy.

The inhibition of the aberrant differentiation of tendon-derived stem cells (TDSCs) is a major target for the regeneration of damaged tendon tissues, as tendinopathy can be caused by the aberrant differentiation of TDSCs. We investigated whether the possible aberrant differentiation of TDSCs can be prevented by using adequate inhibitors. TDSCs extracted from chemically induced tendinopathy and injury-with-overuse tendinopathy models were cultured with 18α-glycyrrhetinic acid (AGA) and T0070907 to block osteogenic differentiation and adipogenic differentiation, respectively. The optimal dose of AGA decreased the osteogenic-specific marker Runx2 (Runt-related transcription factor 2), and T0070907 blocked the adipogenic-specific marker peroxisome proliferator-activated receptor gamma (PPARγ) in mRNA levels. We also found that AGA induced tenogenic differentiation in mRNA levels. However, T0070907 did not affect the tenogenic differentiation and regenerative capacity of TDSCs. We expect that optimal doses of AGA and T0070907 can prevent tendinopathy by inhibiting osteogenic and adipogenic differentiation, respectively. In addition, AGA and T0070907 may play important roles in the treatment of tendinopathy.

Nervonic Acid Inhibits Replicative Senescence of Human Wharton's Jelly-Derived Mesenchymal Stem Cells.

Cellular senescence causes cell cycle arrest and promotes permanent cessation of proliferation. Since the senescence of mesenchymal stem cells (MSCs) reduces proliferation and multipotency and increases immunogenicity, aged MSCs are not suitable for cell therapy. Therefore, it is important to inhibit cellular senescence in MSCs. It has recently been reported that metabolites can control aging diseases. Therefore, we aimed to identify novel metabolites that regulate the replicative senescence in MSCs. Using a fecal metabolites library, we identified nervonic acid (NA) as a candidate metabolite for replicative senescence regulation. In replicative senescent MSCs, NA reduced senescence-associated ß-galactosidase positive cells, the expression of senescence-related genes, as well as increased stemness and adipogenesis. Moreover, in non-senescent MSCs, NA treatment delayed senescence caused by sequential subculture and promoted proliferation. We confirmed, for the first time, that NA delayed and inhibited cellular senescence. Considering optimal concentration, duration, and timing of drug treatment, NA is a novel potential metabolite that can be used in the development of technologies that regulate cellular senescence.

Self-assembled peptide-substance P hydrogels alleviate inflammation and ameliorate the cartilage regeneration in knee osteoarthritis.

BACKGROUND: Self-assembled peptide (SAP)-substance P (SP) hydrogels can be retained in the joint cavity longer than SP alone, and they can alleviate inflammation and ameliorate cartilage regeneration in knee osteoarthritis (OA). We conducted a preclinical study using diverse animal models of OA and an in vitro study using human synoviocytes and patient-derived synovial fluids to demonstrate the effect of SAP-SP complex on the inflammation and cartilage regeneration. METHODS: Surgical induction OA model was prepared with New Zealand white female rabbits and chemical induction, and naturally occurring OA models were prepared using Dunkin Hartely female guinea pigs. The SAP-SP complex or control (SAP, SP, or saline) was injected into the joint cavities in each model. We performed micro-computed tomography (Micro-CT) analysis, histological evaluation, immunofluorescent analysis, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay and analyzed the recruitment of intrinsic mesenchymal stem cells (MSCs), macrophage activity, and inflammatory cytokine in each OA model. Human synoviocytes were cultured in synovial fluid extracted from human OA knee joints injected with SAP-SP complexes or other controls. Proliferative capacity and inflammatory cytokine levels were analyzed. RESULTS: Alleviation of inflammation, inhibition of apoptosis, and enhancement of intrinsic MSCs have been established in the SAP-SP group in diverse animal models. Furthermore, the inflammatory effects on human samples were examined in synoviocytes and synovial fluid from patients with OA. In this study, we observed that SAP-SP showed anti-inflammatory action in OA conditions and increased cartilage regeneration by recruiting intrinsic MSCs, inhibiting progression of OA. CONCLUSIONS: These therapeutic effects have been validated in diverse OA models, including rabbits, Dunkin Hartley guinea pigs, and human synoviocytes. Therefore, we propose that SAP-SP may be an effective injectable therapeutic agent for treating OA. In this manuscript, we report a preclinical study of novel self-assembled peptide (SAP)-substance P (SP) hydrogels with diverse animal models and human synoviocytes and it displays anti-inflammatory effects, apoptosis inhibition, intrinsic mesenchymal stem cells recruitments and cartilage regeneration.

Telemedicine Protocols for the Management of Patients with Acute Spontaneous Intracerebral Hemorrhage in Rural and Medically Underserved Areas in Gangwon State: Recommendations for Doctors with Less Expertise at Local Emergency Rooms.

Previously, we reported the concept of a cloud-based telemedicine platform for patients with intracerebral hemorrhage (ICH) at local emergency rooms in rural and medically underserved areas in Gangwon state by combining artificial intelligence and remote consultation with a neurosurgeon. Developing a telemedicine ICH treatment protocol exclusively for doctors with less ICH expertise working in emergency rooms should be part of establishing this system. Difficulties arise in providing appropriate early treatment for ICH in rural and underserved areas before the patient is transferred to a nearby hub hospital with stroke specialists. This has been an unmet medical need for decade. The available reporting ICH guidelines are realistically possible in university hospitals with a well-equipped infrastructure. However, it is very difficult for doctors inexperienced with ICH treatment to appropriately select and deliver ICH treatment based on the guidelines. To address these issues, we developed an ICH telemedicine protocol. Neurosurgeons from four university hospitals in Gangwon state first wrote the guidelines, and professors with extensive ICH expertise across the country revised them. Guidelines and recommendations for ICH management were described as simply as possible to allow more doctors to use them easily. We hope that our effort in developing the telemedicine protocols will ultimately improve the quality of ICH treatment in local emergency rooms in rural and underserved areas in Gangwon state.

Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells.

BACKGROUND: In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related signaling pathways, four different microarray experiments were reanalyzed before radiotherapy. RESULTS: Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1) was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2). Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM) and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway. CONCLUSIONS: Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that integrin signaling via adhesion molecules could be a target for radiosensitization.

Geometry image super-resolution with AnisoCBConvNet architecture for efficient cloth modeling.

We propose an anisotropic constrained-boundary convolutional neural networks (hereafter, AnisoCBConvNet) that can stably express high-quality meshes without oscillation by applying super-resolution operations to low-resolution cloth meshes. As a training set for the neural network, we use a pair between simulation data of low resolution (LR) cloth and data obtained by applying the same simulation to high resolution (HR) cloth with increased quad mesh resolution of LR cloth. The actual data used for training are 2D geometry images converted from 3D meshes. The proposed AnisoCBConvNet is used to train an image synthesizer that converts LR geometry images to HR geometry images. In particular, by controlling the weights anisotropically near the boundary, the problem of surface wrinkling caused by oscillation is alleviated. When the HR geometry image obtained through AnisoCBConvNet is converted back to the HR cloth mesh, details including wrinkles are expressed better than the input cloth mesh. In addition, our results improved the noise problem in the existing geometry image approach. We tested AnisoCBConvNet-based super-resolution in various simulation scenarios, and confirmed stable and efficient performance in most of the results. By using our method, it will be possible to effectively produce CG VFX created using high-quality cloth simulation in games and movies.

Wharton's Jelly-Derived Mesenchymal Stem Cells with High Aurora Kinase A Expression Show Improved Proliferation, Migration, and Therapeutic Potential.

Mesenchymal stem cells (MSCs) are effective therapeutic agents that contribute to tissue repair and regeneration by secreting various factors. However, donor-dependent variations in MSC proliferation and therapeutic potentials result in variable production yields and clinical outcomes, thereby impeding MSC-based therapies. Hence, selection of MSCs with high proliferation and therapeutic potentials would be important for effective clinical application of MSCs. This study is aimed at identifying the upregulated genes in human Wharton's jelly-derived MSCs (WJ-MSCs) with high proliferation potential using mRNA sequencing. Aurora kinase A (AURKA) and dedicator of cytokinesis 2 (DOCK2) were selected as the upregulated genes, and their effects on proliferation, migration, and colony formation of the WJ-MSCs were verified using small interfering RNA (siRNA) techniques. mRNA expression levels of both the genes were positively correlated with the proliferation capacity of WJ-MSCs. Moreover, AURKA from human WJ-MSCs regulated the antiapoptotic effect of skeletal muscle cells by upregulating the chemokine (C motif) ligand (XCL1); this was further confirmed in the mdx mouse model. Taken together, the results indicated that AURKA and DOCK2 can be used as potential biomarkers for proliferation and migration of human WJ-MSCs. In particular, human WJ-MSCs with high expression of AURKA might have therapeutic efficacy against muscle diseases, such as Duchenne muscular dystrophy (DMD).

Wharton's Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499.

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3-5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFßR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic "off-the-shelf" cellular products for the treatment of DMD and possibly other muscle disorders.

Conservative management of traumatic acute intramural hematoma of duodenal 2nd and 3rd portion: A case report and review of literature.

Traumatic intramural duodenal hematoma (IMDH) is a rare disease occurring usually in children. The treatment modality of traumatic IMDH varies according to clinical manifestations. We had a case of a young man who had traumatic IMDH and treated nonoperatively. He had 3 weeks of conservative care and has been discharged, with follow up abdominal CT scan showing complete resolution of the hematoma. In conclusion, patient with traumatic acute intramural hematoma of duodenal 2nd and 3rd portion have excellent clinical outcomes with conservative therapy.

Consumer use of publicly released hospital performance information: assessment of the National Hospital Evaluation Program in Korea.

OBJECTIVE: To assess the extent of consumer use of publicly released hospital performance information by the National Health Evaluation Program (HEP) in Korea. DESIGN: A questionnaire survey with 385 outpatients visiting four general hospitals in Seoul. MAIN OUTCOME MEASURES: The consumer use of performance information was assessed by the consumers' intention to: (1) recommend hospitals with good performance reports, according to HEP, to their relatives; (2) switch to other hospitals with a better performance and (3) keep the performance report for future use. RESULTS: Overall, 52-75% of the respondents expressed their intention to use the hospital performance information. Logistic regression analysis results showed that people would use the performance information if they considered HEP to be effective in improving the quality of health care and the performance reports to be trustworthy and useful in choosing hospitals. CONCLUSION: This study provides evidence that consumers in a health care system with few restrictions for provider choice, such as in Korea, have a high potential to utilize the provider performance information in their decision making. If public use of the performance information becomes common, policy makers should acknowledge the critical value of the quality of the performance report in order to avoid misleading consumers.

Effect of platelet-rich plasma on the degenerative rotator cuff tendinopathy according to the compositions.

BACKGROUND: There are controversies about platelet-rich plasma (PRP) as an established treatment option for rotator cuff (RC) tendinopathy. The purpose of the study was to find the relation of cellular component with clinical efficacy in RC tendinopathy and to find the composition of PRP in treating RC tendinopathy. METHODS: A total 30 patients were recruited and divided into PRP and control groups. In the PRP group, 2 ml of PRP solution was injected to the hypoechoic lesion of degenerative supraspinatus via 22-gauge syringe with peppering technique. Patients in the control group were taught rotator cuff strengthening exercises. American Shoulder and Elbow Surgeons (ASES), Constant-Murley score, and numeric rating scale (NRS) were measured before, 6 weeks after, 12 weeks after, and 24 weeks after the procedure. PRP compositions were analyzed using the 1 ml of PRP solution. RESULTS: Linear regression analysis showed no significant difference of ASES and Constant-Murley scores between the groups at 6 weeks (P = 0.582 and 0.258) and at 12 weeks (P = 0.969 and 0.795) but showed a significant difference at 24 weeks (P = 0.050 and 0.048). Independent t test showed significant group difference of NRS at 6 weeks (P = 0.031) but not at 12 and 24 weeks (P = 0.147 and 0.935). 5.19 pg/ml in IL-1ß and 61.79 µg/ml in TGF-ß1 were acquired as cutoff values to predict meaningful improvement. The PRP subgroup above IL-1ß or TGF-ß1 cutoff value showed significant differences in all clinical outcomes compared with the exercise group while the PRP subgroup below the cutoff value showed no significant differences in linear regression analysis. CONCLUSIONS: Our study can help to find the optimal PRP condition and to enhance the effect of PRP on RC tendinopathy. TRIAL REGISTRATION: All the patients were registered in our Institutional Ethics Committee (approval number 2014-05-009).

Effects of bone marrow aspirate concentrate and platelet-rich plasma on patients with partial tear of the rotator cuff tendon.

BACKGROUND: We compared the clinical course of rotator cuff tears between rotator cuff exercise and bone marrow aspirate concentration (BMAC)-platelet rich plasma (PRP) injection to identify the therapeutic effects of BMAC-PRP on partial tear of the rotator cuff tendon. METHODS: Twenty-four patients with partial tear of the rotator cuff tendon participated in this study. Twelve patients underwent extraction of BMACs and PRP and received the injection of BMAC-PRP at the tear site under ultrasound guidance. Twelve patients in the control group were asked to perform the rotator cuff exercise for 3 months. Visual analog scale (VAS) and manual muscle test (MMT) scores of the supraspinatus muscle were measured, and the American Shoulder and Elbow Surgeons (ASES) score was recorded before, 3 weeks, and 3 months after injection. Tear size was measured by the greatest longitudinal tear length. RESULTS: The change in the VAS differed between groups at 3 months (P = 0.039) but not at 3 weeks (P = 0.147). The ASES scores in the BMAC-PRP group changed from 39.4 ± 13.0 to 54.5 ± 11.5 at 3 weeks and 74.1 ± 8.5 at 3 months while those in the control group changed from 45.9 ± 12.4 to 56.3 ± 12.3 at 3 weeks (P = 0.712) and 62.2 ± 12.2 at 3 months (P = 0.011). The tear size decreased at 3 weeks or 3 months after the BMAC-PRP injection but was not significantly different from that in the control group. CONCLUSIONS: BMAC-PRP improved pain and shoulder function in patients with partial tear of the rotator cuff tendon. TRIAL REGISTRATION: The patients were registered in the institutional board registry of Samsung Medical Center (registry number 2014-07-173 ).

Nanotopographic cues and stiffness control of tendon-derived stem cells from diverse conditions.

BACKGROUND: Tendon-derived stem cells (TDSCs) are key factors associated with regeneration and healing in tendinopathy. The aim of this study was to investigate the effects of mechanical stiffness and topographic signals on the differentiation of TDSCs depending on age and pathological conditions. MATERIALS AND METHODS: We compared TDSCs extracted from normal tendon tissues with TDSCs from tendinopathic Achilles tendon tissues of Sprague Dawley rats in vitro and TDSCs cultured on nanotopographic cues and substrate stiffness to determine how to control the TDSCs. The tendinopathy model was created using a chemical induction method, and the tendon injury model was created via an injury-and-overuse method. Norland Optical Adhesive 86 (NOA86) substrate with 2.48 GPa stiffness with and without 800 nm-wide nanogrooves and a polyurethane substrate with 800 nm-wide nanogrooves were used. RESULTS: TDSCs from 5-week-old normal tendon showed high expression of type III collagen on the flat NOA86 substrate. In the 15-week normal tendon model, expression of type III collagen was high in TDSCs cultured on the 800 nm NOA86 substrates. However, in the 15-week tendon injury model, expression of type III collagen was similar irrespective of nanotopographic cues or substrate stiffness. The expression of type I collagen was also independent of nanotopographic cues and substrate stiffness in the 15-week normal and tendon injury models. Gene expression of scleraxis was increased in TDSCs cultured on the flat NOA86 substrate in the 5-week normal tendon model (P=0.001). In the 15-week normal tendon model, scleraxis was highly expressed in TDSCs cultured on the 800 nm and flat NOA86 substrate (P=0.043). However, this gene expression was not significantly different between the substrates in the 5-week tendinopathy and 15-week tendon injury models. CONCLUSION: Development and maturation of tendon are enhanced when TDSCs from normal tendons were cultured on stiff surface, but not when the TDSCs came from pathologic models. Therapeutic applications of TDSCs need to be flexible based on tendon age and tendinopathy.

Prediction of persistent hemodynamic depression after carotid angioplasty and stenting using artificial neural network model.

OBJECTIVES: To assess and compare predictive factors for persistent hemodynamic depression (PHD) after carotid artery angioplasty and stenting (CAS) using artificial neural network (ANN) and multiple logistic regression (MLR) or support vector machines (SVM) models. PATIENTS AND METHODS: A retrospective data set of patients (n=76) who underwent CAS from 2007 to 2014 was used as input (training cohort) to a back-propagation ANN using TensorFlow platform. PHD was defined when systolic blood pressure was less than 90mmHg or heart rate was less 50 beats/min that lasted for more than one hour. The resulting ANN was prospectively tested in 33 patients (test cohort) and compared with MLR or SVM models according to accuracy and receiver operating characteristics (ROC) curve analysis. RESULTS: No significant difference in baseline characteristics between the training cohort and the test cohort was observed. PHD was observed in 21 (27.6%) patients in the training cohort and 10 (30.3%) patients in the test cohort. In the training cohort, the accuracy of ANN for the prediction of PHD was 98.7% and the area under the ROC curve (AUROC) was 0.961. In the test cohort, the number of correctly classified instances was 32 (97.0%) using the ANN model. In contrast, the accuracy rate of MLR or SVM model was both 75.8%. ANN (AUROC: 0.950; 95% CI [confidence interval]: 0.813-0.996) showed superior predictive performance compared to MLR model (AUROC: 0.796; 95% CI: 0.620-0.915, p<0.001) or SVM model (AUROC: 0.885; 95% CI: 0.725-0.969, p<0.001). CONCLUSIONS: The ANN model seems to have more powerful prediction capabilities than MLR or SVM model for persistent hemodynamic depression after CAS. External validation with a large cohort is needed to confirm our results.

Effect of Bone Marrow Aspirate Concentrate-Platelet-Rich Plasma on Tendon-Derived Stem Cells and Rotator Cuff Tendon Tear.

Bone marrow aspirate concentrates (BMACs) and platelet-rich plasma (PRP) are good sources to control the differentiation of tendon-derived stem cells (TDSCs), but there has been no study about the effect of the BMAC-PRP complex on TDSCs and tendinopathy. The aim of this study was to investigate the effect of BMAC-PRP on the TDSCs and to find the therapeutic effect of BMAC-PRP on the rotator cuff tendon tear. The chondrogenic and osteogenic potential of TDSCs decreased, but the adipogenic potential of TDSCs revealed no significant difference when they were cocultured with BMAC-PRP. Cell proliferation was significantly greater in TDSCs cocultured with BMAC-PRP than in TDSCs. The degree of wound closure (percentage) was different between TDSCs and TDSCs with BMAC-PRP. There was no significant difference in expression of collagen type I and type III in immunocytochemical staining in the presence of BMAC-PRP. Initial visual analog scale (VAS) score was 5.8 ± 1.9, which changed to 5.0 ± 2.3 at 3 weeks and 2.8 ± 2.3 at 3 months after the BMAC-PRP injection (p < 0.01). The American Shoulder Elbow Surgeon score changed from 39.4 ± 13.0 at baseline to 52.9 ± 22.9 at 3 weeks and 71.8 ± 19.7 at 3 months after the injection (p < 0.01). The initial torn area of the rotator cuff tendon was 30.2 ± 24.5 mm2, and this area was reduced to 22.5 ± 18.9 mm2 at 3 months, but the change was not significant (p > 0.05). The data indicate that BMAC-PRP enhances the proliferation and migration of TDSCs and prevents the aberrant chondrogenic and osteogenic differentiation of TDSCs, which might provide a mechanistic basis for the therapeutic benefits of BMAC-PRP for rotator cuff tendon tear.

Therapeutic effects of neuropeptide substance P coupled with self-assembled peptide nanofibers on the progression of osteoarthritis in a rat model.

Osteoarthritis (OA) is a progressively degenerative disease that is accompanied by articular cartilage deterioration, sclerosis of the underlying bone and ultimately joint destruction. Although therapeutic medicine and surgical treatment are done to alleviate the symptoms of OA, it is difficult to restore normal cartilage function. Mesenchymal stem cell (MSC) transplantation is one of the therapeutic trials for treating OA due to its potential, and many researchers have recently reported on the effects of MSCs associated with OA therapy. However, cell transplantation has limitations including low stem cell survival rates, limited stem cell sources and long-term ex vivo culturing. In this study, we evaluated the efficacy of neuropeptide substance P coupled with self-assembled peptide hydrogels in a rat knee model to prevent OA by mobilizing endogenous MSCs to the defect site. To assess the effect of the optimal concentration of SP, varying concentrations of bioactive peptides (substance P (SP) with self-assembled peptide (SAP)) were used to treat OA. OA was induced by unilateral anterior cruciate and medial collateral ligament transection of the knee joints. Forty rats were randomly allocated into 5 groups: SAP-0.5SP (17.5 µg of SP), SAP-SP group (35 µg of SP), SAP-2SP group (70 µg of SP), SAP-SP-MSC group, and control group. At 2 weeks post-surgical induction of OA, each mixture was injected into the joint cavity of the left knee. Histologic examination, immunofluorescence staining, quantitative real time-polymerase chain reaction and micro-computed tomography analysis were done at 6 weeks post-surgical induction. As shown by our results, the SAP-SP hydrogel accelerated tissue regeneration by anti-inflammatory modulation shown by an anti-inflammation test using dot-blot in vitro. Additionally, the treatment of OA in the SAP-SP group showed markedly improved cartilage regeneration through the recruitment of MSCs. Thus, these cells could be infiltrating into the defect site for the regeneration of OA defects. In addition, from the behavioral studies on the rats, the number of rears significantly increased 2 and 4 weeks post-injection in all the groups. Our results show that bioactive peptides may have clinical potential for inhibiting the progression of OA as well as its treatment by recruiting autologous stem cells without cell transplantation.