LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models.

BACKGROUND & AIMS: Treatments directly targeting fibrosis remain limited. Given the unique intrinsic features of macrophages and their capacity to engraft in the liver, we genetically engineered bone marrow-derived macrophages with a chimeric antigen receptor (CAR) to direct their phagocytic activity against hepatic stellate cells (HSCs) in multiple mouse models. This study aimed to demonstrate the therapeutic efficacy of CAR macrophages (CAR-Ms) in mouse models of fibrosis and cirrhosis and to elucidate the underlying mechanisms. METHODS: uPAR expression was studied in patients with fibrosis/cirrhosis and in murine models of liver fibrosis, including mice treated with carbon tetrachloride, a 5-diethoxycarbonyl-1, 4-dihydrocollidine diet, or a high-fat/cholesterol/fructose diet. The safety and efficacy of CAR-Ms were evaluated in vitro and in vivo. RESULTS: Adoptive transfer of CAR-Ms resulted in a significant reduction in liver fibrosis and the restoration of function in murine models of liver fibrosis. CAR-Ms modulated the hepatic immune microenvironment to recruit and modify the activation of endogenous immune cells to drive fibrosis regression. These CAR-Ms were able to recruit and present antigens to T cells and mount specific antifibrotic T-cell responses to reduce fibroblasts and liver fibrosis in mice. CONCLUSION: Collectively, our findings demonstrate the potential of using macrophages as a platform for CAR technology to provide an effective treatment option for liver fibrosis. CAR-Ms might be developed for treatment of patients with liver fibrosis. IMPACT AND IMPLICATIONS: Liver fibrosis is an incurable condition that afflicts millions of people globally. Despite the clear clinical need, therapies for liver fibrosis are limited. Our findings provide the first preclinical evidence that chimeric antigen receptor (CAR)-macrophages (CAR-Ms) targeting uPAR can attenuate liver fibrosis and cirrhosis. We show that macrophages expressing this uPAR CAR exert a direct antifibrotic effect and elicit a specific T-cell response that augments the immune response against liver fibrosis. These findings demonstrate the potential of using CAR-Ms as an effective cell-based therapy for the treatment of liver fibrosis.

Analysis of the association between urinary glyphosate exposure and fatty liver index: a study for US adults.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition that often goes unrecognized in the population, and many risk factors for this disease are not well understood. Glyphosate (GLY) is one of the most commonly used herbicides worldwide, and exposure to this chemical in the environment is significant. However, studies exploring the association between GLY exposure and NAFLD remain limited. Therefore, the aim of this study was to assess the association between urinary glyphosate (uGLY) level and fatty liver index (FLI) using data from the National Health and Nutrition Examination Survey (NHANES), which includes uGLY measurements. METHODS: The log function of uGLY was converted and expressed as Loge(uGLY) with the constant "e" as the base and used for subsequent analysis. The association between Loge(uGLY) (the independent variable) level and FLI (the dependent variable) was assessed by multiple linear regression analysis. Smoothing curve fitting and a generalized additive model were used to assess if there was a nonlinear association between the independent and the dependent variables. A subgroup analysis was used to find susceptible individuals of the association between the independent variable and the dependent variable. RESULTS: A final total of 2238 participants were included in this study. Participants were categorized into two groups (< -1.011 and ≥ -1.011 ng/ml) based on the median value of Loge(uGLY). A total of 1125 participants had Loge(uGLY) levels ≥ -1.011 ng/ml and higher FLI. The result of multiple linear regression analysis showed a positive association between Loge(uGLY) and FLI (Beta coefficient = 2.16, 95% CI: 0.71, 3.61). Smoothing curve fitting and threshold effect analysis indicated a linear association between Loge(uGLY) and FLI [likelihood ratio(LLR) = 0.364]. Subgroup analyses showed that the positive association between Loge(uGLY) and FLI was more pronounced in participants who were female, aged between 40 and 60 years, had borderline diabetes history, and without hypertension history. In addition, participants of races/ethnicities other than (Mexican American, White and Black) were particularly sensitive to the positive association between Loge(uGLY) and FLI. CONCLUSIONS: A positive linear association was found between Loge(uGLY) level and FLI. Participants who were female, 40 to 60 years old, and of ethnic backgrounds other than Mexican American, White, and Black, deserve more attention.

Long non-coding RNA DANCR increases spinal cord neuron apoptosis and inflammation of spinal cord injury by mediating the microRNA-146a-5p/MAPK6 axis.

OBJECTIVE: This research was to unravel the impact of the lncRNA differentiation antagonizing non-protein coding RNA (DANCR)/microRNA (miR)-146a-5p/mitogen-activated protein kinase 6 (MAPK6) axis on spinal cord injury (SCI). METHODS: SCI mouse models were established and injected with si-DANCR or miR-146a-5p agomir. The recovery of motor function was assessed by Basso Mouse Scale. SCI was pathologically evaluated, and serum inflammatory factors were measured in SCI mice. Mouse spinal cord neurons were injured by H2O2 and transfected, followed by assessment of proliferation and apoptosis. DANCR, miR-146a-5p, and MAPK6 in tissues and cells were detected, as well as their relationship. RESULTS: DANCR increased and miR-146a-5p decreased in SCI. Silencing DANCR or enhancing miR-146a-5p stimulated the proliferation of mouse spinal cord neurons and reduced apoptosis. DANCR was bound to miR-146a-5p to target MAPK6. DANCR affected the proliferation and apoptosis of spinal cord neurons by mediating the miR-146a-5p/MAPK6 axis. Downregulating DANCR or upregulating miR-146a-5p improved inflammation, the destruction of spinal cord tissue structure, and apoptosis in SCI mice. CONCLUSION: DANCR affects spinal cord neuron apoptosis and inflammation of SCI by mediating the miR-146a-5p/MAPK6 axis.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.

The Prognostic Role of a Combined Fibrinogen and Neutrophil-to-Lymphocyte Ratio Score in Patients with Resectable Hepatocellular Carcinoma: A Retrospective Study.

BACKGROUND Inflammation and activation of the coagulation cascades have a role in the pathogenesis of malignancy, including hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic role of the combined fibrinogen and neutrophil-to-lymphocyte ratio (F-NLR) in patients with resectable HCC. MATERIAL AND METHODS This retrospective study included 292 patients with HCC who underwent surgical resection. The receiver operating characteristic (ROC) curve was used to determine the cut-off value of preoperative fibrinogen (Fib) levels and the neutrophil-to-lymphocyte ratio (NLR). The. Hyperfibrinogenemia was >3.35 g/L, and an increased NLR was ≥2.47. The F-NLR was calculated for all patients. Kaplan-Meier survival curves, univariate analysis, multivariate analysis, and subgroup analysis were used to identify independent prognostic factors for overall survival (OS) and disease-free survival (DFS). The receiver operating characteristic (ROC) curve analysis of the F-NLR score and OS, according to the Barcelona Clinic Liver Cancer (BCLC) stage, was performed. RESULTS Increased F-NLR scores were significantly associated with the presence of tumor thrombus (P=0.001), larger tumor diameter (P<0.001), vascular invasion (P<0.001), and increased BCLC stage (P<0.001). Multivariate analysis showed that the F-NLR score was an independent predictor of OS (P<0.001) and DFS (P=0.002). The prognostic role of F-NLR was significant for BCLC stage 0-I (P=0.004; P<0.001) and BCLC stage II-III (P=0.026; P=0.005) for OS and DFS, respectively. CONCLUSIONS In patients with resectable HCC, the combined F-NLR score, a new indicator of systemic inflammation, was an independent prognostic indicator.

Low Noise Interface ASIC of Micro Gyroscope with Ball-disc Rotor.

A low noise interface ASIC for micro gyroscope with ball-disc rotor is realized in 0.5µm CMOS technology. The interface circuit utilizes a transimpedance pre-amplifier which reduces input noise. The proposed interface achieves 0.003 o/s/Hz1/2 noise density and 0.003 o/s sensitivity with ±100 o/s measure range. The functionality of the full circuit, including circuit analysis, noise analysis and measurement results, has been demonstrated.

MiR-19b-3p attenuates IL-1ß induced extracellular matrix degradation and inflammatory injury in chondrocytes by targeting GRK6.

Osteoarthritis (OA) is characterized by degradation of articular cartilage. MiRNAs are involved in the regulation of chondrogenesis and OA. We aimed to investigate effects and mechanisms of miR-19b-3p in regulating chondrocytes viability, cartilage degradation and inflammatory response. Primary chondrocytes were isolated from cartilages in control subjects and patients with OA. Murine ATDC5 cells were pre-conditioned with IL-1ß in vitro. Expressions and interaction of miR-19b-3p with G protein-coupled receptor kinase 6 (GRK6), and their effects on inflammation, chondrocytes viability and cartilage degradation were determined after miR-19b-3p mimic or GRK6 siRNA transfection. MiR-19b-3p was significantly decreased in OA chondrocytes and IL-1ß-stimulated ATDC5 cells, in paralleled with the elevated type-II-collagen, aggrecan, MMP13 and GRK6 expression. MiR-19b-3p mimic dramatically increased the viability of chondrocytes and suppressed cell apoptosis. It also increased type-II-collagen, aggrecan expression and glycosaminoglycan (sGAG) content, and decreased the expression of MMP-1 and MMP-13 that controlled by IL-1ß. Overexpression of miR-19b-3p inhibited the production of IL-6 and IL-8 in ATDC5 cells. However, the protective effects of miR-19b-3p mimic on IL-1ß induced cell death; IL-8 production and sGAG decrease were greatly discounted by GRK6 lentiviral vectors. Luciferase reporter assay confirmed that GRK6 gene was a direct target ofmiR-19b-3p. GRK6 siRNA transfection antagonized the IL-1ß-induced chondrocytes injury, extracellular matrix degradation and inflammatory response. MiR-19b-3p mimic and GRK6 siRNA showed comparable inhibitory effect on IL-1ß-provoked NF-κB as reflected by the expression of p-p65. NF-κB translocation inhibition with PS1154 reversed the effects of IL-1ß on IL-8 and sGAG. Collectively, miR-19b-3p attenuated OA by targeting GRK6-NF-κB pathway.

CCN2 and CCN5 exerts opposing effect on fibroblast proliferation and transdifferentiation induced by TGF-ß.

Epidural fibrosis might occur after lumbar discectomy and contributes to failed back syndrome. Transforming growth factor (TGF)-ß has been reported to influence multiple organ fibrosis, in which connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 2 (CCN2) and CCN5 are involved. However, the effect of CCN2 and CCN5 on TGF-ß induced fibrosis has not yet been elucidated. This study reports that CCN2 and CCN5 play opposing roles in cell proliferation and transdifferentiation of human skin fibroblasts or rabbit epidural scar-derived fibroblasts exposed to TGF-ß. We observed that TGF-ß1 induced fibroblasts proliferation and differentiation in a dose-dependent manner (from 0 µg/L to 20 µg/L). Meanwhile, CCN2 expression is up-regulated while CCN5 expression is inhibited by TGF-ß1 exposure. Furthermore, it is demonstrated that CCN2 overexpression leads to promoted proliferation and elevated collagen and α-smooth muscle actin (α-SMA) expression, which are inhibited by CCN5 overexpression. Moreover, it is shown that the cysteine knot (CT) domain, present in CCN2 but absent in CCN5, plays an essential part in fibroblast proliferation and differentiation. Additionally, enhanced TGF-ß and CCN2 expression but decreased CCN5 expression is found in rabbit epidural scar-derived fibroblasts. Overall, the results show the opposing effects of CCN2 and CCN5 on fibroblast proliferation and transdifferentiation induced by TGF-ß.

Randomized controlled trial of early rehabilitation after intracerebral hemorrhage stroke: difference in outcomes within 6 months of stroke.

BACKGROUND AND PURPOSE: Mechanisms, acute management, and outcomes for patients who experience intracerebral hemorrhage may differ from patients with ischemic stroke. Studies of very early rehabilitation have been mainly undertaken in patients with ischemic stroke, and it is unknown if benefits apply to those with intracerebral hemorrhage. We hypothesized that early rehabilitation, within 48 hours of stroke, would improve survival and functional outcomes in patients with intracerebral hemorrhage. METHODS: This was a multicenter, randomized controlled study, with blinded assessment of outcome at 3 and 6 months. Eligible patients were randomized to receive standard care or standard care plus early rehabilitation. Primary outcome includes survival. Secondary outcomes includes health-related quality of life using the 36-item Short Form Questionnaire, function measured with the modified Barthel Index, and anxiety measured with the Zung Self-Rated Anxiety Scale. RESULTS: Two hundred forty-three of 326 patients were randomized (mean age, 59 years; 56% men). At 6 months, patients receiving standard care were more likely to have died (adjusted hazard ratio, 4.44; 95% confidence interval [CI], 1.24-15.87); for morbidity outcomes, a 6-point difference in the Physical Component Summary score of the 36-item Short Form Questionnaire (95% CI, 4.2-8.7), a 7-point difference for the Mental Component Summary score (95% CI, 4.5-9.5), a 13-point difference in Modified Barthel Index scores (95% CI, 6.8-18.3), and a 6-point difference in Self-Rating Anxiety Scale scores (95% CI, 4.4-8.3) was reported in favor of the intervention groups. CONCLUSIONS: For the first time, we have shown that commencing rehabilitation within 48 hours of intracerebral hemorrhage improves survival and functional outcomes at 6 months after stroke in hospitalized patients in China. CLINICAL TRIAL REGISTRATION URL: http://www.chictr.org/en. Unique identifier: ChiCTR-TRC-13004039.

Let-7b-5p regulates proliferation and apoptosis in multiple myeloma by targeting IGF1R.

Multiple myeloma (MM) is the most common cause of death from hematological malignancy worldwide, and recent studies have revealed that let-7b-5p can play an inhibitory role in tumorigenesis. However, the role of let-7b-5p in MM still remains unclear. The aim of this study was to elucidate the molecular mechanisms by which let-7b-5p acts as a tumor suppressor in MM. Here, quantitative real-time polymerase chain reaction results showed that the expression of let-7b-5p was remarkably reduced in MM tissues and MM cell lines (RPMI-8226 and U266 cells). Furthermore, over-expression of let-7b-5p significantly suppressed RPMI-8226 cell proliferation and induced S/G2 cell cycle arrest and apoptosis. Luciferase reporter assay results demonstrated that insulin-like growth factor receptor 1 (IGF1R) was negatively regulated by let-7b-5p at the post-transcriptional level. The mRNA and protein levels of IGF1R in RPMI-8226 cells were down-regulated by let-7b-5p. Furthermore, the cell phenotype altered by let-7b-5p inhibitor can be rescued by IGF1R silencing (si-IGF1R). Taken together, our results demonstrated that let-7b-5p functions as a tumor suppressor in MM, suggesting that let-7b-5p may be a potential therapeutic target for MM.

Abnormal expression of chondroitin sulphate N-acetylgalactosaminyltransferase 1 and Hapln-1 in cartilage with Kashin-Beck disease and primary osteoarthritis.

PURPOSE: Kashin-Beck disease (KBD) is an endemic degenerative osteoarthritis associated with extracellular matrix degradation. The aim of this investigation was to evaluate the role of targeting genes in the pathogenesis of KBD and primary osteoarthritis (OA) involved in extracellular matrix degradation. METHODS: Agilent 44 K human whole-genome oligonucleotide microarrays were used to detect the gene expression in KBD and OA cartilage. The mRNA and protein expressions of CSGalNAcT-1 and Hapln-1 in chondrocytes were verified by reverse transcription polymerase chain reaction (RT-PCR) and western blot, and their expression in cartilage were verified with immunocytochemical analysis. Meanwhile, CSGalNAcT-1 and Hapln-1 protein levels in the selenium intervention group of KBD with different concentrations (0.25, 0.1 and 0.05 µg/ml) were detected by western blot. RESULTS: CSGalNAcT-1 and Hapln-1 were down-regulated in KBD and OA at both mRNA and protein levels, and were increased in Se(Selenium) groups compared to KBD free-Se group. However, Wnt 3a, ß-catenin and Runx-2 were up-regulated in OA and KBD at protein levels. Additionally, immunohistochemical staining showed that CSGalNAcT-1 and Hapln-1 were reduced in all zones of KBD and OA articular cartilage, but not significantly reduced in the up zone of OA articular cartilage. CONCLUSIONS: The CSGalNAcT-1 and Hapln-1 were down-regulated in both KBD and OA cartilage. CSGalNAcT-1 may be involved in the damage of articular cartilage of KBD and OA by regulating Hapln-1 in the Wnt/ß-catenin signalling pathway. It was indicated that CSGalNAcT-1 and Hapln-1 may play important roles in the pathogenesis of KBD and OA.

A Readout Circuit for MEMS Gas Sensor.

In recent years, the application of gas sensors is becoming more and more extensive. Driven by potential applications such as the Internet of Things, its technology development direction begins with miniaturization, integration, modularization, and intelligence. However, there is a bottleneck in the research of interface circuits, which restricts the development of gas sensors in volume, power consumption, and intelligence. To solve this problem, a MEMS gas sensor interface circuit based on ADC technology is proposed in this paper. Under the condition of the Huahong 110 nm process, the working voltage is 3.3 V, the resistance change of 100 Ω~1 MΩ can be detected, the conversion error is in the range of 0.5~1%, and the maximum power consumption is 986 µW. The overall layout area is 0.49 × 0.77 mm2. Finally, the correctness of the circuit function is verified by post-layout simulation.

MiR-19b-3p Attenuates Chondrocytes Injury by Inhibiting MAPK/NF-Κb Axis via Targeting SOCS1.

In this study, miR-19b-3p was downregulated in osteoarthritic cartilage tissues and IL-1ß-stimulated primary chondrocytes, and miR-19b-3p overexpression reversed the inhibitory effect of IL-1ß on cell viability, the promotion effects of apoptosis, inflammatory factor secretion and extracellular matrix degradation, whereas the opposite effect was observed with miR-19b-3p inhibitor. Moreover, SOCS1 is a target gene of miR-19b-3p. Furthermore, SOCS1 overexpression enhanced cell injury compared with IL-1ß alone treatment, whereas knockdown of SOCS1 restored cell damage caused by IL-1ß. Further studies revealed that miR-19b-3p promoted chondrocyte injury repair by suppressing SOCS1 expression, and we found that was mediated by blocking the MAPK/NF-κB axis. Taken together, our findings may provide a new therapeutic strategy for osteoarthritis.

[Comparative study of two elastic fixation systems in single-segment lumbar disc herniation surgery for nucleus pulposus extraction].

OBJECTIVE: To investigate the clinical application of two elastic pedicle internal fixation systems in single-segment lumbar disc herniation fenestration. METHODS: A retrospective analysis of 64 patients with lumbar intervertebral disc herniation treated by surgery from June 2019 to March 2021. According to the different elastic fixation systems placed during the operation, the patients were divided into ordinary pedicle screw elastic rod link group (elastic rod group) and a special elastic pedicle screw rigid rod fixed connection group (elastic screw group). There were 33 cases in the elastic rod group, including 18 males and 15 females, aged from 30 to 69 years old with an average of(49.18±10.23) years old;and 31 cases in the elastic screw group, including 16 males and 15 females, aged from 32 to 68 with an average of (49.81±9.24) years old. The operation time, intraoperative blood loss, postoperative wound drainage, and postoperative landing time of the two groups were recorded separately. The visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) score, and Oswestry Disability Index (ODI) were compared before and 3, 12 months after operation. The height of the adjacent vertebral space on the lateral DR film before and 12 months after the operation was measured. The clinical efficacy was evaluated by Macnab standard. RESULTS: All the patients successfully completed the operation, and were followed up. The operation time, intraoperative blood loss, postoperative wound drainage and postoperative landing time in the elastic rod group were(63.73±12.01) min, (89.55±16.07) ml, (81.67±16.00) ml, (3.45±0.75) d , while in the elastic nail group was (62.96±11.54) min, (88.35±17.14) ml, (82.29±15.40) ml, (3.29±0.78) d, the difference was not statistically significant. The symptoms of low back pain and lower extremity numbness were significantly improved in all patients after operation. There was no significant difference in VAS, JOA score and ODI between the two groups before and after surgery (P>0.05). At 12 months after operation, there was no significant difference in the height of the adjacent vertebral space between the upper adjacent vertebral body and the same segment before operation(P>0.05), and there was no significant difference between the groups before and after the operation. According to Macnab criteria, the elastic rod group was excellent in 30 cases, good in 2 cases, fair in 1 case, while the elastic nail group was excellent in 29 cases, good in 2 cases, fair in 0 cases, and there was no significant difference(Z=-0.42, P=0.68). CONCLUSION: In fenestrated nucleus pulposus extraction for lumbar disc herniation, the two elastic pedicle internal fixation systems are equally effective and can be used. The elastic screw internal fixation system has certain advantages when the distance between the two vertebral bodies is short, and the elastic rod cannot be placed or is difficult to be placed, and it is more widely used.

Prognostic value of LECT2 and relevance to immune infiltration in hepatocellular carcinoma.

Background: Previous studies have shown that Leukocyte cell-derived chemotaxin2 (LECT2) is associated with the development of HCC. However, there are still no studies with a comprehensive analysis of the role of LECT2 in hepatocellular carcinoma (HCC). Methods: TCGA data sets were used to analyze the expression of LECT2 in HCC. In addition, the prognostic value of LECT2 in HCC was also investigated. DriverDBv3 was used to analyze the Mutation, CNV, and methylation profiles of LECT2. And, validated by immunohistochemistry in 72 HCC samples. The prognostic value of LECT2 and the correlation with clinicopathological features were analyzed. The GO/KEGG enrichment analysis of LECT2 co-expression and gene set enrichment analysis (GSEA) was performed using the R software package. The PPI interaction network was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) database. Immune infiltration was estimated by the XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, CIBERSORT abs and CIBERSORT algorithms, and Spearman was used to analyzing their correlation with LECT2. Moreover, we analyzed the correlation of LECT2 expression with immune checkpoint molecules and HLA genes. Finally, we analyzed the IC50 values of six chemotherapeutic drugs by the pRRophetic package. Results: Reduced LECT2 expression levels found in HCC patients. Moreover, decreased levels of LECT2 were associated with poor overall survival, disease-free survival, disease-specific survival, and progression-free survival. Besides, methylation was significantly associated with LECT2 expression. The functional enrichment analysis revealed that LECT2 may affect HCC progression through various pathways such as JAK/STAT signaling pathway, cell cycle, and pathways in cancer. Additionally, the results showed that LECT2 expression was negatively correlated with immune infiltration of B cells, Neutrophil, Monocyte, Cancer-associated fibroblast, and Myeloid dendritic cell, and positively correlated with T cell CD8+ naive, Endothelial cell, and Hematopoietic stem cell. LECT2 expression was negatively correlated with multiple immune checkpoint molecules and HLA genes. Chemosensitivity analysis showed that chemosensitivity was lower in the LECT2 high expression group. We validated the prognostic value of LECT2 and analysis of clinicopathological features showed a lower TNM stage in the group with high expression of LECT2. Conclusion: Low expression of LECT2 in HCC is closely associated with poor prognosis, LECT2 may have potential clinical applications due to its unique immunological effects.

An m6A-Related lncRNA Signature Predicts the Prognosis of Hepatocellular Carcinoma.

Objective: The purpose of this study was to establish an N6-methylandenosine (m6A)-related long non-coding RNA (lncRNA) signature to predict the prognosis of hepatocellular carcinoma (HCC). Methods: Pearson correlation analysis was used to identify m6A-related lncRNAs. We then performed univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct an m6A-related lncRNA signature. Based on the cutoff value of the risk score determined by the X-title software, we divided the HCC patients into high -and low-risk groups. A time-dependent ROC curve was used to evaluate the predictive value of the model. Finally, we constructed a nomogram based on the m6A-related lncRNA signature. Results: ZEB1-AS1, MIR210HG, BACE1-AS, and SNHG3 were identified to comprise an m6A-related lncRNA signature. These four lncRNAs were upregulated in HCC tissues compared to normal tissues. The prognosis of patients with HCC in the low-risk group was significantly longer than that in the high-risk group. The M6A-related lncRNA signature was significantly associated with clinicopathological features and was established as a risk factor for the prognosis of patients with HCC. The nomogram based on the m6A-related lncRNA signature had a good distinguishing ability and consistency. Conclusion: We identified an m6A-related lncRNA signature and constructed a nomogram model to evaluate the prognosis of patients with HCC.

NLR, A Convenient Early-Warning Biomarker of Fatal Outcome in Patients With Severe Fever With Thrombocytopenia Syndrome.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality. Methods: A retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified. Results: A total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan-Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be <3 days. Conclusion: The SFTSV viral load and NLR showed great efficacy in predicting the fatal outcome of patients with SFTS, and NLR is a convenient and efficient early-warning biomarker that helps healthcare workers focus on patients with high risks of fatal outcomes. The efficacy of gamma-globulin provided a new idea for the treatment of SFTS, which needs further analysis in future studies.

A Pan-Cancer Analysis of the Oncogenic Role of Cell Division Cycle-Associated Protein 4 (CDCA4) in Human Tumors.

PURPOSE: To unravel the oncogenic role of CDCA4 in different cancers from the perspective of tumor immunity. METHODS: Raw data on CDCA4 expression in tumor samples and paracancerous samples were obtained from TCGA and GTEX databases. In addition, we investigated pathological stages and the survival analysis of CDCA4 in pan-cancer across Gene Expression Profiling Interactive Analysis (GEPIA) database. Cox Proportional Hazards Model shows that high CDCA4 levels are associated with several vital indicators in oncology. On the one hand, we explored the correlation between CADA4 expression and tumor immune infiltration by the TIMER tool; On the other hand, we utilized the methods of CIBERSORT and ESTIMATE computational to evaluate the proportion of tumor infiltrating immune cells (TIIC) and the amounts of stromal and immune components based on TCGA database. The use of antineoplastic drugs and the expression of CDCA4 also showed a high correlation via linear regression. Protein-Protein Interaction analysis was performed in the GeneMANIA database, and enrichment analysis was performed and predicted signaling pathways were identified by using Gene Ontology and Kyoto Encyclopedia of Genes. The correlation between CDCA4 expression with Copy number variations (CNV) and methylation is detailed, respectively. Molecular biology experiments including Western blotting, flow cytometry, EDU staining, Transwell and Wound Healing assay to validate the cancer promoting role of CDCA4 in hepatocellular carcinoma (HCC). RESULTS: Most tumors highly expressed CDCA4. Elevated CDCA4 expression was associated with poor OS and DFS. There was a significant correlation between CDCA4 expression and TITCs. Moreover, markers of TIICs exhibited distinct patterns of CDCA4 associated immune infiltration. In addition, we pay attention to the association between the expression of CDCA4 and the use of the anti-tumor drugs. CDCA4 is related to biological progress (BP), cellular component (CC) and molecular function (MF). Dopaminergic Synapse, AMPK, Sphingolipid, Chagas Disease, mRNA Surveillance were significantly enriched pathways in positive and negative correlation genes with CDCA4. CNV is thought to be a positive correlation with CDCA4 expression. Conversely, methylation is negative correlation with CDCA4 expression. Molecular biology experiments confirm a cancer promoting role for CDCA4 in HCC. CONCLUSION: CDCA4 may serve as a biomarker for cancer immunologic infiltration and poor prognosis, providing a new way of thinking for cancer treatment.

[Comparison of clinical effects of different anterior surgical methods for the treatment of single segment cervical disc herniation].

OBJECTIVE: To compare the clinical effects of different anterior surgical methods in treating single segment cervical disc herniation. METHODS: The clinical data of 46 patients with single-segment cervical disc herniation underwent surgical treatment from September 2013 to September 2018 were retrospectively analyzed. The patients were divided into three groups according to different surgical methods. Among them, 23 patients in the anterior percutanousendomic cervical dissection (APECD) group, there were 8 males and 15 females, aged (47±3) years old, prominent segments were C3,4 of 1 case, C4,5 of 6 cases, and C5,6 of 16 cases;10 patients in cervical disc replacement(CDR) group, there were 4 males and 6 females, aged (46± 3) years old, prominent segments were C3,4 of 1 case, C4,5 of 6 cases, C5,6 of 3 cases;13 patients in transcervical anterior cervical disc fusion (ACDF) group, there were 8 males and 5 females, aged (53±2) years old, protruding segments were C3,4 of 1 case, C4,5 of 3 cases, C5,6 of 9 cases. The operation time, intraoperative blood loss, and length of hospitalization were compared among three groups;visual analogue scale (VAS) and Japanese Orthopaedic Association(JOA) score were used to evaluate the clinical efficacy. RESULTS: All 46 patients were followed up for 12 to 24 (17.57±3.15)months. The follow-up time of APECD, CDR, ACDF groups were (17.30±3.25), (17.80±3.16), (17.85±2.88) months, and operation time were (95.48 ±13.85), (58.50±7.09), (76.00±15.72) min, respectively, there were no significant differences in follow-up time and operation time between two groups(P>0.05). The intraoperative blood loss of APECD, CDR, ACDF groups were (80.00±20.22), (82.60±7.20), (121.54±18.75) ml, there was significant difference between CDR group and ACDF group (P<0.05);and there was no significant difference between other groups (P>0.05). The length of hospitalization was (6.95±1.50) days in APECD group, (6.60± 0.80) days in CDR group, (6.54±0.75) days in ACDF group, and there was no significant difference between two groups (P> 0.05). At the latest follow up, VAS scores were decreasedfrom preoperative 6.78±0.83 to 2.57±0.65 in APECD group, decreased from 5.70±0.78 to 2.00±0.45 in CDR group, decreased from 6.77±0.42 to 1.38±0.49 in ACDF group. The JOA scores at final follow-up were increased from 8.91±0.97 to 13.04±1.40 in APECD group, and the improvement rate of (65±15)%;increased from 11.50±1.20 to 14.90±1.14 in CDR group, and the improvement rate of (76±19)%;increased from 8.54±0.93 to 14.00±0.96 in ACDF group, and the improvement rate of (74±8)%;there was significant difference in improvement rate between APECD group and CDR group (P<0.05). At final follow-up, the activities of the responsible segment in APECD group and CDR group were well preserved and improved (P<0.05). In the APECD group, the symptoms of two cases recurred during the mid-term follow-up (4 months and 6 months after surgery), one of which improved after strictly conservative treatment;the other one received ACDF surgery a second time, and the postoperative follow-up effect was satisfactory. CONCLUSION: The three anterior surgical approaches can achieve satisfactory clinical results for the treatment of single-segment cervical disc herniation. However, the improvement rate of the CDR group and the activity of the retained responsibility segment are better than those of the other two groups. APECD surgery may have recurrence.