Toonanoronoids A-E, five new limonoids from Toona ciliata var. yunnanensis.

Five new B-seco-limonoids, namely toonanoronoids A-E (1-5), in conjunction with three previously reported compounds, were isolated from the EtOAc extract of the twigs and leaves of Toona ciliata var. yunnanensis. Their structures were elucidated through comprehensive spectroscopic and X-ray crystallographic analysis. The cytotoxic activities of new compounds against five human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) were screened, Compounds 4 and 5 exerted inhibition toward two tumor cell lines (HL-60, SW-480) with IC50 values between 1.7 and 5.9 µM.

Digital measurement of deciduous tooth dimensions in China: A cross-sectional survey.

OBJECTIVE: Crown dimensions data of deciduous teeth hold anthropological, forensic, and archaeological value. However, such information remains scarce for the Chinese population. This multi-center study aimed to collect a large sample of deciduous crown data from Chinese children using three-dimensional measurement methods and to analyze their dimensions. DESIGN: A total of 1592 children's deciduous dentition samples were included, and the sample size was distributed according to Northeast, North, East, Northwest, Southwest and South China. Digital dental models were reconstructed from plaster dental models. Independent sample t test, paired t test, principal component analysis (PCA), and factor analysis (FA) were used to analyze the tooth crown dimensions. RESULT: 18,318 deciduous teeth from 1592 children were included. Males exhibited slightly larger values than females. The range of sexual dimorphism percentages for each measurement was as follows: mesiodistal diameter (0.40-2.08), buccolingual diameter (0.13-2.24), and maxillogingival diameter (0.48-3.37). The FA results showed that the main trend of crown dimensions changes was the simultaneous increase or decrease in mesiodistal diameter, buccolingual diameter and maxillogingival diameter in three directions. CONCLUSION: This is the first large-scale survey of deciduous tooth crown dimensions in China, which supplements the data of deciduous tooth measurement and provides a reference for clinical application.

Alterations in oxidative stress biomarkers and helper T-cell subgroups in patients with periodontitis and IgA nephropathy.

OBJECTIVE: Investigating the changes in the oxidative stress levels and helper T lymphocyte (Th) subsets in patients with periodontitis and IgA nephropathy (IgAN) to determine their relationship. BACKGROUND: IgAN has a high prevalence, poor prognosis, and no effective cure. Accumulating evidence has implicated a close relationship between periodontitis and chronic kidney diseases, in which both IgAN and chronic periodontitis show chronic inflammation and abnormal metabolism. However, few studies have been conducted on the relationship between the two diseases from this perspective. METHODS: We divided 86 IgAN patients into patients with healthy periodontium (IgAN-H, n = 34) and patients with periodontitis IgAN (IgAN-P, n = 52); moreover, we divided 72 systemically healthy participants into patients with periodontitis (H-P, n = 35) and participants with healthy periodontium (H-H, n = 37). The proportions of Th subsets in peripheral blood were estimated using flow cytometry. Cytokine levels in plasma were assessed using cytokine assay kits. Enzyme-linked immunosorbent assay was used to evaluate the plasma levels of oxidative stress. RESULTS: Our results from analyzing the Th cell subsets indicated that Th2 cell counts in the IgAN-P group were significantly lower than those in the IgAN-H group, while Th17 cell counts were increased (p < 0.05). Moreover, the Th1/Th2 ratio and interleukin-6 levels in the IgAN-P group were significantly higher than those in the H-H group (p < 0.01). Compared with that in the H-H group, in the remaining three groups, plasma total oxidation state (TOS) levels were increased (p < 0.01), while plasma total antioxidant state (TAS) levels were decreased (p < 0.05). Furthermore, estimated glomerular filtration rate was negatively correlated with the probing depth and gingival bleeding index. IgAN was a risk factor for periodontitis, while TAS was a protective factor for periodontitis. The oxidative stress index (OSI) might be valuable for distinguishing periodontitis patients from healthy controls (area under the receiver operator characteristic curve = 0.951). CONCLUSION: IgAN is an independent risk factor of periodontitis, and the Th17 cell-mediated inflammatory response might be associated with the occurrence of periodontitis in patients with IgAN. Patients with coexisting IgAN and periodontitis exhibit increased oxidative stress, in which TOS and OSI are potential biomarkers for diagnosing periodontitis.

LDER: a classification framework based on ERP enhancement in RSVP task.

Objective.Rapid serial visual presentation (RSVP) based on electroencephalography (EEG) has been widely used in the target detection field, which distinguishes target and non-target by detecting event-related potential (ERP) components. However, the classification performance of the RSVP task is limited by the variability of ERP components, which is a great challenge in developing RSVP for real-life applications.Approach.To tackle this issue, a classification framework based on the ERP feature enhancement to offset the negative impact of the variability of ERP components for RSVP task classification named latency detection and EEG reconstruction was proposed in this paper. First, a spatial-temporal similarity measurement approach was proposed for latency detection. Subsequently, we constructed a single-trial EEG signal model containing ERP latency information. Then, according to the latency information detected in the first step, the model can be solved to obtain the corrected ERP signal and realize the enhancement of ERP features. Finally, the EEG signal after ERP enhancement can be processed by most of the existing feature extraction and classification methods of the RSVP task in this framework.Main results.Nine subjects were recruited to participate in the RSVP experiment on vehicle detection. Four popular algorithms (spatially weighted Fisher linear discrimination-principal component analysis (PCA), hierarchical discriminant PCA, hierarchical discriminant component analysis, and spatial-temporal hybrid common spatial pattern-PCA) in RSVP-based brain-computer interface for feature extraction were selected to verify the performance of our proposed framework. Experimental results showed that our proposed framework significantly outperforms the conventional classification framework in terms of area under curve, balanced accuracy, true positive rate, and false positive rate in four feature extraction methods. Additionally, statistical results showed that our proposed framework enables better performance with fewer training samples, channel numbers, and shorter temporal window sizes.Significance.As a result, the classification performance of the RSVP task was significantly improved by using our proposed framework. Our proposed classification framework will significantly promote the practical application of the RSVP task.

The role of PRX1-expressing cells in periodontal regeneration and wound healing.

The ideal outcome of wound healing is the complete restoration of the structure and function of the original tissue. Stem cells are one of the key factors in this process. Currently, the strategy of periodontal regeneration based on mesenchymal stem cells (MSCs) is generally used to expand stem cells in vitro and then transplant them in vivo. However, their clinical application is limited. In fact, the human body has the capacity to regenerate through stem cells residing in different tissues, even without external therapeutic intervention. Stem cell niches are present in many adult tissues, such as the periodontal ligament and gingiva, and stem cells might remain in a quiescent state in their niches until they are activated in response to a regenerative need. Activated stem cells can exit the niche and proliferate, self-renew, and differentiate to regenerate original structures. Thus, harnessing the regenerative potential of endogenous stem cells in situ has gained increasing attention as a simpler, safer, and more applicable alternative to stem cell transplantation. Nevertheless, there are several key problems to be solved in the application of periodontal mesenchymal stem cells. Thus, animal studies will be especially important to deepen our knowledge of the in vivo mechanisms of mesenchymal stem cells. Studies with conditional knockout mice, in which the expression of different proteins can be eliminated in a tissue-specific manner, are especially important. Post-natal cells expressing the paired-related homeobox protein 1 (PRX1 or PRRX1), a transcription factor expressed in the mesenchyme during craniofacial and limb development, have been shown to have characteristics of skeletal stem cells. Additionally, following wounding, dermal Prx1+ cells are found out of their dermal niches and contribute to subcutaneous tissue repair. Postnatal Prx1+ cells are uniquely injury-responsive. Meanwhile, current evidence shows that Prx1+ cells contribute to promote dentin formation, wound healing of alveolar bone and formation of mouse molar and periodontal ligament. Initial result of our research group also indicates Prx1-expressing cells in bone tissue around the punch wound area of gingiva increased gradually. Collectively, this review supports the future use of PRX1 cells to stimulate their potential to play an important role in endogenous regeneration during periodontal therapy.

Interference of ALOX5 alleviates inflammation and fibrosis in high glucose­induced renal mesangial cells.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), seriously threatening the health of individuals. The 5-lipoxygenase (ALOX5) gene has been reported to be associated with diabetes, but whether it is involved in DN remains unclear. The present study aimed to explore the role of ALOX5 in DN and to clarify the potential mechanism. Mouse renal mesangial cells (SV40 MES-13) were treated with high glucose (HG) to mimic a DN model in vitro. The expression level of ALOX5 was assessed using reverse transcription-quantitative PCR and western blotting. Cell Counting Kit-8 and flow cytometric assays were performed to determine cell proliferation, the cell cycle and apoptosis. Immunofluorescence was carried out to detect the expression of Ki67 and proliferating cell nuclear antigen (PCNA). The inflammatory cytokines were assessed using ELISA. The expression of fibrosis- and NF-κB-related proteins was determined using western blotting. The results revealed that ALOX5 was significantly upregulated in HG-induced SV40 MES-13 cells. Interference of ALOX5 greatly hindered HG-induced cell viability loss, as well as increasing the expression of Ki67 and PCNA. In addition, HG induced cell cycle arrest in the G1 phase and cell apoptosis, which were then partly abolished by interference of ALOX5. Moreover, the elevated production of inflammatory cytokines and upregulated fibrosis-related proteins induced by HG were weakened by interference of ALOX5. Eventually, interference of ALOX5 was found to reduce the activity of NF-κB signaling in HG-induced SV40 MES-13 cells. Collectively, interference of ALOX5 serves as a protective role in HG-induced kidney cell injury, providing a potential therapeutic strategy of DN treatment.

Effect of type 2 diabetes mellitus and periodontitis on the Th1/Th2 and Th17/Treg paradigm.

PURPOSE: To investigate the effect of type 2 diabetes mellitus (T2DM) and periodontitis on the Th1/Th2/Th17/Treg paradigm. METHODS: A total of 107 volunteers (aged 18-78 years) were recruited. Peripheral blood samples from patients with periodontitis and T2DM (n= 43), patients with periodontitis only (n= 20), patients with T2DM only (n= 23), and healthy controls (n= 21) were collected. Blood pressure, glycated hemoglobin, fasting plasma glucose, probing depth, gingival index, and clinical attachment loss were measured. The circulating proportions of Th1, Th2, Th17, and Treg cells were estimated by flow cytometry. The data were analyzed by a 2x2 factorial ANOVA. RESULTS: We observed higher ratios of Th1/Th2 and Th17/Treg cells among patients with T2DM (P< 0.05) than among healthy controls. The proportion of Th17 cells in patients with periodontitis and T2DM was higher than that in other groups (P< 0.05). T2DM exhibited a predominant effect on the proportion of Th1 cells (F= 18.127, P= 0.000) and the Th17/Treg ratio (F= 45.384, P= 0.000). A significant "T2DM x periodontitis" interaction effect on the proportion of Th2, Th17, Treg cells, and the Th1/Th2 ratio (P< 0.05) was also noticed. The area under curve of Th17 was 0.711 (95% CI= 0.584 to 0.803, P< 0.01) in the receiver operating characteristic curve analysis. CLINICAL SIGNIFICANCE: The results suggest that the proportion of Th2, Th17, Treg cells and the Th1/Th2 ratio is indicative of immune activation and inflammation, which are evident in patients with type 2 diabetes mellitus (T2DM) and periodontitis. The data indicate that the high expression of Th17 cells may be a relevant biological factor that can be associated with an increased risk of developing chronic periodontitis in patients with T2DM.

Comprehensive Analysis of the Mechanism of Periodontitis-Related mRNA Expression Combined with Upstream Methylation and ceRNA Regulation.

Background: Periodontitis is a multifactorial disease mainly caused by the formation of plaque biofilm, which can lead to the gradual destruction of tooth-supporting tissues. Current research on the genetics and epigenetics of periodontitis remains relatively limited, and the molecular mechanisms remain largely unknown. Objective: Our aims were to construct competitive endogenous RNA (ceRNA) network and determine DNA methylation patterns of target genes to help elucidate the pathogenesis of periodontitis. Methods: We analyzed the expression profiles of the GSE16134, GSE54710, GSE10334, and GSE59932 datasets from the Gene Expression Omnibus database through the weighted gene coexpression network analysis system and screened mRNAs that are regulated by the level of methylation and are associated with the occurrence of periodontitis. Next, a lncRNA-miRNA-mRNA ceRNA network was constructed using databases including miRanda and TargetScan. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted for genes in the clinically significant modules. Finally, a protein-protein interaction network was built. Results: We finally identified four mRNAs, four miRNAs, and six lncRNAs as shared differentially expressed genes related to the periodontitis inflammation pathway. IL-6, IFNA17, CXCL12, and TNFRSF13C were identified as key genes whose expression was significantly enriched in the nuclear factor κB and TLR4 pathways. Moreover, the expression of 28 genes were downregulated by hypermethylation and 70 genes were upregulated by hypomethylation. Conclusions: The constructed ceRNA network can improve our understanding of the pathogenesis of periodontitis. Candidate mRNAs from the ceRNA network could serve as new therapeutic targets and prognostic biomarkers in periodontitis.

Association between CYP2B6 c.516G >T variant and acute leukaemia: A protocol for systematic review and meta-analysis.

BACKGROUND: Acute leukemia (AL) is a kind of malignant tumor of hematopoietic system. A number of studies have suggested that Single Nucleotide Polymorphisms are significantly associated with risk of AL. Present study performs meta-analysis to evaluate the association between CYP2B6 c.516G>T variant and AL risk. METHODS: Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang were searched for literatures to September 30, 2019, both in English and Chinese. Relative risk and its 95% confidence intervals were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 13.0. software. RESULTS: A total of 7 studies, including 1038 cases and 1648 controls, were analyzed. Our results indicated that CYP2B6 c.516G>T variant was significantly related to an increased the risk of AL under dominant model, recessive model, homozygote model, and allelic model. In addition, subgroup analyses were also performed by disease classification, country, and study design. No significant associations were obtained between CYP2B6 c.516G>T variant and the risk of AL under the recessive model in the design of hospital-based (relative risk = 0.98; 95% confidence interval: 0.95-1.01; P  = 0.118). CONCLUSION: Our meta-analysis indicated that the CYP2B6 variant is significantly associated with AL risk, in which CYP2B6 c.516G>T is related to an increased risk of AL.

Research progress on the role of T helper cells 17 and interleukin 17 in oral mucosal diseases / 口腔疾病防治

@#T helper 17 (Th17) cells are a new type of CD4+ T helper cell. They participate in the immune and inflammatory response by secreting specific interleukin-17 (IL-17). In oral mucosal diseases, oral lichen planus (OLP), recurrent aphthous ulcer (RAU) and Behcet′s disease (BD) are associated with Th17 cells and IL-17. There were 17 kinds of proteins in the saliva of patients with OLP that could upregulate the expression of Th17 cells and induce the secretion of IL-17. IL-17 can stimulate epithelial cells, endothelial cells and fibroblasts to produce a variety of cytokines, such as IL-6, IL-8, granulocyte macrophage colony-stimulating factor and cell adhesion molecule-1, leading to the production and aggravation of inflammation. Th17/Tc17 cell-targeted therapy can significantly improve the clinical symptoms of OLP patients′ mucosa and skin. IL-17 can stimulate oral keratinocytes through the IL-17RA or IL-17RE receptor and produce proinflammatory effects in RAU. Th17 cells in the peripheral blood of BD patients are significantly increased, while Treg cells are significantly decreased.

Research progress on micro-osteoperforation-assisted orthodontic treatment / 口腔疾病防治

@#As a minimally invasive procedure, micro-osteoperforations (MOPs) achieve desired therapeutic effect with minimal surgical intervention. The operation is relatively simple, and the effect of assisted orthodontic treatment is obvious. However, due to the lack of long-term follow-up studies, there is no unified consensus on the long-term stability of the procedure. This article reviews the research status of MOPs, biological and biomechanical mechanisms, clinical applications and limitations. MOPs can shorten orthodontic treatment time and accelerate tooth movement by exerting regional acceleratory phenomena (RAP). At the same time, this procedure will not damage the health of the periodontal tissue, and the postoperative bleeding and postoperative reaction are minor. In addition, the pain and discomfort of patients were relatively mild and acceptable. However, it also has limitations, mainly including the limited time of the RAP effect of MOPs. Although this procedure is a minimally invasive surgery, there is still a risk of treating regional bone defects. At present, it is still necessary to increase the sample size and extend the follow-up time to evaluate the long-term stability of MOPs.

Thermodynamic Analysis of a Hybrid Trigenerative Compressed Air Energy Storage System with Solar Thermal Energy.

The comprehensive utilization technology of combined cooling, heating and power (CCHP) systems is the leading edge of renewable and sustainable energy research. In this paper, we propose a novel CCHP system based on a hybrid trigenerative compressed air energy storage system (HT-CAES), which can meet various forms of energy demand. A comprehensive thermodynamic model of the HT-CAES has been carried out, and a thermodynamic performance analysis with energy and exergy methods has been done. Furthermore, a sensitivity analysis and assessment capacity for CHP is investigated by the critical parameters effected on the performance of the HT-CAES. The results indicate that round-trip efficiency, electricity storage efficiency, and exergy efficiency can reach 73%, 53.6%, and 50.6%, respectively. Therefore, the system proposed in this paper has high efficiency and flexibility to jointly supply multiple energy to meet demands, so it has broad prospects in regions with abundant solar energy resource.

Long non-coding RNA BLACAT1 expedites osteosarcoma cell proliferation, migration and invasion via up-regulating SOX12 through miR-608.

BACKGROUND: Osteosarcoma is the most common type of bone malignancy. Increasing evidence indicated that long non-coding RNAs (lncRNAs) possess multiple functions in the development of cancer and can be used as indicators of prognosis and diagnosis. LncRNA BLACAT1 has been found to promote the proliferation of breast cancer cells. However, the role of BLACAT1 in osteosarcoma remains largely unknown. METHODS: QRT-PCR analysis was employed to evaluate mRNA expressions. Western blot was performed to measure relevant protein level. Colony formation and EdU assays were conducted to certify proliferative ability. TUNEL assay was finalized to assess apoptotic cells. Wound-healing and transwell assays were utilized for the exploration of migrating and invasive abilities. The subcellular distribution of BLACAT1 was studied by nucleus-cytoplasm separation assay. Relevant mechanical experiments were combined to elucidate molecular relationship between molecules. RESULTS: BLACAT1 was highly expressed in osteosarcoma. BLACAT1 promoted the proliferation and migration of osteosarcoma cells. BLACAT1 acted as a sponge for miR-608 to augment the expression of Sex determining region Y-box protein 12 (SOX12), the direct target of miR-608. Further, inhibiting miR-608 recovered the repressive effect of silenced BLACAT1 on the malignant behaviors of osteosarcoma cells. CONCLUSION: This study highlighted the contribution of BLACAT1/miR-608/SOX12 axis to the progression of osteosarcoma, suggesting novel targets for osteosarcoma therapy.

SP1-mediated upregulation of LINGO-1 promotes degeneration of retinal ganglion cells in optic nerve injury.

BACKGROUNDS: Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system-specific leucine-rich repeat protein, LINGO-1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO-1 signaling and contribute to LINGO-1-mediated death of RGCs are unclear. METHODS: The expression of SP1 was profiled in optic nerve crush (ONC)-injured RGCs. LINGO-1 level was examined after SP1 overexpression by qRT-PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO-1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO-1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA. RESULTS: We demonstrate that SP1 was upregulated in ONC-injured RGCs. SP1 was bound to the LINGO-1 promoter, which led to increased expression of LINGO-1. Treatment with recombinant Nogo-66 or LINGO-1 promoted apoptosis of RGCs cultured under serum-deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO-1 colocalized and were upregulated in ONC-injured retinas. Silencing of SP1 in vivo reduced LINGO-1 expression and protected the structure of RGCs from ONC-induced injury, but there was no sign of recovery in VEP. CONCLUSIONS: Our findings imply that SP1 regulates LINGO-1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO-1-mediated RGC death in optic nerve injury.

Technological Research of a Clean Energy Router Based on Advanced Adiabatic Compressed Air Energy Storage System.

As a fundamental infrastructure of energy supply for future society, energy Internet (EI) can achieve clean energy generation, conversion, storage and consumption in a more economic and safer way. This paper demonstrates the technology principle of advanced adiabatic compressed air energy storage system (AA-CAES), as well as analysis of the technical characteristics of AA-CAES. Furthermore, we propose an overall architectural scheme of a clean energy router (CER) based on AA-CAES. The storage and mutual conversion mechanism of wind and solar power, heating, and other clean energy were designed to provide a key technological solution for the coordination and comprehensive utilization of various clean energies for the EI. Therefore, the design of the CER scheme and its efficiency were analyzed based on a thermodynamic simulation model of AA-CAES. Meanwhile, we explored the energy conversion mechanism of the CER and improved its overall efficiency. The CER based on AA-CAES proposed in this paper can provide a reference for efficient comprehensive energy utilization (CEU) (93.6%) in regions with abundant wind and solar energy sources.

Operative treatments compared with nonoperative treatment of displaced midshaft clavicular fractures.

BACKGROUND: Few reports on external fixation to treat displaced midshaft clavicular fractures exist. We sought to compare the clinical effects of external fixation, plate fixation, and nonoperative treatment for treating displaced midshaft clavicular fractures in adults. MATERIAL AND METHODS: Eighty-nine patients with a displaced midshaft fracture of the clavicle were selected (according to inclusion criteria) for a retrospective analysis and assigned to either operative treatment with external fixation (29 patients), plate fixation (30 patients) or nonoperative treatment with a sling (30 patients). The average follow-up period is 32 months. Outcome analysis included: Constant shoulder score (CSS); disabilities of the arm, shoulder and hand score (DASH); nonunion rate; satisfaction of shoulder appearance. RESULTS: Eighty-five cases were successfully followed up. No significant difference was observed between external fixation and plate fixation (p > 0.05 and p = 0.132, respectively). The operative groups achieved better effects (p < 0.001) compared to the nonoperative treatment. The healing time of the three groups were: 10.4 ± 2.3 weeks for external fixation; 12.1 ± 2.5 weeks for plate fixation; and 15.7 ± 2.2 weeks for nonoperative treatment. In the follow-up, patients in the external fixation group (96%) and plate fixation group (93%) were more likely to be satisfied with the appearance of the shoulder than were those in the nonoperative group (77%). CONCLUSION: The external fixation and plate fixation are overall better than the nonoperative treatment. As to choose between the two, it depends on the local soft tissue condition, surgeon's techniques, communication between doctor and patients and so on.

Inhibition of the leucine-rich repeat protein lingo-1 enhances RGC survival in optic nerve injury.

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (lingo-1) is selectively expressed on neurons and oligodendrocytes in the central nervous system and acts as a negative regulator in neural repair, implying a potential role in optic neuropathy. The aim of the present study was to determine whether adeno-associated virus serotype 2 (AAV2) vector-mediated transfer of lingo-1 short hairpin RNA could reduce nerve crush-induced axonal degeneration and enhance axonal regeneration following optic nerve (ON) injury in vivo. The expression of lingo-1 was knocked down in vivo using a green fluorescent protein (GFP)-tagged AAV2 encoding lingo-1 shRNA via intravitreal injection in adult Sprague-Dawley rats. Silencing effects of AAV2-lingo-1-shRNA were confirmed by detecting GFP labelling of RGCs, and by quantifying lingo-1 expression levels with reverse transcription-quantitative polymerase chain reaction and western blotting. Rats received an intravitreal injection of AAV2-lingo-1-shRNA or negative control shRNA. The ON crush (ONC) injury was performed 2 weeks after the intravitreal injection. RGC density, lesion volume of the injured ON and the visual electrophysiology [flash visual evoked potential (F-VEP)] at different time points post-injury were determined. Transduction with lingo-1-shRNA decreased lingo-1 expression levels and promoted RGC survival following ONC. Lingo-1-shRNA promoted ON tissue repair and functional recovery. The mechanism underlying the effect of AAV2-lingo-1-shRNA on RGCs may be the phosphorylation of protein kinase B (Akt) at Ser473 and activation of the Akt signaling pathway acting downstream of lingo-1. The results of the current study indicate that the inhibition of lingo-1 may enhance RGC survival and facilitate functional recovery following ON injury, representing a promising potential strategy for the repair of optic neuropathy.

A Pharmacogenomic Landscape in Human Liver Cancers.

Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes.

Human liver cancers, including hepatocellular carcinomas and intra-hepatic cholangiocarcinomas, are often diagnosed late with poor prognosis. A better understanding of cancer initiation could provide potential preventive therapies and increase survival. Models for studying human liver cancer initiation are largely missing. Here, using directly reprogrammed human hepatocytes (hiHeps) and inactivation of p53 and RB, we established organoids possessing liver architecture and function. HiHep organoids were genetically engineered to model the initial alterations in human liver cancers. Bona fide hepatocellular carcinomas were developed by overexpressing c-Myc. Excessive mitochondrion-endoplasmic reticulum coupling induced by c-Myc facilitated hepatocellular carcinoma initiation and seemed to be a target of preventive treatment. Furthermore, through the analysis of human intra-hepatic cholangiocarcinoma-enriched mutations, we demonstrate that the RAS-induced lineage conversion from hepatocytes to intra-hepatic cholangiocarcinoma cells can be prevented by the combined inhibition of Notch and JAK-STAT. Together, hiHep organoids represent a system that can be genetically manipulated to model cancer initiation and identify potential preventive therapies.

A 4-miRNA signature act as a novel prognostic biomarker in patients with Sarcoma.

BACKGROUND: A sarcoma is a rare form of cancer that can develop throughout the body and has a poor prognosis. Micro RNA may be used as molecular markers in sarcoma patients to predict patient outcomes. METHODS: In this study, miRNA expression data of sarcoma tissues samples were downloaded from The Cancer Genome Atlas (TCGA) database. The univariable cox regression and log likelihood were performed to screen the miRNAs related with prognosis. The Cox proportional hazard regression model was used to establish a multi-gene prognostic model based on the expression value of the miRNAs. The survival curve was created by the KM method. The interaction network and function annotation of the target genes were analyzed to investigate the mechanism of the key miRNAs. RESULTS: Hsa-miR-190b, hsa-miR-3170, hsa-miR-4762, hsa-miR-18a were identified and used to establish the prediction model. The target genes of the 4 miRNAs were involved in cancer signaling pathways as revealed by KEGG. Cox regression analysis showed that the prognostic model of miRNA was an independent influencing factor in Sarcoma patients (P<0.05). Survival analysis confirmed that the overall survival rate of sarcoma patients with low risk scores was significantly higher than those with high risk scores (P<0.01). CONCLUSIONS: The miRNA prognosis model established in this study can be used to predict the prognosis of Sarcoma patients, and these 4 miRNAs may involve in cancer signaling pathways by regulating these target genes.