The suppressive effect of the specific KCC2 modulator CLP290 on seizure in mice.

Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl- cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl-]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.

Genetic correlation, shared loci, but no causality between bipolar disorder and inflammatory bowel disease: A genome-wide pleiotropic analysis.

BACKGROUND AND AIMS: The comorbidity between bipolar disorder (BD) and inflammatory bowel disease (IBD) has been widely reported in observational studies. However, unclear whether this comorbidity reflects a shared genetic architecture. METHODS: Leveraging large-scale genome-wide association study (GWAS) summary statistics of BD, IBD and its subtypes, ulcerative colitis (UC) and Crohn's disease (CD), we performed a genome-wide pleiotropic analysis to estimate heritability and genetic correlation, identify pleiotropy loci/genes, and explore the shared biological pathway. Mendelian randomization (MR) studies were subsequently employed to infer whether the potential causal relationship is present. RESULTS: We found a positive significant genetic correlation between BD and IBD (rg = 0.10, P = 7.00 × 10-4), UC (rg = 0.09, P = 2.90 × 10-3), CD (rg = 0.08, P = 6.10 × 10-3). In cross-trait meta-analysis, a total of 29, 24, and 23 independent SNPs passed the threshold for significant association between BD and IBD, UC, and CD, respectively. We identified five novel pleiotropy genes including ZDHHC2, SCRN1, INPP4B, C1orf123, and BRD3 in both BD and IBD, as well as in its subtypes UC and CD. Pathway enrichment analyses revealed that those pleiotropy genes were mainly enriched in several immune-related signal transduction pathways and cerebral disease-related pathways. MR analyses provided no evidence for a causal relationship between BD and IBD. CONCLUSION: Our findings corroborated that shared genetic basis and common biological pathways may explain the comorbidity of BD and IBD. These findings further our understanding of shared genetic mechanisms underlying BD and IBD, and potentially provide points of intervention that may allow the development of new therapies for these co-occurrent disorders.

L1 cell adhesion molecule high expression is associated with poor prognosis in surgically resected brain metastases from lung adenocarcinoma.

OBJECTIVES: Accurate prognosis assessment across the heterogeneous population of brain metastases is very important, which may facilitate clinical decision-making and appropriate stratification of future clinical trials. Previous studies have shown the L1 Cell Adhesion Molecule (L1CAM) is potentially involved in human malignancies of multiple different samples and unfavorable survival. However, no data of L1CAM are available for the brain metastases from lung adenocarcinoma, especially for the one with neurosurgical resection. METHOD: The authors investigated the L1CAM expression in cranial metastatic lesions for patients with brain metastases from lung adenocarcinoma after neurosurgical resection using tissue microarrays that were obtained from the Department of Neurosurgery at the Cancer Hospital of the Chinese Academy of Medical Sciences. Furthermore, the relationship between L1CAM expression and clinic-pathological parameters, including overall survival time, was analyzed to assess the prognostic value of L1CAM. RESULTS: L1CAM high expression was found in 62.30% of brain metastases from lung adenocarcinoma and significantly correlated with brain metastasis number (p = 0.028) and Lung-molGPA score (p = 0.042). Moreover, L1CAM expression was an independent predictor of survival for brain metastases after neurosurgical resection in a multivariate analysis. Patients with L1CAM high expression had unfavorable overall survival time (p = 0.016). In addition, the multivariate analysis also showed age and extracranial transfer were also the independent prognostic factors for this type of patient with brain metastases. CONCLUSIONS: A subset of brain metastases from lung adenocarcinoma aberrantly expresses L1CAM. L1CAM is a novel independent prognostic factor for brain metastasis from lung adenocarcinoma after neurosurgical resection.

Deficient DNASE1L3 facilitates neutrophil extracellular traps-induced invasion via cyclic GMP-AMP synthase and the non-canonical NF-κB pathway in diabetic hepatocellular carcinoma.

Objective: Diabetic hepatocellular carcinoma (HCC) patients have high mortality and metastasis rates. Diabetic conditions promote neutrophil extracellular traps (NETs) generation, which mediates HCC metastasis and invasion. However, whether and how diabetes-induced NETs trigger HCC invasion is largely unknown. Here, we aimed to observe the effects of diabetes-induced NETs on HCC invasion and investigate mechanisms relevant to a DNA sensor cyclic GMP-AMP synthase (cGAS). Methods: Serum from diabetic patients and healthy individuals was collected. Human neutrophil-derived NETs were isolated for stimulating HCC cell invasion. Data from the SEER and TCGA databases were used for bioinformatics analysis. In HCC cells and allograft models, NETs-triggered invasion was observed. Results: Diabetic HCC patients had poorer survival than non-diabetic ones. Either diabetic serum or extracted NETs caused HCC invasion. Induction of diabetes or NETosis elicited HCC allograft invasion in nude mice. HCC cell invasion was attenuated by the treatment with DNase1. In TCGA_LIHC, an extracellular DNase DNASE1L3 was downregulated in tumor tissues, while function terms (the endocytic vesicle membrane, the NF-κB pathway and extracellular matrix disassembly) were enriched. DNASE1L3 knockdown in LO2 hepatocytes or H22 cell-derived allografts facilitated HCC invasion in NETotic or diabetic nude mice. Moreover, exposure of HCC cells to NETs upregulated cGAS and the non-canonical NF-κB pathway and induced expression of metastasis genes (MMP9 and SPP1). Both cGAS inhibitor and NF-κB RELB knockdown diminished HCC invasion caused by NETs DNA. Also, cGAS inhibitor was able to retard translocation of NF-κB RELB. Conclusion: Defective DNASE1L3 aggravates NETs DNA-triggered HCC invasion on diabetic conditions via cGAS and the non-canonical NF-κB pathway.

Identification of prognostic biomarkers for breast cancer brain metastases based on the bioinformatics analysis.

PURPOSE: The prognosis of breast cancer (BC) patients who develop into brain metastases (BMs) is very poor. Thus, it is of great significance to explore the etiology of BMs in BC and identify the key genes involved in this process to improve the survival of BC patients with BMs. PATIENTS AND METHODS: The gene expression data and the clinical information of BC patients were downloaded from TCGA and GEO database. Differentially expressed genes (DEGs) in TCGA-BRCA and GSE12276 were overlapped to find differentially expressed metastatic genes (DEMGs). The protein-protein interaction (PPI) network of DEMGs was constructed via STRING database. ClusterProfiler R package was applied to perform the gene ontology (GO) enrichment analysis of DEMGs. The univariate Cox regression analysis and the Kaplan-Meier (K-M) curves were plotted to screen DEMGs associated with the overall survival and the metastatic recurrence survival, which were identified as the key genes associated with the BMs in BC. The immune infiltration and the expressions of immune checkpoints for BC patients with brain relapses and BC patients with other relapses were analyzed respectively. The correlations among the expressions of key genes and the differently infiltrated immune cells or the differentially expressed immune checkpoints were calculated. The gene set enrichment analysis (GSEA) of each key gene was conducted to investigate the potential mechanisms of key genes involved in BC patients with BMs. Moreover, CTD database was used to predict the drug-gene interaction network of key genes. RESULTS: A total of 154 DEGs were identified in BC patients at M0 and M1 in TCGA database. A total of 667 DEGs were identified in BC patients with brain relapses and with other relapses. By overlapping these DEGs, 17 DEMGs were identified, which were enriched in the cell proliferation related biological processes and the immune related molecular functions. The univariate Cox regression analysis and the Kaplan-Meier curves revealed that CXCL9 and GPR171 were closely associated with the overall survival and the metastatic recurrence survival and were identified as key genes associated with BMs in BC. The analyses of immune infiltration and immune checkpoint expressions showed that there was a significant difference of the immune microenvironment between brain relapses and other relapses in BC. GSEA indicated that CXCL9 and GPR171 may regulate BMs in BC via the immune-related pathways. CONCLUSION: Our study identified the key genes associated with BMs in BC patients and explore the underlying mechanisms involved in the etiology of BMs in BC. These findings may provide a promising approach for the treatments of BC patients with BMs.

Climate change drives NDVI variations at multiple spatiotemporal levels rather than human disturbance in Northwest China.

Changes in land management and climate alter vegetation dynamics; however, the factors driving vegetation changes remain elusive at multiple spatiotemporal levels. Here, we assess the drivers of changes in greenness from 2000 to 2015 in Northwest China (NW China). We used multiple stepwise linear regression (MSLR), redundancy analysis (RDA), and 12 other models to quantify the impacts of precipitation and temperature metrics, gross domestic product (GDP), population, and grazing intensity on the normalized difference vegetation index (NDVI) at three administrative levels (county, town, and village), four temporal levels (yearly, May, July, and September), two vegetation types (woodland and grassland), and at annual precipitation gradients of <200, 200-400, and >400 mm. The results suggest that NW China underwent vegetation greening from 2000 to 2015. Precipitation and temperature were the most influential factors contributing to the NDVI change. Population was the main determinant of NDVI under the precipitation gradient of <200 mm, and the effect of GDP on NDVI was moderate. On the temporal scale, annual precipitation, precipitation before the previous year, and precipitation in the current year determined the NDVI in May, July, and September, respectively, for both woodland and grassland. At multiple scales, climate change was the primary driver of vegetation change in NW China, rather than human disturbance. These findings expand our understanding on drivers of NDVI at multiple levels over a long period. Measures to manage decreasing vegetation coverage may be more effective and could be implemented sooner based on predicted climate change in drylands worldwide.

L1 cell adhesion molecule high expression is associated with poor prognosis in surgically resected brain metastases from lung adenocarcinoma

Abstract Objectives Accurate prognosis assessment across the heterogeneous population of brain metastases is very important, which may facilitate clinical decision-making and appropriate stratification of future clinical trials. Previous studies have shown the L1 Cell Adhesion Molecule (L1CAM) is potentially involved in human malignancies of multiple different samples and unfavorable survival. However, no data of L1CAM are available for the brain metastases from lung adenocarcinoma, especially for the one with neurosurgical resection. Method The authors investigated the L1CAM expression in cranial metastatic lesions for patients with brain metastases from lung adenocarcinoma after neurosurgical resection using tissue microarrays that were obtained from the Department of Neurosurgery at the Cancer Hospital of the Chinese Academy of Medical Sciences. Furthermore, the relationship between L1CAM expression and clinic-pathological parameters, including overall survival time, was analyzed to assess the prognostic value of L1CAM. Results L1CAM high expression was found in 62.30% of brain metastases from lung adenocarcinoma and significantly correlated with brain metastasis number (p = 0.028) and Lung-molGPA score (p = 0.042). Moreover, L1CAM expression was an independent predictor of survival for brain metastases after neurosurgical resection in a multivariate analysis. Patients with L1CAM high expression had unfavorable overall survival time (p = 0.016). In addition, the multivariate analysis also showed age and extracranial transfer were also the independent prognostic factors for this type of patient with brain metastases. Conclusions A subset of brain metastases from lung adenocarcinoma aberrantly expresses L1CAM. L1CAM is a novel independent prognostic factor for brain metastasis from lung adenocarcinoma after neurosurgical resection.

Medium-term efficacy of arthroscopic debridement vs conservative treatment for knee osteoarthritis of Kellgren-Lawrence grades I-III.

BACKGROUND: Arthroscopic debridement is a mature treatment for knee osteoarthritis (KOA). Due to the differences in the research subjects, methods, and efficacy evaluation indexes, there are great differences in the surgical efficacy reported in the literature. AIM: To compare the medium-term efficacy of arthroscopic debridement and conservative treatment for KOA of Kellgren-Lawrence grades I-III. METHODS: Patients with KOA of Kellgren-Lawrence grades I-III who were admitted to the orthopedic clinic of our hospital from July 2018 to December 2018 and agreed to undergo arthroscopic surgery were included in an arthroscopic debridement group, and those who refused surgical treatment were included in a conservative treatment group. Gender, age, body mass index (BMI), side of KOA, American hospital for special surgery knee score (HSS score) before treatment, visual analogue scale (VAS) score during walking and rest before treatment, conservative treatment content, and surgical procedure were recorded. Outpatient visits were conducted at the 1st, 3rd, 6th, 12th, and 24th mo after treatment in the two groups. The changes of HSS score and VAS score in each group before and after treatment were statistically analyzed, and the differences of HSS score and VAS score in different treatment stages between the two groups were also compared. RESULTS: In the conservative treatment group, there were 80 patients with complete follow-up data, including 20 males and 60 females, aged 58.75 ± 14.66 years old. And in the knee arthroscopic debridement group, there were 98 patients with complete follow-up data, including 24 males and 74 females, aged 59.27 ± 14.48 years old. There was no statistically significant difference in the general data (gender, age, BMI, side of KOA, Kellgren-Lawrence grade distribution, HSS score, and VAS score) between the two groups before treatment. The HSS scores of the conservative treatment group at the 1st, 3rd, 6th, 12th, and 24th mo after treatment were significantly higher than that before treatment (P < 0.05). There was no statistical difference in HSS score of the conservative treatment group among the 1st, 3rd, 6th, 12th, and 24th mo (P > 0.05). The HSS score of the knee arthroscopic debridement group at the 1st mo after surgery was significantly higher than that before surgery (P < 0.05). HSS scores of the knee arthroscopic debridement group at the 3rd, 6th, 12th, and 24th mo were significantly higher than those before surgery and at the 1st mo after surgery (P < 0.05). There were no statistically significant differences in HSS scores at the 3rd, 6th, 12th, and 24th mo after surgery (P > 0.05). HSS scores at the 3rd, 6th, 12th, and 24th mo were significantly higher in the arthroscopic debridement group than in the conservative treatment group (P < 0.05). There was no statistical difference in HSS scores between the two groups before treatment and at the 1st mo of follow-up (P > 0.05). VAS scores during walking and rest were significantly decreased in both groups, and the VAS score during rest was significantly lower in the arthroscopic debridement group than in the conservative treatment group, but there was no significant difference in the VAS score during walking between the two groups after treatment. CONCLUSION: Compared with conservative treatment, arthroscopic debridement can significantly improve the knee resting pain and knee functional status of patients with KOA of Kellgren-Lawrence grades I-III within 2 years after treatment.