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Supplementary Figure from Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective antitumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered the maturation of intratumoral high endothelial venules and limited the formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent antitumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective antitumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting.

Supplementary Data from Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective antitumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered the maturation of intratumoral high endothelial venules and limited the formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent antitumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective antitumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting.

Background The stem cells of the stem cell banks have prominent problems for insufficient sources, easy contamination, unstable biological characteristics after serial subcultivations, and high cost. Methods After collecting the construction processes of the existing stem cell banks and suggestions from authoritative experts in the past 10 years, 230 reference principles were obtained, and finally, the principles of “5C” for the establishment of modern standardized stem cell banks were summarized, and their related applications on the management of sports injuries were reviewed as well. Results The basic principles of “5C” for the establishment of modern standardized stem cell banks include (1) principle of informed consent, (2) confidentiality principle, (3) conformity principle, (4) contamination-free principle, and (5) commonweal principle. The applications of stem cells on repairs, reconstructions, and regenerations of sports injuries were also reviewed, especially in tissue-engineered cartilage, tissue-engineered meniscus, and tissue-engineered ligament. Conclusions The proposal of the basic principles of “5C” is conducive to relevant stem cell researchers and clinical medical experts to build modern stem cell banks in a more standardized and efficient manner while avoiding some major mistakes or problems that may occur in the future. On this basis, stem cells from stem cell banks would be increasingly used in the management of sports injuries. More importantly, these days, getting stem cell samples are difficult in a short time, and such banks with proper legal consent may help the scientific community.

Current research on plant food-derived phenolic compounds as angiotensin-I-converting enzyme (ACE) inhibitors has been well documented. Pomegranate juice (PJ) has been reported positively contributed to ACE inhibition. Microbial fermentation is a preferable technique to regulate the biotransformation of phenolic compounds and their bioaccessibility, therefore promoting the ACE inhibitory activity in plant food with antihypertension potential. In this study, the remarkable improvements of ACE inhibitory activity and antioxidant capacity in Lactobacillus plantarum fermented PJ were observed. A consecutive study of phenolic compounds biotransformation, ACE inhibition kinetics and structure-activity relationship were performed. This study firstly highlights the relationship between the enhanced ACE inhibitory activity in fermented PJ and the biotransformation of phenolic compounds, providing a new way to reinforce plant food ACE inhibition potential by microbial fermentation.

Mesenchymal stem cells (MSCs)-derived exosomes are being increasingly focused as the new biological pro-regenerative therapeutic agents for various types of tissue injury. Here, we explored the potential of a novel exosome-based therapeutic application combined with a local fibrin delivery strategy for tendon repair. After discovering that bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) promoted the proliferation, migration and tenogenic differentiation of tendon stem/progenitor cells (TSPCs) in vitro, we embedded BMSCs-exos in fibrin and injected it into the defect area of rat patellar tendon, and the results showed that the exosomes could be controlled-released from the fibrin, retained within the defect area, and internalized by TSPCs. BMSCs-exos embedded in fibrin significantly improved the histological scores, enhanced the expression of mohawk, tenomodulin, and type I collagen, as well as the mechanical properties of neotendon, and also promoted the proliferation of local TSPCs in vivo. Overall, we demonstrated the beneficial role of BMSCs-exos in tendon regeneration, and that fibrin-exosomes delivery system represents a successful local treatment strategy of exosomes. This study brings prospects in the potential application of exosomes in novel therapies for tendon injury. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells have been identified as a preferred approach in tissue regeneration. In this study, we reported bone marrow mesenchymal stem cells (BMSCs) promote the proliferation and migration of tendon stem/progenitor cells (TSPCs) via the paracrine signaling effect of the nanoscale exosomes. We also demonstrated that the application of BMSCs-derived exosomes might be a promising approach to activate the regenerative potential of endogenous TSPCs in tendon injured region, and fibrin-exosomes delivery system represents a successful local treatment strategy of exosomes.

Meniscus deficiency, the most common and refractory disease in human knee joints, often progresses to osteoarthritis (OA) due to abnormal biomechanical distribution and articular cartilage abrasion. However, due to its anisotropic spatial architecture, complex biomechanical microenvironment, and limited vascularity, meniscus repair remains a challenge for clinicians and researchers worldwide. In this study, we developed a 3D printing-based biomimetic and composite tissue-engineered meniscus scaffold consisting of polycaprolactone (PCL)/silk fibroin (SF) with extraordinary biomechanical properties and biocompatibility. We hypothesized that the meticulously tailored composite scaffold could enhance meniscus regeneration and cartilage protection. Methods: The physical property of the scaffold was characterized by scanning electron microscopy (SEM) observation, degradation test, frictional force of interface assessment, biomechanical testing, and fourier transform infrared (FTIR) spectroscopy analysis. To verify the biocompatibility of the scaffold, the viability, morphology, proliferation, differentiation, and extracellular matrix (ECM) production of synovium-derived mesenchymal stem cell (SMSC) on the scaffolds were assessed by LIVE/DEAD staining, alamarBlue assay, ELISA analysis, and qRT-PCR. The recruitment ability of SMSC was tested by dual labeling with CD29 and CD90 by confocal microscope at 1 week after implantation. The functionalized hybrid scaffold was then implanted into the meniscus defects on rabbit knee joint for meniscus regeneration, comparing with the Blank group (no scaffold) and PS group. The regenerated meniscus tissue was evaluated by histological and immunohistochemistry staining, and biomechanical test. Macroscopic and histological scoring was performed to assess the outcome of meniscus regeneration and cartilage protection in vivo. Results: The combination of SF and PCL could greatly balance the biomechanical properties and degradation rate to match the native meniscus. SF sponge, characterized by fine elasticity and low interfacial shear force, enhanced energy absorption capacity of the meniscus and improved chondroprotection. The SMSC-specific affinity peptide (LTHPRWP; L7) was conjugated to the scaffold to further increase the recruitment and retention of endogenous SMSCs. This meticulously tailored scaffold displayed superior biomechanics, structure, and function, creating a favorable microenvironment for SMSC proliferation, differentiation, and extracellular matrix (ECM) production. After 24 weeks of implantation, the histological assessment, biochemical contents, and biomechanical properties demonstrated that the polycaprolactone/silk fibroin-L7 (PS-L7) group was close to the native meniscus group, showing significantly better cartilage protection than the PS group. Conclusion: This tissue engineering scaffold could greatly strengthen meniscus regeneration and chondroprotection. Compared with traditional cell-based therapies, the meniscus tissue engineering approach with advantages of one-step operation and reduced cost has a promising potential for future clinical and translational studies.

Ultrasound-responsive microspheres (MPs) derived from natural polysaccharides and injectable hydrogels have been widely investigated as a biocompatible, biodegradable, and controllable drug delivery system and cell scaffolds for tissue engineering. In this study, kartogenin (KGN) loaded poly (lactide-co-glycolic acid) (PLGA) MPs (MPs@KGN) were fabricated by premix membrane emulsification (PME) method which were sonicated by an ultrasound transducer. Furthermore, carboxymethyl chitosan-oxidized chondroitin sulfate (CMC-OCS) hydrogel were prepared via the Schiff’ base reaction-embedded MPs to produce a CMC-OCS/MPs scaffold. In the current work, morphology, mechanical property, porosity determination, swelling property, in vitro degradation, KGN release from scaffolds, cytotoxicity, and cell bioactivity were investigated. The results showed that MPs presented an obvious collapse after ultrasound treatment. The embedded PLGA MPs could enhance the compressive elastic modulus of soft CMC-OCS hydrogel. The cumulative release KGN from MPs exhibited a slow rate which would display an appropriate collapse after ultrasound, allowing KGN to maintain a continuous concentration for at least 28 days. Moreover, the composite CMC-OCS@MPs scaffolds exhibited faster gelation, lower swelling ratio, and lower in vitro degradation. CCK-8 and LIVE/DEAD staining showed these scaffolds did not influence rabbit bone marrow mesenchymal stem cells (rBMMSCs) proliferation. Then these scaffolds were cultured with rBMMSCs for 2 weeks, and the immunofluorescent staining of collagen II (COL-2) showed that CMC-OCS hydrogel embedded with MPs@KGN (CMC-OCS@MPs@KGN) with ultrasound had the ability to increase the COL-2 synthesis. Overall, due to the improved mechanical property and the ability of sustained KGN release, this injectable hydrogel with ultrasound-responsive property is a promising system for cartilage tissue engineering.

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis., Loss of cartilage tissue is a hallmark of osteoarthritis. Here the authors show that BNTA, a small molecule identified in a chemical screen, promotes ECM generation in human osteoarthritic chondrocytes and cartilage explants, and suppresses pathology in a rat model of osteoarthritis.

Synovium-derived mesenchymal stem cells (SMSCs) are attractive tissue-specific cells for cartilage regeneration because of their easy availability, higher chondrogenic potential, and joint specificity. In the present study, we established a hybrid scaffold to codeliver SMSCs and transforming growth factor beta (TGF-β), which can integrate the scaffolds, the growth factor, and the autogenous cells within rabbit cartilage defects. A chitosan hydrogel and a decellularized bone matrix were used to fabricate the gel-solid duplex phase biomaterials, which were proven to retain more cells, promote tissue integration, and provide mechanical support. In vitro experiments demonstrated that this hybrid scaffold could release TGF-β in a controlled biphasic pattern, which can promote cell proliferation and chondrogenic differentiation of loaded rabbit SMSCs. For in vivo experiments, we filled cartilage defects with the hybrid materials, delivering autogenous SMSCs and TGF-β simultaneously via chitosan's sol-gel transition. Histological analysis, magnetic resonance imaging, and nanoindentation assessment indicated superior cartilage regeneration using this codelivery system compared with that from routine microfracture or control delivery scaffolds. Beyond cartilage regeneration, the easy preparation, favorable biophysical properties, and controlled release ability make this codelivery system applicable to transport other tissue-specific cells or biofactors for tissue engineering.

Background/aim Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm of uncertain etiology, and the efficacy of surgical resection is not satisfactory. Therefore, there is an urgent need to explore the pathogenesis and identify novel therapeutic targets for TGCT. Materials and methods Synovial tissues were collected from patients with TGCT and osteoarthritis (OA). Differences of mRNA expression between TGCT and OA were explored using mRNA-seq. In addition, fibroblast-like synoviocytes (FLS) were treated with small interfering RNA (siRNA) or adenovirus in order to knockdown or overexpress β-arrestin2 (Arrb2), respectively. FLS proliferation and apoptosis were evaluated using the MTT assay and the caspase 3 activity assay, respectively. Results The expression of Arrb2 in TGCT was significantly higher than that in OA. The overexpression of Arrb2 promoted the proliferation of FLS and inhibited its apoptosis, while knocking down Arrb2 had the opposite effect. Further studies showed that Arrb2 can activate the PI3K-Akt signaling pathway, leading to increased proliferation of TGCT. Conclusion Arrb2 facilitates the proliferation and inhibits the apoptosis of TGCT FLS through activating the PI3K-Akt cell survival pathway, providing new insight into the molecular mechanism of TGCT.

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that characterized by progressive destruction of articular cartilage. There is no effective disease-modifying therapy for the condition due to limited understanding of the molecular mechanisms on cartilage maintenance and destruction. Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 in OA pathogenesis remains largely unknown. Here we show that typical necrotic cell morphology is observed within human OA cartilage samples in situ, and that RIP1 is significantly upregulated in cartilage from both OA patients and experimental OA rat models. Intra-articular RIP1 overexpression is sufficient to induce structural and functional defects of cartilage in rats, highlighting the crucial role of RIP1 during OA onset and progression by mediating chondrocyte necroptosis and disrupting extracellular matrix (ECM) metabolism homeostasis. Inhibition of RIP1 activity by its inhibitor necrostatin-1 protects the rats from trauma-induced cartilage degradation as well as limb pain. More importantly, we identify bone morphogenetic protein 7 (BMP7) as a novel downstream target that mediates RIP1-induced chondrocyte necroptosis and OA manifestations, thereby representing a non-canonical regulation mode of necroptosis. Our study supports a model whereby the activation of RIP1-BMP7 functional axis promotes chondrocyte necroptosis and subsequent OA pathogenesis, thus providing a new therapeutic target for OA.

Emerging evidence suggests that osteoarthritis (OA) is associated with high cholesterol levels. However, the specific mechanism remains unclear. Here, we found that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using global Lrp3−/− mice in vivo and LRP3 lentiviral vector-transduced chondrocytes in vitro, we identified that LRP3 positively regulated chondrocyte extracellular matrix metabolism, and its deficiency aggravated the degeneration of OA cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuated anterior cruciate ligament transection (ACLT)-induced OA progression in rats. Furthermore, LRP3 knockdown upregulated syndecan-4 (SDC4) expression by activating the Ras signaling pathway. We identified SDC4 as a downstream molecular target of LRP3 in OA pathogenesis. Together, these findings suggest that the cholesterol-LRP3-SDC4 axis plays critical roles in the OA development, and the LRP3 gene therapy may provide a new therapeutic regimen for OA treatment.

In this paper, we present the electronic, optical, and water-splitting properties of the Fe-doped ZnO monolayer by the first-principles method. The acquired results demonstrate that the Fe doping induces band level and decreases the band gap of the ZnO monolayer whereas the intrinsic vacancies also induce band levels and enrich the optoelectronic properties. The results of the formation energy validate the Fe doping in ZnO. We observed that the zinc vacancy can be created easily in an oxygen-rich condition, whereas oxygen vacancy is easy to be created when oxygen is poor. The optical properties of Fe-doped ZnO were calculated and the change in optical properties versus incident photons is presented. The relation between the obtained band and density of states (DOS) and the relation between the optical properties and DOS are discussed in detail. We found that the induced band level from Fe and intrinsic vacancies can enhance the optical properties under the visible and near-ultraviolet region. The Zn15FeO16 and Zn14Fe2O16 were taken as an example to demonstrate a water-splitting property of the Fe-doped ZnO monolayer. This work demonstrates that Fe doping and the corresponding intrinsic vacancies can improve the performance of ZnO monolayer-based optoelectronic devices and photocatalysts. This research will advance the practical applications of Fe-doped ZnO monolayer into new territory.

Nucleoside homeostasis, which is mediated by transporters and channels, is essential for all life on Earth. In Escherichia coli, NupG mediates the transport of nucleosides and was deemed to be the prototype of the nucleoside proton symporter (NHS) family and the major facilitator superfamily. To date, the substrate recognition and transport mechanisms of NHS transporters are still elusive. Here, we report two crystal structures of NupG (WT and D323A NupG) resolved at 3.0 A. Both structures reveal an identical inward-open conformation. Together with molecular docking and molecular dynamics simulations and in vitro uridine-binding assays, we found that the uridine binding site, which locates in the central cavity between N and C domains of NupG, is constituted by R136, T140, F143, Q225, N228, Q261, E264, Y318, and F322. Moreover, we found that D323 is very important for substrate binding via in vitro uridine-binding assays using D323 mutations, although it does not have a direct contact with uridine. Our structural and biochemical data therefore provide an important framework for the mechanistic understanding of nucleoside transporters of the NHS family.

Requirements engineering is a discipline that concerned with capturing, analyzing, allocating, tracing and managing requirements in system development process. With further improvement of requirements for aircraft safety, economy, environment protection and comfort, the development of airframe segment not only focuses on compliance with airworthiness regulations, but also pay more attention to Maintainability, Interchangeability, Manufacturability, etc. This paper focus on the research about application of requirements engineering in the development of airframe segment of civil aircraft. The requirements engineering approach and method is introduced. The investigation and application of the requirements engineering method in the civil aircraft airframe segment development is performed. We analyze the requirements capture process of airframe segment based on sources of requirements, introduce the requirement information architecture of aircraft and build the traceability network of airframe segment, research how can we ensure the requirements are correct and complete, and what we developed in final satisfy the specified requirements.

Objectives The aim of our study was to measure synovial fluid levels of ghrelin in patients with ACL injury to evaluate its potential function as a diagnostic biomarker for cartilage injury. Methods Patients were prospectively recruited in this study, compromising a cohort of subjects that had synovial fluid samples collected. Patients’ synovial fluid sampling was collected to evaluate ghrelin level. Venous blood samples were taken from all subjects to test inflammation markers IL-6, TNF-α, MMP-3, MMP-13 and also serum ghrelin level. Correlation between synovial fluid ghrelin level and inflammatory biomarkers were analyzed using spearman’s correlation analysis. The best cut-off of synovial fluid ghrelin level was defined using Medcalc. Results Patients in the ACL reconstruction with cartilage damage had lowest synovial fluid ghrelin level (ACL reconstruction with cartilage damage group: 264.6±65 pg/ml, ACL reconstruction without cartilage damage group: 466.8±92.6 pg/ml, healthy controls: 471.5±89.3 pg/ml, P

Background Unlike bone tissue, little progress has been made regarding cartilage regeneration, and many challenges remain. Furthermore, the key roles of cartilage lesion caused by traumas, focal lesion, or articular overstress remain unclear. Traumatic injuries to the meniscus as well as its degeneration are important risk factors for long-term joint dysfunction, degenerative joint lesions, and knee osteoarthritis (OA) a chronic joint disease characterized by degeneration of articular cartilage and hyperosteogeny. Nearly 50% of the individuals with meniscus injuries develop OA over time. Due to the limited inherent self-repair capacity of cartilage lesion, the Biomaterial drug-nanomedicine is considered to be a promising alternative. Therefore, it is important to elucidate the gene potential regeneration mechanisms and discover novel precise medication, which are identified through this study to investigate their function and role in pathogenesis. Methods We downloaded the mRNA microarray statistics GSE117999, involving paired cartilage lesion tissue samples from 12 OA patients and 12 patients from a control group. First, we analyzed these statistics to recognize the differentially expressed genes (DEGs). We then exposed the gene ontology (GO) annotation and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. Protein-protein interaction (PPI) networks were then constructed, from which we attained eight significant genes after a functional interaction analysis. Finally, we identified a potential nanomedicine attained from this assay set, using a wide range of inhibitor information archived in the Search Tool for the Retrieval of Interacting Genes (STRING) database. Results Sixty-six DEGs were identified with our standards for meaning (adjusted P-value < 0.01, |log2 - FC| ≥1.2). Furthermore, we identified eight hub genes and one potential nanomedicine - Selenocysteine based on these integrative data. Conclusion We identified eight hub genes that could work as prospective biomarkers for the diagnostic and biomaterial drug treatment of cartilage lesion, involving the novel genes CAMP, DEFA3, TOLLIP, HLA-DQA2, SLC38A6, SLC3A1, FAM20A, and ANO8. Meanwhile, these genes were mainly associated with immune response, immune mediator induction, and cell chemotaxis. Significant support is provided for obtaining a series of novel gene targets, and we identify potential mechanisms for cartilage regeneration and final nanomedicine immunotherapy in regenerative medicine.

Rationale: Pigmented villonodular synovitis (PVNS) is a destructive benign tumor-like hyperplastic disease that occurs in synovial tissue. Fibroblast-like synoviocytes (FLS) are the predominant cell type comprising the structure of the PVNS synovial lining layer. Due to a high recurrence rate, high invasion, migration, and cartilage destruction ability, PVNS causes substantial damage to patients and the efficacy of surgical resection is not satisfactory. Therefore, exploring the pathogenesis and identifying novel therapeutic targets for PVNS are urgently required. Currently, the pathogenesis of PVNS remains unclear, and there is uncertainty and controversy regarding whether PVNS is an inflammatory or a neoplastic disease. Cadherin-11 is a classical molecule that mediates hemophilic cell-to-cell adhesion in FLS and plays an important role in the normal synovium lining layer formation. This study aimed to explore the role of inflammation and cadherin-11 in PVNS pathogenesis and determine the effects of cadherin-11 as a molecular target for PVNS treatment. Methods: FLS were primarily cultured from PVNS patients during arthroscopic synovectomy. The level of cytokines in the PVNS synovial fluid was evaluated using a human antibody array. Cadherin-11 expression of PVNS FLS was detected by qPCR, Western blots, tissue immunohistochemistry, and cell immunofluorescence. Cadherin-11 was down-regulated by siRNA or up-regulated with a plasmid, with or without inflammatory factor stimulation, and PI3K/Akt was inhibited with LY294002. The capacity of migration and invasion of PVNS FLS was tested using Transwell and wound-healing assays. Activation of the nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was detected by Western blots. Chondrocyte damage by PVNS FLS was assessed with a co-culture assay. Results: Inflammatory factors (IL-1β and TNF-α) in the synovial fluid of PVNS patients were significantly up-regulated. Cadherin-11 was highly expressed in the FLS of PVNS patients, and positively correlated with recurrence, extra-articular migration, and cartilage destruction of PVNS. Knocking down of cadherin-11 inhibited the migration and invasion of PVNS FLS. Moreover, inflammatory factors up-regulated the expression of cadherin-11, which activated the NF-κB and MAPK signaling pathways and led to cartilage destruction. Inhibition of cadherin-11 blocked IL-1β- and TNF-α-induced activation of the above pathways, migration and invasion of PVNS FLS, and damage of chondrocyte. In addition, the elevation of cadherin-11 expression, together with the migration and invasion, of PVNS FLS was down-regulated by the inhibition of the PI3K/Akt signaling pathway. Conclusions: Cadherin-11 plays an important role in the pathogenesis of PVNS and forms a positive feedback loop with inflammatory factors, which further activates the NF-κB and MAPK pathways to trigger an inflammatory cascade. Cadherin-11-mediated inflammation results in PVNS with high recurrence, invasiveness, and strong cartilage destruction ability, and eventually promotes the transformation of PVNS from the initial inflammatory disease to neoplastic disease. Thus, inhibition of cadherin-11 together with its related inflammatory reaction, represents a new therapeutic strategy for PVNS.

Lamadian Oilfield has entered the late stage of ultra-high water cut development, and the producing conditions of each sublayer are different. In order to know the producing conditions of each sublayer more clearly, it is necessary to count the reserves and output conditions of each sublayer. Therefore, it is necessary to finely divide the liquid and oil production of each sublayer of the production well. The former liquid splitting method only considered the formation influencing factors, that is, the splitting method of formation coefficient, which could not meet the differences of different water cut in each sublayer at present. Through the research of fine liquid splitting method, we can clearly understand the production of each oil well layer in the block, the production status and adjustment potential of each sub-layer, thus guiding the adjustment and tapping potential of block layering measures. It provides a theoretical basis for the later development of ultra-high water cut block.

BackgroundFew studies have investigated whether the mini-medial parapatellar (MMP) and quadriceps-sparing (QS) approaches have good long-term results compared to the conventional medial parapatellar (MP) approach in terms of clinical evaluations and radiographic assessments for total knee arthroplasty (TKA). The purpose of this study was to perform comparisons among the MMP, QS and MP approaches with a follow-up at 10 to 17 years.MethodsThis is a retrospective comparative study of 93 patients who underwent MMP TKA (32 TKAs), QS TKA (47 TKAs) or MP TKA (31 TKAs) with the same arthroplasty system. The clinical evaluations were performed according to the new American Knee Society score (KSS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analogue scale (VAS), range of motion (ROM), incidence of anterior knee pain (AKP), the Feller patellofemoral score (PFS), the reoperation rate and the complication rates. Radiographic assessments included observation of the mechanical axis of the lower limb and calculations of the lateral distal femoral angle (LDFA), femoral flexion angle (FFA), medial proximal tibial angle (MPTA), tibial slope angle (TSA), lateral patella displacement (LPD), and lateral patella tilt (LPT).ResultsThere were no differences in the long-term follow-up results of the new KSS, WOMAC score, ROM, VAS, patellofemoral functions, reoperation rate or complication rates among the groups. In addition, no radiographic differences in terms of lower limb mechanical axis or femoral, tibial or patellar position were observed.ConclusionThese results provide conclusive evidence that equivalent, long-term clinical results can be obtained using any one of these three approaches.

Meniscal allograft transplantation yields good and excellent results but is limited by donor availability. The purpose of the study was to evaluate the effectiveness of radiated deep-frozen xenogenic meniscal tissue (RDF-X) as an alternative graft choice in meniscal transplantation. The xenogenic meniscal tissues were harvested from the inner 1/3 part of the porcine meniscus and then irradiated and deeply frozen. The medial menisci of rabbits were replaced by the RDF-X. Meniscal allograft transplantation, meniscectomy and sham operation served as controls. Only a particular kind of rabbit-anti-pig antibody (molecular ranging 60–80 kD) was detected in the blood serum at week 2. The menisci of the group RDF-X grossly resembled the native tissue and the allograft meniscus with fibrocartilage regeneration at postoperative 1 year. Cell incorporation and the extracellular matrix were mostly observed at the surface and the inner 1/3 part of the newly regenerated RDF-X, which was different from the allograft. The biomechanical properties of the group RDF-X were also approximate to those of the native meniscus except for the compressive creep. In addition, chondroprotection was achieved after the RDF-X transplantation although the joint degeneration was not completely prevented. To conclude, the RDF-X could be a promising alternative for meniscal transplantation with similar tissue regeneration capacity to allograft transplantation and superior chondroprotection. The potential minor immunological rejection should be further studied before its clinical application.