Contributions of joint damage-related events to gout pathogenesis: new insights from laboratory research.

Epidemiological and imaging findings indicate that gout frequently affects damaged joints. Recent studies suggest that the relationship between gout and joint damage may be more complex than a simple unidirectional link and that joint damage may promote the development of gout at affected sites. In this article, we review the clinical associations and recent laboratory research identifying events in the setting of osteoarthritis or joint injury that can alter the intraarticular microenvironment and locally regulate monosodium urate crystallisation and deposition or amplify the inflammatory response to deposited crystals. This includes cartilage matrix proteins or fibres released into the articular space that accelerates the crystallisation process, as well as the lack of lubricin and fibroblast priming that enhances the immune response towards the deposited crystals. These findings provide new insights into gout pathogenesis and offer a possible explanation for the site preference of gout in the damaged joint.

Type II collagen facilitates gouty arthritis by regulating MSU crystallisation and inflammatory cell recruitment.

OBJECTIVE: Increasing evidence suggests that impaired cartilage is a substantial risk factor for the progression from hyperuricaemia to gout. Since the relationship between cartilage matrix protein and gout flares remains unclear, we investigated its role in monosodium urate (MSU) crystallisation and following inflammation. METHODS: Briefly, we screened for cartilage matrix in synovial fluid from gouty arthritis patients with cartilage injuries. After identifying a correlation between crystals and matrix molecules, we conducted image analysis and classification of crystal phenotypes according to their morphology. We then evaluated the differences between the cartilage matrix protein-MSU complex and the pure MSU crystal in their interaction with immune cells and identified the related signalling pathway. RESULTS: Type II collagen (CII) was found to be enriched around MSU crystals in synovial fluid after cartilage injury. Imaging analysis revealed that CII regulated the morphology of single crystals and the alignment of crystal bows in the co-crystalline system, leading to greater phagocytosis and oxidative stress in macrophages. Furthermore, CII upregulated MSU-induced chemokine and proinflammatory cytokine expression in macrophages, thereby promoting the recruitment of leucocytes. Mechanistically, CII enhanced MSU-mediated inflammation by activating the integrin ß1(ITGB1)-dependent TLR2/4-NF-κB signal pathway. CONCLUSION: Our study demonstrates that the release of CII and protein-crystal adsorption modifies the crystal profile and promotes the early immune response in MSU-mediated inflammation. These findings open up a new path for understanding the relationship between cartilage injuries and the early immune response in gout flares.

A Dual-Mechanism Targeted Bioorthogonal Prodrug Therapy.

Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the in situ albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.

PDSM-LGCN: Prediction of drug sensitivity associated microRNAs via light graph convolution neural network.

Cancer has become one of the critical diseases threatening human life and health. The sensitivity difference of cancer drugs has always been a critical cause of the treatment come to nothing. Once drug resistance occurs, it will make the anticancer treatment or even various drugs ineffective. With the deepening of cancer research, a growing number of evidence shows that microRNA has a particular regulatory effect on the sensitivity of cancer drugs, which provides new research ideas. However, using traditional biological experiments to verify and discover the relations of microRNA-drug sensitivity is cumbersome and time-consuming, significantly slowing down cancer drug sensitivity's research progress. Therefore, this paper proposes a computational method (PDSM-LGCN) that spreads information through the high-order connection between cancer drug sensitivity and microRNA. At the same time, the model constructs an optimized-GCN as an embedding propagation layer to obtain the practical embeddings of microRNA and medicines. Finally, based on a collaborative filtering algorithm, the model brings the prediction score between microRNA and drug sensitivity. The results of fivefold cross-validation show that the AUC of PDSM-LGCN is 0.8872, and the AUPR is as high as 0.9026. At the same time, we also reproduced the five latest models of similar problems and compared the results. Our model has the best comprehensive effect among them. In addition, the reliability of PDSM-LGCN was further confirmed through the case study of Cisplatin and Doxorubicin, which can be used as a powerful tool for clinical and biological research. The source code and datasets can be obtained from https://github.com/19990915fzy/PDSM-LGCN/.

The application of a novel hydrodynamic cavitation device to debride intra-articular monosodium urate crystals.

INTRODUCTION: Efficient and complete debridement of intra-articular deposits of monosodium urate crystals is rarely achieved by existing arthroscopic tools such as shavers or radiofrequency ablation, while cavitation technology represents a prospective solution for the non-invasive clearance of adhesions at intra-articular interfaces. METHODS: Simulation modeling was conducted to identify the optimal parameters for the device, including nozzle diameters and jet pressures. Gouty arthritis model was established in twelve rats that were equally and randomly allocated into a cavitation debridement group or a curette debridement group. A direct injection nozzle was designed and then applied on animal model to verify the effect of the cavitation jet device on the removal of crystal deposits. Image analysis was performed to evaluate the clearance efficiency of the cavitation device and the pathological features of surrounding tissue were collected in all groups. RESULTS: To maximize cavitation with the practical requirements of the operation, an experimental rig was applied, including a 1 mm direct injection nozzle with a jet pressure of 2.0 MPa at a distance of 20 mm and a nitrogen bottle as high-pressure gas source. With regards to feasibility of the device, the clearance rates in the cavitation group were over 97% and were significantly different from the control group. Pathological examination showed that the deposition of monosodium urate crystals was removed completely while preserving the normal structure of the collagen fibers. CONCLUSIONS: We developed a promising surgical device to efficiently remove intra-articular deposits of monosodium urate crystals. The feasibility and safety profile of the device were also verified in a rat model. Our findings provide a non-invasive method for the intraoperative treatment of refractory gouty arthritis.

Outcomes of a novel all-inside arthroscopic anterior talofibular ligament repair for chronic ankle instability.

PURPOSE: This study aimed to introduce a novel all-inside arthroscopic anterior talofibular ligament (ATFL) repair for chronic ankle instability (CAI) with a knotless suture anchor technique-Hugging Repair, evaluate clinical outcomes, and analyze the associated risk factors. METHODS: A total of 84 patients (42 males and 42 females, mean age: 36.1 ± 11.2 years, range: 19-68 years) who underwent Hugging Repair from January 1, 2016 to December 31, 2018, were enrolled in this retrospective study. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Foot and Ankle Outcome Score (FAOS), Tegner score, and Numerical Rating Scale (NRS) were evaluated pre-operatively and at final follow-up. The potential risk factors such as age, body mass index (BMI), sex, post-injury duration (time from injury to surgery), follow-up time, number of anchors, concomitant injuries [e.g., osteochondral defects (OCD), sinus tarsi syndrome (STS), anterior ankle impingement (AAI)], first-time treatment, and number of ankle sprains were also analyzed through multiple regression analysis. RESULTS: There were 68 (81%) patients followed up for a mean time of 42 (range: 35-50) months. The median AOFAS score increased from 65 (35-72) to 90 (77-100), KAFS increased from 64 (38-71) to 90 (62-100), FAOS increased from 68 (50-70) to 97 (68-100), Tegner score increased from 1 (1-3) to 4 (2-7), and NRS increased from 3.5 (2-5) to 1 (0-3). No correlation was found between the functional scores and risk factors mentioned above. In the multivariate model, age was significantly negatively associated with KAFS, FAOS, and Tegner activity scale (P = 0.013; P = 0.002; P = 0.000); female was significantly associated with poorer Tegner activity scale (P = 0.004); and the presence of concomitant injuries was significantly negatively associated with AOFAS score (P = 0.033). CONCLUSION: The novel all-inside arthroscopic ATFL repair for CAI with a knotless suture anchor technique-Hugging Repair is a safe and suitable technique that achieves satisfactory clinical outcomes and provides an effective option for the treatment of CAI. Risk factors for patients who underwent all-inside ATFL repair were older age, female sex, and concomitant injuries.

The role of ERBB4 mutations in the prognosis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have witnessed the achievements of convincing clinical benefits that feature the significantly prolonged overall survival (OS) of patients suffering from advanced non-small cell lung cancer (NSCLC), according to reports recently. Sensitivity to immunotherapy is related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, a further investigation into the novel biomarkers of the prognosis on ICIs treatment is required. In addition, there is an urgent demand for the establishment of a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients. METHODS: In this study, the gene mutation and clinical data of NSCLC patients was obtained from the TCGA database, followed by the analysis of the detailed clinical information and mutational data relating to two advanced NSCLC cohorts receiving the ICIs treatment from the cBioPortal of Cancer Genomics. The Kaplan-Meier plot method was used to perform survival analyses, while selected variables were adopted to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from the cBioPortal of Cancer Genomics. RESULTS: The mutation frequencies of TP53 and ERBB4 were 54% and 8% in NSCLC, respectively. The mutual exclusive analysis in cBioPortal has indicated that ERBB4 does show co-occurencing mutations with TP53. Patients with ERBB4 mutations were confirmed to have better prognosis for ICIs treatment, compared to those seeing ERBB4 wild type (PFS: exact p = 0.017; OS: exact p < 0.01) and only TP53 mutations (OS: p = 0.021). The mutation status of ERBB4 and TP53 was tightly linked to DCB of ICIs treatment, PD-L1 expression, TMB value, and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy. CONCLUSION: ERBB4 mutations could serve as a predictive biomarker for the prognosis of ICIs treatment. The systematic nomogram was proven to have the great potential for evaluating the efficacy of ICIs therapy for advanced NSCLC patients.

LRGCPND: Predicting Associations between ncRNA and Drug Resistance via Linear Residual Graph Convolution.

Accurate inference of the relationship between non-coding RNAs (ncRNAs) and drug resistance is essential for understanding the complicated mechanisms of drug actions and clinical treatment. Traditional biological experiments are time-consuming, laborious, and minor in scale. Although several databases provide relevant resources, computational method for predicting this type of association has not yet been developed. In this paper, we leverage the verified association data of ncRNA and drug resistance to construct a bipartite graph and then develop a linear residual graph convolution approach for predicting associations between non-coding RNA and drug resistance (LRGCPND) without introducing or defining additional data. LRGCPND first aggregates the potential features of neighboring nodes per graph convolutional layer. Next, we transform the information between layers through a linear function. Eventually, LRGCPND unites the embedding representations of each layer to complete the prediction. Results of comparison experiments demonstrate that LRGCPND has more reliable performance than seven other state-of-the-art approaches with an average AUC value of 0.8987. Case studies illustrate that LRGCPND is an effective tool for inferring the associations between ncRNA and drug resistance.

Parental LC-PUFA biosynthesis capacity and nutritional intervention with alpha-linolenic acid affect performance of Sparus aurata progeny.

Environmental factors such as nutritional interventions during early developmental stages affect and establish long-term metabolic changes in all animals. Diet during the spawning period has a nutritional programming effect in offspring of gilthead seabream and affects long-term metabolism. Studies showed modulation of genes such as fads2, which is considered to be a rate-limiting step in the synthesis of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA). However, it is still unknown whether this adaptation is related to the presence of precursors or to limitations in the pre-formed products, n-3 LC-PUFA, contained in the diets used during nutritional programming. This study investigated the combined effects of nutritional programming on Sparusaurata through broodstock diets during the spawning period and in broodfish showing higher or lower fads2 expression levels in the blood after 1 month of feeding with a diet containing high levels of plant protein sources and vegetable oils (VM/VO). Broodfish showing high fads2 expression had a noticeable improvement in spawning quality parameters as well as in the growth of 6 month old offspring when challenged with a high VM/VO diet. Further, nutritional conditioning with 18:3n-3-rich diets had an adverse effect in comparison to progeny obtained from fish fed high fish meal and fish oil (FM/FO) diets, with a reduction in growth of juveniles. Improved growth of progeny from the high fads2 broodstock combined with similar muscle fatty acid profiles is also an excellent option for tailoring and increasing the flesh n-3 LC-PUFA levels to meet the recommended dietary allowances for human consumption.

TfOH-Catalyzed Cascade C-H Activation/Lactonization of Phenols with α-Aryl-α-diazoesters: Rapid Access to α-Aryl Benzofuranones.

Aryl benzofuranones are privileged structural units present in natural products and pharmaceutically relevant compounds with high bioactivity and therapeutic value; synthetic access to these scaffolds remains an area of intensive interest. A new and efficient TfOH-catalyzed cascade ortho C-H activation/lactonization of phenols with α-aryl-α-diazoacetates is reported. This metal-free protocol provides an operationally simple and rapid method for the one-pot assembly of diverse α-aryl benzofuranones in high yields with broad substrate scope, a readily starting material, good chemo-regioselectivity, and excellent functional group compatibility.

Galangin Reverses Hepatic Fibrosis by Inducing HSCs Apoptosis via the PI3K/Akt, Bax/Bcl-2, and Wnt/ß-Catenin Pathway in LX-2 Cells.

Hepatic fibrosis (HF) is a common disease, with currently no available treatment. Galangin, a natural flavonoid extracted from Alpinia officinaruim Hance, has multiple effects demonstrated in previous studies. The aim of the present study was to explore the anti-fibrogenic effect of galangin in vitro, and research its potential molecular mechanisms. LX-2 cells were chosen as an in vitro HF model, and were treated with galangin in different concentrations. Cell viability was analyzed using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis was measured using flow cytometry, and the anti-fibrogenic effect of galangin was determined using RT-quantitative (q)PCR, immunofluorescence, and Western blotting. The results show that the proliferation of LX-2 cells was efficiently inhibited by galangin, and apoptosis was induced in a dose-dependent manner. Both the mRNA and protein expression of alpha-smooth muscle actin (α-SMA) and collagen I were markedly downregulated. Galangin also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and Wnt/ß-catenin signaling pathways and increased the Bax/Bcl-2 ratio. The results of this study suggest that galangin has an anti-fibrogenic effect and may represent a promising agent in the treatment of hepatic fibrosis.

Effects of Dietary Lipid Composition and Fatty Acid Desaturase 2 Expression in Broodstock Gilthead Sea Bream on Lipid Metabolism-Related Genes and Methylation of the fads2 Gene Promoter in Their Offspring.

Polyunsaturated fatty acids (PUFA) in parental diets play a key role in regulating n-3 LC-PUFA metabolism of the offspring. However, it is not clear whether this metabolic regulation is driven by the precursors presented in the diet or by the parental ability to synthesize them. To elucidate this, broodstocks of gilthead sea bream with different blood expression levels of fads2, which encodes for the rate-limiting enzyme in the n-3 LC-PUFA synthesis pathway, were fed either a diet supplemented with alpha-linolenic acid (ALA, 18:3n-3) or a control diet. The progenies obtained from these four experimental groups were then challenged with a low LC-PUFA diet at the juvenile stage. Results showed that the offspring from parents with high fads2 expression presented higher growth and improved utilization of low n-3 LC-PUFA diets compared to the offspring from parents with low fads2 expression. Besides, an ALA-rich diet during the gametogenesis caused negative effects on the growth of the offspring. The epigenetic analysis demonstrated that methylation in the promoter of fads2 of the offspring was correlated with the parental fads2 expression levels and type of the broodstock diet.

Dietary vegetable oil suppressed non-specific immunity and liver antioxidant capacity but induced inflammatory response in Japanese sea bass (Lateolabrax japonicus).

High percentage of dietary vegetable oil (VO) induced negative effects on immunity in numerous fish species. The present study was conducted to investigate whether VO could exert anti-immunological effects by regulating non-specific immunity, liver antioxidant capacity and nuclear factor kappa beta (NF-κB) signaling in Japanese sea bass (Lateolabrax japonicus). Three iso-nitrogenous and iso-lipid diets were formulated by replacing 0% (FO, the control), 50% (FV) and 100% (VO) of fish oil with vegetable oil. Each diet was randomly fed to triplicate groups of fish for 10 weeks. Results showed that the alternative complement pathway (ACP) activity and the disease resistance were significantly lower in fish fed VO diets compared with the control group (P < 0.05). Liver superoxide dismutase (SOD), catalase (CAT) and glutathion peroxidase (GPx) enzyme activities, as well as total antioxidant capacity (T-AOC) significantly decreased in fish fed VO diets (P < 0.05). Meanwhile, significantly low level of liver SOD1 and CAT mRNA, nuclear factor erythroid 2-related factor 2 (Nrf2) of both mRNA and protein were observed in fish fed VO diets when compared with fish fed FO diets (P < 0.05). However, the transcription level of TNFα and IL1ß was significantly higher in the liver of fish fed VO diets, which might be attributed to the activation of NF-κB signaling pathway since the protein expression of p65, one of the key members of NF-κB family, was significantly increased (P < 0.05). These results suggested that dietary VO could lower the ACP activity, disease resistance and liver antioxidant capacity, but it could also exacerbate inflammatory response by activating NF-κB signaling pathway in Japanese sea bass.

Stiff-Soft Hybrid Biomimetic Nano-Emulsion for Targeted Liver Delivery and Treatment of Early Nonalcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) poses a risk for numerous metabolic diseases. To date, the U.S. Food and Drug Administration has not yet approved any medications for the treatment of NAFLD, for which developing therapeutic drugs is urgent. Dihydromyricetin (DMY), the most abundant flavonoid in vine tea, has been shown to be hepatoprotective. Its application was limited by low bioavailability in vivo; Methods: In order to improve the bioavailability of DMY and achieve liver-targeted delivery, we designed a DMY-loaded stiff-soft hybrid biomimetic nano drug delivery system (DMY-hNE). The in vivo absorption, distribution, pharmacokinetic profiles, and anti-NAFLD efficacy of DMY-hNE were studied; Results: DMY-hNE was composed of a stiff core and soft shell, which led to enhanced uptake by gastrointestinal epithelial cells and increased penetration of the mucus barrier, thus improving the in vivo absorption, plasma DMY concentration, and liver distribution versus free DMY. In an early NAFLD mouse model, DMY-hNE effectively ameliorated fatty lesions accompanied with reduced lipid levels and liver tissue inflammation; Conclusions: These findings suggested that DMY-hNE is a promising platform for liver drug delivery and treatment of hepatopathy.

NCK1-AS1 promotes the proliferation, migration, invasion, and EMT of non-small cell lung cancer by regulating the miR-361-5p/ADAM10 axis.

Lung cancer, one of the most frequently diagnosed cancers, causes a huge number of mortalities globally. Among lung cancers, non-small cell lung cancer (NSCLC) is the most recorded. Despite accumulating research, the molecular basis of NSCLC progression remains poorly known. Therefore, we aim to assess the function of NCK1-AS1 in NSCLC and elucidate the molecular mechanism. Firstly, we quantified the NCK1-AS1 level in tumors and adjacent healthy tissues. NCK1-AS1 was significantly upregulated in NSCLC tumors, which was associated with poor prognosis in patients. Silencing NCK1-AS1 significantly inhibited the proliferation, migration, and invasion, as well as the EMT of NSCLC cell lines. Starbase bioinformatic prediction revealed that NCK1-AS1 targets miR-361-5p which acts to regulate ADAM10 gene expression. Our result showed that NCK1-AS1 upregulation markedly reduced miR-361-5p mRNA expression, while increasing ADAM10 expression. For the first time, we demonstrated that NCK1-AS1 regulates the miR-361-5p/ADAM10 axis, thereby promoting NSCLC progression. NCK1-AS1 might be developed as a therapeutic target for treating NSCLC.

Galangin delivered by retinoic acid-modified nanoparticles targeted hepatic stellate cells for the treatment of hepatic fibrosis.

Hepatic fibrosis (HF) is a chronic hepatic pathological process induced by various liver injuries, with few available therapies. Previous research studies revealed that HF is characterized by the accumulation of excess extracellular matrix in the liver, mainly overexpressed by activated hepatic stellate cells (HSC). Therefore, HSC have been targeted in clinical trials for the management of HF. The aim of the present study was to develop an anti-HF drug delivery system with acrylic resin (Eudragit® RS100, Eud RS100) nanoparticles (NPs) through modification by retinoic acid (RA), modified for binding the retinol-binding protein reporter (RBPR) in HSC. Galangin (GA), is a multiple effects flavonoid which has demonstrated an anti-HF effect in our previous studies. In this study, GA was utilized for the treatment of HF. The results revealed that the NPs were well formed (diameter: 70 nm), spherical in shape, and exhibited uniform distribution and a high encapsulation efficiency. Moreover, a prominent controlled release effect and a significant increase in bioavailability was observed following the encapsulation of GA in NPs. These findings indicated that the limitation of low bioavailability due to the hydrophobic feature of GA was overcome. Furthermore, the pharmacodynamics studies demonstrated that NPs could drastically influence the anti-HF effects of GA after modification with retinoic acid. The results of the present study suggested that retinoic acid-modified GA NPs represent a promising candidate in the development of an anti-HF drug delivery system for the treatment of HF.

UPLC-Q-TOF-MS/MS analysis on the chemical composition of malts under different germination cycles and prepared with different processing methods.

OBJECTIVE: To investigate changes in the chemical composition of malts under different germination cycles and prepared with different processing methods, thus providing a reference for the clinical application of malt in disease treatment. METHODS: Nine malt samples were analyzed by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS), and the MS fragmentation pathway of 4 compounds (including hordenine, gramine, N-methyltyramine and catechin) were also analyzed. RESULTS: By database comparison and literature search, we detected 31 compounds in raw barley and 33 compounds in both raw malt and roasted malt. Nonetheless, the most of these 33 compounds were detected higher contents in raw malt than in roasted malt. Besides, we detected 15 compounds in brown malt. At Day1 of germination, 31 compounds were detected in malt, without two alkaloids (representative: hordenine). At Day2-5, 33 compounds were detected, with different contents as shown by the peak area comparison; hordenine had a gradually increasing abundance; and nearly one third of the chemical components in barley increased gradually, one third decreased gradually, and one third tended to be stable. CONCLUSION: Malts under different germination cycles and prepared with different processing methods have varying active ingredients, and especially brown malt exhibits a serious loss of compounds. The tight association between the chemical composition and clinical application of malt offers a basis to the clinically scientific and reasonable selection of Chinese medicinal materials for treatment purposes.

Positron emission tomography/computed tomography and endobronchial ultrasound-guided transbronchial needle aspiration to evaluate the status of N2 in preoperative non-small cell lung cancer: a diagnostic test.

Background: As a minimally invasive method, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was more accurate than non-invasive methods such as positron emission tomography (PET) and computed tomography (CT) to evaluate the lymph nodes in preoperative non-small cell lung cancer (NSCLC). PET/CT has more anatomical advantages than PET scanning and is more accurate in lung cancer staging. However, no relevant studies have comparatively evaluated PET/CT and EBUS-TBNA for NSCLC patients. Methods: A total of 112 patients were included in this retrospective analysis. The golden diagnosis of N2 status was postoperative pathological results. In EBUS-TBNA puncture specimens, if clear malignant tumor cells could be seen, the results were taken as positive. In PET/CT image analysis, the CT values, short diameter, and maximum standardized uptake value (SUVmax) of each lymph node were recorded to evaluate N2 status. The results of PET/CT and EBUS-TBNA were compared with the final pathological results, and respective sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. - Then, the patients were divided into adenocarcinoma group and squamous cell carcinoma group -and the results were calculated and compared with the above method. Results: The results showed that EBUS-TBNA had a higher diagnostic value for mediastinal lymph nodes than PET/CT, and the difference was statistically significant (P<0.001). In NSCLC patients, the results showed that the sensitivity (P=0.013), specificity (P<0.001), PPV (P<0.001), NPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than that of PET/CT (AUC =0.954 and 0.636, respectively). In adenocarcinoma cases, specificity (P<0.001), PPV (P<0.001), NPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than that of PET/CT (AUC =0.957 and 0.596, respectively).In cases with squamous cell carcinoma, specificity (P=0.003), PPV (P<0.001), and accuracy (P<0.001) of EBUS-TBNA were higher than PET/CT (AUC =0.952 and 0.657, respectively). Conclusions: For preoperative diagnosis of mediastinal lymph node metastases in NSCLC, EBUS-TBNA is more accurate than PET/CT. For those patients with suspected mediastinal lymph node metastasis, EBUS-TBNA should be preferred method to evaluate the status of mediastinal lymph nodes.

Detection of Prognostic Biomarkers for Hepatocellular Carcinoma through CircRNA-associated CeRNA Analysis.

BACKGROUND AND AIMS: The prognosis of hepatocellular carcinoma (HCC) is extremely poor; therefore, there is an urgent need for novel prognostic molecular biomarkers of HCC. The current investigation utilized circular (circ)RNA-associated competing endogenous (ce)RNAs analysis in order to identify significant prognostic biomarkers of HCC. METHODS: CircRNAs and mRNAs that were differentially expressed between normal and HCC tissues were identified. Their respective functions were predicted with Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A nomogram was used for model verification. RESULTS: A ceRNA network composed of differentially expressed circRNAs and mRNAs was constructed. Significant hub nodes in the ceRNA network were hsa_circ_0004662, hsa_circ_0005735, hsa_circ_0006990, hsa_circ_0018403 and hsa_circ_0100609. By using this information, a prognostic risk assessment tool was developed based on the expressions of seven genes (PLOD2, TARS, RNF19B, CCT2, RAN, C5orf30 and MCM10). Furthermore, multivariate Cox regression analysis revealed risk and T-stage parameters as independent prognostic factors. The nomograms that were constructed from risk and T-stage groups were used to further assess the prediction of HCC patient survival rates. The nomogram, which consisted of risk and T-stage scores assessment models, was found to be an independent factor for predicting prognosis of HCC. CONCLUSIONS: Five circRNAs, including hsa_circ_0004662, hsa_circ_0005735, hsa_circ_0006990, hsa_circ_0018403 and hsa_circ_0100609, that may play key roles in the progression of HCC were identified. Seven gene signatures were identified, which were associated with the aforementioned circRNAs, including PLOD2, TARS, RNF19B, CCT2, RAN, C5orf30 and MCM10, all of which were significant genes involved in the pathophysiology of HCC. These genes may be used as a prognosticating tool in HCC patients.

Low Regional Homogeneity of Intrinsic Cerebellar Activity in Ankle Instability: An Externally Validated rs-fMRI Study.

PURPOSE: Joint deafferentation after post-ankle sprain ligament healing can disrupt sensory input from the ankle and induce maladaptive neuroplasticity, especially in the cerebellum. This study aimed to determine whether the regional homogeneity of intrinsic cerebellar activity differs between patients with ankle instability and healthy controls without a history of ankle injury. METHODS: The current study used a primary data set of 18 patients and 22 healthy controls and an external UK Biobank data set of 16 patients with ankle instability and 69 healthy controls for a cross-database, cross-sectional investigation. All participants underwent resting-state functional magnetic resonance imaging to calculate their regional homogeneity (ReHo) value. Between-group comparisons of the sensorimotor-related subregions of the cerebellum were first performed in the primary data set to identify low cerebellar ReHo in patients with multiple comparison corrections, and the surviving subregions were then externally validated in the UK Biobank data set. Correlation analyses between the ReHo values and clinical features were also performed. RESULTS: The ReHo value of cerebellar lobule VIIIb was significantly lower in the ankle instability group than in the controls (0.170 ± 0.016 vs 0.184 ± 0.019 in the primary data set, 0.157 ± 0.026 vs 0.180 ± 0.042 in the UK Biobank data set). The ReHo values of this subregion showed a significant positive correlation with the Cumberland Ankle Instability Tool scores in the ankle instability group (r = 0.553, P-corrected = 0.0348). CONCLUSIONS: Patients with ankle instability had lower intraregional coherence in cerebellar lobule VIIIb than that of controls, which was also positively correlated with the intensity of self-reported ankle instability.