Dysregulation of metalloproteinases in spinal ligament degeneration.

PURPOSE: Degenerative changes in the spinal ligaments, such as hypertrophy or ossification, are important pathophysiological mechanisms of secondary spinal stenosis and neurological compression. Extracellular matrix (ECM) remodeling is one of the major pathological changes in ligament degeneration, and in this remodeling, ECM proteinase-mediated degradation of elastin and collagen plays a vital role. Zinc-dependent endopeptidases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin-1 motifs (ADAMTSs) are key factors in ECM remodeling. This review aims to elucidate the underlying mechanisms of these metalloproteinases in the initiation and progression of spinal ligament degeneration. METHODS: We clarify current literature on the dysregulation of MMPs/ADAMs/ADAMTS and their endogenous inhibitors in degenerative spinal ligament diseases. In addition, some instructive information was excavated from the raw data of the relevant high-throughput analysis. RESULTS AND CONCLUSIONS: The dysregulation of metalloproteinases and their endogenous inhibitors may affect ligament degeneration by involving several interrelated processes, represented by ECM degradation, fibroblast proliferation, and osteogenic differentiation. Antagonists of the key targets of the processes may in turn ease ligament degeneration.

A new phosphate purification method for igneous weathering profiles.

RATIONALE: The oxygen isotope composition of phosphate (δ18 OPO4 ) is widely employed for reconstructing paleotemperature and tracing biogeochemical phosphorus cycling. However, existing phosphate purification protocols do not work well for igneous rocks and igneous weathering profiles (IWPs). A reliable purification method is needed for measuring δ18 OPO4 in these materials. METHODS: Our phosphate purification method includes two steps of cation exchange resin treatment separated by a step of calcium phosphate precipitation (R-Ca-R method). In addition, the silver phosphate precipitation in our procedure is featured by slow evaporation to crystallization until the appearance of ammonium nitrate or silver nitrate crystals. We evaluated our methods on weathered and pristine igneous rocks, phosphorite rocks, KH2 PO4 , and (NH4 )2 HPO4 solutions. RESULTS: Our purification method converted over 99.9% phosphate in solution to calcium phosphate, which can be easily decalcified by cation resin. The improved silver phosphate precipitation method produced high phosphate yields (97.1%-99.5%) and retained original δ18 OPO4 within analytical uncertainty (2σ = 0.6‰). We applied the purification and precipitation method on five igneous rocks and IWPs, and obtained δ18 OPO4 values ranging from 6.4‰ to 8.0‰. Duplicate phosphate extractions yielded δ18 OPO4 values differing by less than 0.3‰. CONCLUSIONS: We developed a new phosphate purification method that is applicable to phosphate extraction in igneous rocks and IWPs. We also proposed a reliable indicator for the termination of silver phosphate precipitation. Our method can achieve high phosphate yield and reproducible δ18 OPO4 value.

UBE3C promotes proliferation and inhibits apoptosis by activating the ß-catenin signaling via degradation of AXIN1 in gastric cancer.

Gastric cancer (GC) remains one of the most frequent cancers worldwide. Previous studies have shown that E3 ubiquitin ligase E3C (UBE3C) promotes the progression of multiple types of cancer. However, little is known about the expression and molecular mechanism of UBE3C in GC. In this study, UBE3C is upregulated in clinical GC samples and RNA-seq data from The Cancer Genome Atlas, and the UBE3C upregulation is correlated with poor clinical outcomes in patients with GC. In vitro, knockdown of UBE3C suppresses proliferation and enhances apoptosis in GC cells by inhibiting ß-catenin signaling pathway. In contrast, in vitro overexpression of UBE3C promotes GC cell proliferation and inhibits apoptosis through the upregulation of ß-catenin signaling by promoting ubiquitination of AXIN1. In vivo, knockdown of UBE3C inhibits tumor growth in a nude mouse model. Concurrently, the UBE3C knockdown resulted in an increase of AXIN1 and a reduction of ß-catenin in the nucleus and cytoplasm in the xenograft tumor tissues. Our results demonstrate that UBE3C promotes GC progression through activating the ß-catenin signaling via degradation of AXIN1. Our data suggest that UBE3C exerts oncogenic effects in GC and thus provides a promising prognostic biomarker and a potential therapeutic target for GC therapy.

[Development of Portable Bowel Sound Monitor].

This paper designs and implements a low power portable bowel sound monitor, which adopts bone conduction transducer to collect bowel sound continuously for long time and transmit to phone by Bluetooth. Then the phone application can record, play and analyse the bowel sound digital data in real time. This paper also designs an experiment to collect bowel sound from healthy people and patients with intestinal obstruction. It is verified by clinicians that this monitor can accurately record and preserve the bowel sound of the detected people, and is not disturbed by the external environment.

TRIM32 promotes cell proliferation and invasion by activating ß-catenin signalling in gastric cancer.

The tripartite motif (TRIM) family comprises more than 70 members involved in the regulation of many cellular pathways. TRIM32 acts as an E3 ubiquitin ligase and has been reported to participate in many human cancers. Here, we aimed to investigate the role of TRIM32 in gastric cancer (GC) and the clinical implications. High expression of TRIM32 was observed in GC tissues and cell lines, and was significantly associated with poor prognosis. Knockdown TRIM32 expression remarkably suppressed the proliferation, migration, and invasion of GC cells in vitro and tumour growth in vivo, whereas overexpression of TRIM32 yielded the opposite results. Western blotting and quantitative reverse-transcription PCR (qRT-PCR) analyses revealed that up-regulation of TRIM32 significantly enhanced expression of ß-catenin protein and of its downstream targets TCF1, cyclin D1, Axin2 and MMP7 mRNAs. Moreover, we found that the mechanism behind the TRIM32-promoted GC progression was related to the ß-catenin signalling pathway. Collectively, these data suggest that TRIM32 promotes GC cell proliferation, migration, and invasion by activating the ß-catenin signalling pathway.

Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling.

In this study, we aimed to investigate the effects of curcumin on cell activities of gastric cancer (GC), and the connection between curcumin and P53, as well as, PI3K signaling. This study was conducted with two cell lines SGC-7901 and BGC-823, both were exposed to curcumin at the concentrations of 0, 10, 20, and 40 µm. MTT assay, flow cytometry (FCM) assay, transmission electron microscopy (TEM) were used to study the underlying mechanisms of curcumin in respective of proliferation, apoptosis, and autophagy. Western blot assay was also employed to detect impacts of curcumin on tophosphatidylinositol-3 kinase (PI3K) and P53 signaling pathways-related proteins. MTT assay displayed that curcumin inhibited GC cell proliferation. FCM results indicated that curcumin induced the apoptosis of GC cells. TEM revealed that curcumin induced autophagy in GC cells. Western blot results showed that curcumin activated P53 signaling pathway and inhibited PI3K signaling pathway. Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells. Additionally, curcumin activated the P53 signaling pathway by up-regulating P53 and P21, which also inhibited PI3K pathway through down-regulating PI3K, p-Akt, and p-mTOR.

Gradient Projection with Approximate L0 Norm Minimization for Sparse Reconstruction in Compressed Sensing.

In the reconstruction of sparse signals in compressed sensing, the reconstruction algorithm is required to reconstruct the sparsest form of signal. In order to minimize the objective function, minimal norm algorithm and greedy pursuit algorithm are most commonly used. The minimum L1 norm algorithm has very high reconstruction accuracy, but this convex optimization algorithm cannot get the sparsest signal like the minimum L0 norm algorithm. However, because the L0 norm method is a non-convex problem, it is difficult to get the global optimal solution and the amount of calculation required is huge. In this paper, a new algorithm is proposed to approximate the smooth L0 norm from the approximate L2 norm. First we set up an approximation function model of the sparse term, then the minimum value of the objective function is solved by the gradient projection, and the weight of the function model of the sparse term in the objective function is adjusted adaptively by the reconstruction error value to reconstruct the sparse signal more accurately. Compared with the pseudo inverse of L2 norm and the L1 norm algorithm, this new algorithm has a lower reconstruction error in one-dimensional sparse signal reconstruction. In simulation experiments of two-dimensional image signal reconstruction, the new algorithm has shorter image reconstruction time and higher image reconstruction accuracy compared with the usually used greedy algorithm and the minimum norm algorithm.

[Development of Abdominal Vacuum Extractor Characterized by Portability and Constant Negative Pressure Which Applying to Battlefield].

There are some problems such as difficulty of pressure control, inconvenience of use and carry, congested easily and dredged hardly in clinical application of vacuum extractor in common use. For solving the above problems, researchers have designed a new portable and pressure stabilized abdominal drainage system which was composed of integral double spherical aspirator and separated double cannula. The new apparatus has achieved good effects in drainage which is suitable for not only rescuing of abdominal trauma and war wound, but also abdominal surgery that manifested as sucking safe and effective, using easily and convenient, that was verified by testing.

High Expression of Cell Division Cycle 42 Promotes Pancreatic Cancer Growth and Predicts Poor Outcome of Pancreatic Cancer Patients.

BACKGROUND: Cell division cycle 42 (CDC42), an important member of the Rho family, is overexpressed in various human cancers. However, its expression and role in pancreatic cancer (PC) are not well understood. AIM: The present study was designed to investigate the expression patterns and underlying cellular mechanisms of CDC42 in PC. METHODS: First, immunohistochemical analysis, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to detect CDC42 expression in clinical pancreatic carcinoma and adjacent tissues. Second, differential expression of CDC42 between PC cells and normal cells was evaluated by qRT-PCR and Western blotting. Third, the correlation between CDC42 expression as well as clinicopathological characteristics and patient survival was analyzed. Finally, CDC42 was knocked down to examine its role both in vivo and in vitro. RESULTS: The results showed significantly increased CDC42 expression in pancreatic tumor tissues compared with adjacent normal tissues, as revealed by qRT-PCR, Western blotting and immunostaining. Compared to PanC-1 cells, CDC42 expression was downregulated in HPDE6-C7 cells as shown by qRT-PCR and Western blotting. High CDC42 expression was observed in 69.2% (83/120) of pancreatic adenocarcinoma patients and was significantly associated with tumor differentiation (p = 0.013), median tumor size (p = 0.005), tumor infiltration (pT stage, p = 0.04), lymph nodal status (pN stage, p = 0.044) and TNM staging (p = 0.003). Multivariate Cox regression analysis revealed CDC42 expression to be an independent predictor of survival of PC patients (HR 3.0, 95% CI 1.60-5.61, p = 0.001). Finally, we found that CDC42 promoted the proliferation of PanC-1 cells both in vivo and in vitro. CONCLUSIONS: Our findings reveal that CDC42 might play an important role in promoting PC development, and the findings suggest that CDC42 might serve as a potential prognostic indicator of PC.

The MSHA strain of Pseudomonas aeruginosa (PA-MSHA) inhibits gastric carcinoma progression by inducing M1 macrophage polarization.

Macrophages play crucial roles in promoting tumor development and progression. In the present study, we found that the mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) was efficient in inducing M1 macrophage polarization. PA-MSHA treatment increases expression of M1-related cytokines and promotes activation of murine peritoneal macrophages (MPM). Interestingly, PA-MSHA inhibits cell proliferation and migration and induces the apoptosis of gastric carcinoma cells. These effects of PA-MSHA on M1 polarization were associated with activation of NF-κB expression. Thus, inducing polarization of M1 by PA-MSHA may be one potential strategy for inhibiting gastric carcinoma progression in mice.

Integrinß1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies because of its broad resistance to chemotherapy. Numerous evidence indicates that integrinß1 is upregulated in some human cancers, and it is correlated with resistance to various therapies. However, the role of integrinß1 in chemotherapy is not clear in pancreatic cancer. The present study evaluates the potential of integrinß1 to predict chemoresistance and prognosis in patients and to modulate resistance to gemcitabine in PDAC cells. Primary drug-resistance (DR) cancer cells were isolated, and DR cells from MiaPaCa-2 and AsPC-1 parent cell lines (PCL) were selected. Integrinß1 expression was determined using immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Changes in drug response after knockdown of integrinß1 via RNA interference (RNAi) were evaluated using the viability of cancer cells as colon formation, proliferation using Western blot of Ki-67 and apoptosis using cleaved caspase-3 immunofluorescence. qRT-PCR and Western blot also detected variations in the activities of cdc42 and AKT after integrinß1 suppression. Patient survival and relative factors were assessed using Kaplan-Meier and Cox regression analyses. Integrinß1 expression was upregulated in PDAC, which was significantly associated with intrinsic and acquired gemcitabine resistance and worse outcomes. The downregulation of integrinß1 attenuated PDAC chemoresistance, and this attenuation partially correlated with reduced Cdc42 and AKT activity, which are target molecules of integrinß1 in some human cancers. These findings identified integrinß1 as a special marker of drug resistance and a serious prognosis, and they furthermore support the use of integrinß1 as a novel potential therapeutic target to overcome chemotherapy resistance. The results also suggest a possible drug-resistant signalling pathway of integrinß1 in PDAC.

Escin Increases the Survival Rate of LPS-Induced Septic Mice Through Inhibition of HMGB1 Release from Macrophages.

BACKGROUND: Previous studies have described the effects of Escin on improving the survival rate of endotoxemic animals. The purpose of this study was to explore the molecular mechanisms of this potentially beneficial treatment. METHODS: First, the survival rate of endotoxemic mice was monitored for up to 2 weeks after Escin pretreatment, Escin post-treatment, or Escin post-treatment + rHMGB1. The effects of Escin on the release of pro-inflammatory cytokines such as TNF-α, IL-1ß, IL-6 and HMGB1 in the serum of endotoxemic mice and LPS-induced macrophages were evaluated by ELISA. Furthermore, the mRNA and protein levels of HMGB1 in LPS-induced macrophages were measured by qRT-PCR and Western blot, respectively. Additionally, the release of pro-inflammatory cytokines such as TNF-α, IL-1ß, IL-6 was evaluated by ELISA in rHMGB1-induced macrophages. Finally, the protein levels and the activity of NF-κB in macrophages were checked by Western blot and ELISA, respectively. RESULTS: Both pretreatment and post-treatment with Escin could improve the survival rate of endotoxemic mice, while exogenous rHMGB1 reversed this effect. In addition, Escin decreased the level of the pro-inflammatory cytokinesTNF-α,IL-1ß, IL-6 and HMGB1 in endotoxemic mice and in LPS-induced macrophages. Escin could also inhibit the mRNA levels and activity of HMGB1. The release of the pro-inflammatory cytokinesTNF-α,IL-1ß, IL-6 could be suppressed in rHMGB1-induced macrophages by Escin. Finally, Escin could suppress the activation of NF- κB in LPS-induced macrophages. CONCLUSION: Escin could improve the survival of mice with LPS-induced endotoxemia. This effect maybe meditated by reducing the release of HMGB1, resulting in the suppression of the release of pro-inflammatory cytokines.

A prospective, randomized, controlled study of ω-3 fish oil fat emulsion-based parenteral nutrition for patients following surgical resection of gastric tumors.

BACKGROUND: Nutrients such as ω-3 fatty acids including fish oil components eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) suppress the growth and promote apoptosis of tumor cells, improve immune function and reduce the effects of systemic inflammatory response syndrome. We sought to investigate the effect of ω-3 fish oil fat emulsion-based parenteral nutrition (PN) on nutritional state, immune function, inflammatory reaction, expression of tumor factors and complication incidence in patients after surgical resection of gastric cancer. METHODS: Forty-eight patients after surgical operation of gastric tumor in hospital were randomly divided into the control group and intervention group. Patients in both groups were treated with iso-nitrogen and iso-caloric parenteral nutrition support. In addition, the intervention group received ω-3 fish oil fat emulsion and the control group received soybean oil. The indicators of nutrition, immune function and inflammation in the two groups were detected on the day before the operation and postoperative day 6. The rate of complication was compared between the two groups. RESULTS: There was no significant difference in nutritional state, liver function and renal function between the two groups (P > 0.05). However, the levels of inflammatory markers were significantly decreased (P < 0.01), and the rate of complication was also decreased in the intervention group as compared with the control group. CONCLUSIONS: ω-3 fish oil fat emulsion-based parenteral nutrition alleviates the inflammatory reaction and reduces the rate of inflammatory complications.

Predictors of iatrogenic splenic injury in radical gastrectomy for gastric cancer.

Background: Iatrogenic splenic injury (ISI) is a recognized complication in radical gastrectomy that may result in incidental splenectomy (IS). However, the predictors of such events remain largely unknown. Methods: Medical records of the patients who underwent radical gastrectomy at our institution between January 2015 and December 2022 were retrospectively reviewed. Potential predictors of ISI and IS were collected and analyzed by multivariate logistic regression. Results were reported as an odds ratio (OR) with 95% confidence intervals (CI). Results: A total of 2916 patients were included, of whom 211 patients (7.2%) suffered from ISI and 75 patients (2.6%) underwent IS. Multivariate analysis demonstrated that BMI≥25 (OR: 3.198 (2.356-4.326), p<0.001), total gastrectomy (OR: 2.201 (1.601-3.025), p<0.001), and the existence of "criminal fold" (OR: 13.899 (2.824-251.597), p=0.011) were independent predictive risk factors for ISI; whereas laparoscopic surgical approach (OR: 0.048 (0.007-0.172), p<0.001) was a protective factor for ISI. Moreover, the existence of "criminal fold" (OR: 15.745 (3.106-288.470), p=0.008) and BMI≥25 (OR: 2.498 (1.002-6.046), p=0.044) were identified as independent risk factors of ISI under laparoscopic gastrectomy. There was no association between sex, age, previous abdominal surgery, neoadjuvant therapy, outlet obstruction, tumor stage, nodal stage, and total lymph node retrieved and ISI. Conclusions: BMI≥25 and total gastrectomy can predict high risk of ISI during radical gastrectomy. Laparoscopic surgery is superior to open gastrectomy in lowing the risk of ISI.

RASSF10 is epigenetically silenced and functions as a tumor suppressor in gastric cancer.

Ras association domain family (RASSF) proteins are encoded by several tumor suppressor genes that are frequently silenced in human cancers. In this study, we investigated RASSF10 as a target of epigenetic inactivation and examined its functions as a tumor suppressor in gastric cancer. RASSF10 was silenced in six out of eight gastric cancer cell lines. Loss or downregulation of RASSF10 expression was associated with promoter hypermethylation, and could be restored by a demethylating agent. Overexpression of RASSF10 in gastric cancer cell lines (JRST, BGC823) suppressed cell growth and colony formation, and induced apoptosis, whereas RASSF10 depletion promoted cell growth. In xenograft animal experiments, RASSF10 overexpression effectively repressed tumor growth. Mechanistic investigations revealed that RASSF10 inhibited tumor growth by blocking activation of ß-catenin and its downstream targets including c-Myc, cyclinD1, cyclinE1, peroxisome proliferator-activated receptor δ, transcription factor 4, transcription factor 1 and CD44. In conclusion, the results of this study provide insight into the role of RASSF10 as a novel functional tumor suppressor in gastric cancer through inhibition of the Wnt/ß-catenin signaling pathway.

A rare gas-containing lumbar synovial cyst treated by percutaneous transforaminal endoscopic cystectomy: A case report and literature review.

Spinal synovial cysts are rare entities for which standard surgical strategies are inconsistent. Here, we present an uncommon intraspinal gas-containing synovial cyst treated by percutaneous transforaminal endoscopic cystectomy. A 52-year-old man presented with radicular pain and intermittent claudication that had persisted for one month. Computed tomography revealed an intraspinal cystic lesion anteromedial to the left L4-L5 articular joint and the center of the lesion manifested gas contents. A transforaminal endoscopic procedure was performed and confirmed as a safe and minimally invasive technique for gas-containing lumbar synovial cysts. It provides a valuable substitution and supplementation to open surgery.

Role of RNA-binding protein tristetraprolin in tumor necrosis factor-α mediated gene expression.

Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of inflammatory diseases. Excessive TNF-α expression induces tristetraprolin (TTP), an RNA-binding protein that regulates mRNA degradation, which in turn downregulates TNF and its downstream genes, thus resulting in anti-inflammatory effects. In order to better understand the TNF-α mediated molecular pathways in inflammatory diseases, embryonic fibroblast (MEF) cell lines derived from TTP-deficient (KO) or wild type (WT) mice were treated with TNF-α and gene expression differences between two cell lines were compared by a microarray essay of 9224 genes. We found that TTP-KO cells had higher expression levels of pro-inflammatory genes than TTP-WT cells, and inflammatory genes were differentially regulated by TNF-α between TTP-KO and TTP-WT cells. Through a study of 2-dimentional gene set matrix analysis, we also found the genes upregulated by TNF-α in TTP KO cells were correlated with the pathologic phenotypes in inflammation, joint, or bone diseases. Our study provided a detailed genetic roadmap for further understanding the regulatory effect of TTP in inflammatory pathways related to human diseases.

[Design and manufacture a set of viewable bi-cavity abdominal puncture device].

To evaluate the rate of early diagnosis for abdominal trauma, we design a set of visible bi-cavity abdominal puncture device to detect and diagnose abdominal organ disease. This paper simply introduces the design and the use of this device.

The Antitumor Effect of TPD52L2 Silencing on Oxaliplatin-Resistant Gastric Carcinoma Is Related to Endoplasmic Reticulum Stress In Vitro.

Tumor protein D52-like 2 or simply TPD52L2 belongs to the TPD52 family which has been implicated in a variety of human carcinomas. However, the TPD52L2 function in the gastric carcinoma oxaliplatin (OXA) resistance remains elusive. The main objective of this study is to evaluate the TPD52L2 effect in OXA-resistant gastric carcinoma cells in vitro. Oxaliplatin-resistant gastric carcinoma cells were generated in MGC-803 and SGC-7901 cells. siRNA-mediated knockdown of TPD52L2 was investigated in OXA-resistant MGC-803-OXA and SGC-7901-OXA cells. qRT-PCR was performed to assess the expression level of TPD52L2 mRNA. TPD52L2 protein expression level, apoptosis, and endoplasmic reticulum (ER) stress-associated proteins were identified via immunoblotting analysis. MTT assay was conducted for the evaluation of cell viability, while colony-forming activity was carried out via crystal violet staining. SGC-7901-OXA and MGC-803-OXA cells were found to be more resistant to OXA, as compared to the parental cell lines. The expression of TPD52L2 was found to be upregulated in OXA-resistant cells. Knockdown of TPD52L2 suppressed cell colony-forming potency, cell growth, and development in OXA-resistant cells. TPD52L2 knockdown also enhanced the PARP and caspase-3 cleavage. ER-associated proteins such as PERK, GRP78, CHOP, and IRE1α were found to be elevated in TPD52L2 knockdown cells. ER stress might be involved in TPD52L2 knockdown-induced apoptosis in OXA-resistant gastric carcinoma cells.

Cartilaginous Metabolomics Reveals the Biochemical-Niche Fate Control of Bone Marrow-Derived Stem Cells.

Joint disorders have become a global health issue with the growth of the aging population. Screening small active molecules targeting chondrogenic differentiation of bone marrow-derived stem cells (BMSCs) is of urgency. In this study, microfracture was employed to create a regenerative niche in rabbits (n = 9). Cartilage samples were collected four weeks post-surgery. Microfracture-caused morphological (n = 3) and metabolic (n = 6) changes were detected. Non-targeted metabolomic analysis revealed that there were 96 differentially expressed metabolites (DEMs) enriched in 70 pathways involved in anti-inflammation, lipid metabolism, signaling transduction, etc. Among the metabolites, docosapentaenoic acid 22n-3 (DPA) and ursodeoxycholic acid (UDCA) functionally facilitated cartilage defect healing, i.e., increasing the vitality and adaptation of the BMSCs, chondrogenic differentiation, and chondrocyte functionality. Our findings firstly reveal the differences in metabolomic activities between the normal and regenerated cartilages and provide a list of endogenous biomolecules potentially involved in the biochemical-niche fate control for chondrogenic differentiation of BMSCs. Ultimately, the biomolecules may serve as anti-aging supplements for chondrocyte renewal or as drug candidates for cartilage regenerative medicine.