Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-ß signaling.

The cytokine transforming growth factor-ß (TGF-ß) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-ß is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature1,2. Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS)3-5. Whether monocytes require TGF-ß for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-ß signaling in CX3CR1+ monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-ß is thus crucial for the functional integration of monocytes into the CNS microenvironment.

Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation.

Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase 1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS-challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using ß-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS-like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid-specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells.

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

Remote cerebellar hemorrhage following repeated lumbar punctures.

BACKGROUND: Remote cerebellar hemorrhage (RCH) is a rare complication in neurosurgery. No case of RCH secondary to repeated lumbar punctures (LPs) has been previously reported. CASE PRESENTATION: A 49-year-old man presented with impaired consciousness following persistent fever. Cerebrospinal fluid examination showed high opening pressure, elevated white blood cells, increased protein level, and decreased glucose level, resulting in a diagnosis of bacterial meningoencephalitis. Treatment with repeated LPs and intrathecal injection of ceftriaxone resulted in an improvement in neurological symptoms. However, on day 31 of treatment, brain magnetic resonance image (MRI) showed streaky bleeding in bilateral cerebellum (zebra sign), leading to a diagnosis of RCH. Close observation and repeated brain MRI imaging without specific treatments led to the absorption of bilateral cerebellar hemorrhage, and the patient was discharged with improved neurological symptoms. Repeated brain MRI scans one month after discharge showed that bilateral cerebellar hemorrhage had improved, and had disappeared one year after discharge. CONCLUSION: We reported a rare occurrence of LPs-induced RCH presenting as isolated bilateral inferior cerebellar hemorrhage. Clinicians should be vigilant of the risk factors for RCH, closely monitoring patients' clinical symptoms and neuroimaging findings to determine the need for specialized treatment. Furthermore, this case highlights the importance of ensuring the safety of LPs and managing any potential complications appropriately.

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges.

Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented.

Role of N6-methyladenosine methylation in glioma: recent insights and future directions.

Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.

Phrenic nerve stimulation for the treatment of central sleep apnea in patients with heart failure.

OBJECTIVE: Central sleep apnea (CSA) is associated with increased morbidity and mortality in patients with heart failure (HF). We aimed to explore the effectiveness of phrenic nerve stimulation (PNS) on CSA in patients with HF. METHODS: This was a prospective and non-randomized study. The stimulation lead was inserted into the right brachiocephalic vein and attached to a proprietary neurostimulator. Monitoring was conducted during the implantation process, and all individuals underwent two-night polysomnography. RESULTS: A total of nine subjects with HF and CSA were enrolled in our center. There was a significant decrease in the apnea-hypopnea index (41 ± 18 vs 29 ± 25, p = 0.02) and an increase in mean arterial oxygen saturation (SaO2) (93% ± 1% vs 95% ± 2%, p = 0.03) after PNS treatment. We did not observe any significant differences of oxygen desaturation index (ODI) and SaO2 < 90% (T90) following PNS. Unilateral phrenic nerve stimulation might also categorically improve the severity of sleep apnea. CONCLUSION: In our non-randomized study, PNS may serve as a therapeutic approach for CSA in patients with HF.

Spinal Cord Injury Induces Permanent Reprogramming of Microglia into a Disease-Associated State Which Contributes to Functional Recovery.

Microglia are resident myeloid cells of the CNS. Recently, single-cell RNA sequencing (scRNAseq) has enabled description of a disease-associated microglia (DAM) with a role in neurodegeneration and demyelination. In this study, we use scRNAseq to investigate the temporal dynamics of immune cells harvested from the epicenter of traumatic spinal cord injury (SCI) induced in female mice. We find that as a consequence of SCI, baseline microglia undergo permanent transcriptional reprogramming into a previously uncharacterized subtype of microglia with striking similarities to previously reported DAM as well as a distinct microglial state found during development. Using a microglia depletion model we showed that DAM in SCI are derived from baseline microglia and strongly enhance recovery of hindlimb locomotor function following injury.SIGNIFICANCE STATEMENT Although disease-associated microglia (DAM) have been the subject of strong research interest during recent years (Keren-Shaul, 2017; Jordão, 2019), their cellular origin and their role in "normal" acute injury processes is not well understood. Our work directly addresses the origin and the role of DAM in traumatic injury response. Further, we use a microglia depletion model to prove that DAM in spinal cord injury (SCI) are indeed derived from homeostatic microglia, and that they strongly enhance recovery. Thus, in this work we significantly expand the knowledge of immune response to traumatic injury, demonstrate the applicability to human injury via our unique access to injured human spinal cord tissue, and provide the community with a comprehensive dataset for further exploration.

An overlooked subset of Cx3cr1wt/wt microglia in the Cx3cr1CreER-Eyfp/wt mouse has a repopulation advantage over Cx3cr1CreER-Eyfp/wt microglia following microglial depletion.

BACKGROUND: Fluorescent reporter labeling and promoter-driven Cre-recombinant technologies have facilitated cellular investigations of physiological and pathological processes, including the widespread use of the Cx3cr1CreER-Eyfp/wt mouse strain for studies of microglia. METHODS: Immunohistochemistry, Flow Cytometry, RNA sequencing and whole-genome sequencing were used to identify the subpopulation of microglia in Cx3cr1CreER-Eyfp/wt mouse brains. Genetically mediated microglia depletion using Cx3cr1CreER-Eyfp/wtRosa26DTA/wt mice and CSF1 receptor inhibitor PLX3397 were used to deplete microglia. Primary microglia proliferation and migration assay were used for in vitro studies. RESULTS: We unexpectedly identified a subpopulation of microglia devoid of genetic modification, exhibiting higher Cx3cr1 and CX3CR1 expression than Cx3cr1CreER-Eyfp/wtCre+Eyfp+ microglia in Cx3cr1CreER-Eyfp/wt mouse brains, thus termed Cx3cr1highCre-Eyfp- microglia. This subpopulation constituted less than 1% of all microglia under homeostatic conditions, but after Cre-driven DTA-mediated microglial depletion, Cx3cr1highCre-Eyfp- microglia escaped depletion and proliferated extensively, eventually occupying one-third of the total microglial pool. We further demonstrated that the Cx3cr1highCre-Eyfp- microglia had lost their genetic heterozygosity and become homozygous for wild-type Cx3cr1. Therefore, Cx3cr1highCre-Eyfp- microglia are Cx3cr1wt/wtCre-Eyfp-. Finally, we demonstrated that CX3CL1-CX3CR1 signaling regulates microglial repopulation both in vivo and in vitro. CONCLUSIONS: Our results raise a cautionary note regarding the use of Cx3cr1CreER-Eyfp/wt mouse strains, particularly when interpreting the results of fate mapping, and microglial depletion and repopulation studies.

Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy.

BACKGROUND: Missense mutations in the mitochondrial alanyl-tRNA synthetase 2 (AARS2) gene are clinically associated with infantile mitochondrial cardiomyopathy or adult-onset leukoencephalopathy with early ovarian failure. To date, approximately 40 cases have been reported related to AARS2 mutations, while its genetic and phenotypic spectrum remains to be defined. CASE PRESENTATION: We identified a 24-year-old Chinese female patient with adult-onset leukoencephalopathy carrying novel compound heterozygous pathogenic mutations in the AARS2 gene (c.718C > T and c.1040 + 1G > A) using a whole-exome sequencing approach. CONCLUSIONS: Our findings further extend the mutational spectrum of AARS2-related leukoencephalopathy and highlight the importance of the whole-exome sequencing in precisely diagnosing adult-onset leukoencephalopathies.

Uncovering sex differences of rodent microglia.

There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.

Mild encephalitis/encephalopathy with a reversible splenial lesion associated with respiratory syncytial virus infection in infants.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinicoradiologic syndrome typically characterized by transient mild encephalitis or encephalopathy with reversible lesions being found in the splenium of corpus callosum (SCC) by magnetic resonance imaging (MRI). A variety of pathogens including influenza virus, rotavirus, and adenovirus associated with MERS have been reported. However, respiratory syncytial virus (RSV)-related MERS is relatively rare in infants. In this study, we report two Chinese infants who suffered from RSV-related MERS. Both infants manifested as fever, seizure, and altered states of consciousness with confirmed detections of RSV-RNA in the specimens from throat swab. Clinical symptoms/signs such as apnea and shallow breathing were also noted in these two infants. Furthermore, brain MRI images indicated reversible isolated lesions with transiently reduced diffusion in the SCC. Fortunately, both of these two infants recovered completely following treatment within a month. Our study suggests that RSV may serve as a novel causative agent for MERS in infants. Clinicians should focus more attention on RSV-related MERS in infants in order to improve early accurate diagnosis and therapeutic decision making.

Clinical features and management of coexisting anti-N-methyl-D-aspartate receptor encephalitis and myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis: a case report and review of the literature.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune encephalitis caused by antibodies targeting the GluN1 subunit of NMDA receptors. Myelin oligodendrocyte glycoprotein (MOG) antibody disorders are now widely accepted as peculiar neuroimmunological diseases with specific clinical and pathological features. Some rare cases of overlapping anti-NMDA receptor encephalitis and MOG antibody-associated diseases have been reported, presenting complex clinical symptoms that make the disease more difficult to recognize. METHOD: In accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, the terms "NMDAR" and "MOG," "NMDAR" and "demyelination," and "MOG" and "encephalitis" were searched in PubMed. Clinical cases with dual-positive anti-NMDA cerebrospinal fluid receptors and MOG serum antibodies during the disease course were included in this study. RESULTS: A total of 25 patients were analyzed in this study. The age at onset ranged from 3 to 54 years. The median number of relapses was 2.8. Administration of intravenous methylprednisolone and immunoglobulin was the most widely used treatment strategy (19/25 patients). Second-line treatments such as administration of mycophenolate mofetil, rituximab, interferon-ß, azathioprine, cyclophosphamide, and temozolomide were also reported, followed by good outcomes. CONCLUSIONS: The rates of coexisting anti-NMDA receptor encephalitis and MOG antibody-associated encephalomyelitis may be underestimated. Clinical symptoms such as seizures and cognitive decline accompanied by atypical central nervous system demyelination serve as warning signs of possible coexisting anti-NMDA receptor encephalitis and MOG antibody-associated encephalomyelitis. These patients could achieve good outcomes under proper immunotherapies.

Role of the SphK-S1P-S1PRs pathway in invasion of the nervous system by SARS-CoV-2 infection.

Global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing. Before an effective vaccine is available, the development of potential treatments for resultant coronavirus disease 2019 (COVID-19) is crucial. One of the disease hallmarks is hyper-inflammatory responses, which usually leads to a severe lung disease. Patients with COVID-19 also frequently suffer from neurological symptoms such as acute diffuse encephalomyelitis, brain injury and psychiatric complications. The metabolic pathway of sphingosine-1-phosphate (S1P) is a dynamic regulator of various cell types and disease processes, including the nervous system. It has been demonstrated that S1P and its metabolic enzymes, regulating neuroinflammation and neurogenesis, exhibit important functions during viral infection. S1P receptor 1 (S1PR1) analogues including AAL-R and RP-002 inhibit pathophysiological responses at the early stage of H1N1 virus infection and then play a protective role. Fingolimod (FTY720) is an S1P receptor modulator and is being tested for treating COVID-19. Our review provides an overview of SARS-CoV-2 infection and critical role of the SphK-S1P-SIPR pathway in invasion of SARS-CoV-2 infection, particularly in the central nervous system (CNS). This may help design therapeutic strategies based on the S1P-mediated signal transduction, and the adjuvant therapeutic effects of S1P analogues to limit or prevent the interaction between the host and SARS-CoV-2, block the spread of the SARS-CoV-2, and consequently treat related complications in the CNS.

Absence of microglia or presence of peripherally-derived macrophages does not affect tau pathology in young or old hTau mice.

Microglia are implicated in the pathophysiology of several neurodegenerative disorders, including Alzheimer's disease. While the role of microglia and peripheral macrophages in regulating amyloid beta pathology has been well characterized, the impact of these distinct cell subsets on tau pathology remains poorly understood. We and others have recently demonstrated that monocytes can engraft the brain and give rise to long-lived parenchymal macrophages, even under nonpathological conditions. We undertook the current study to investigate the regulation of tau pathology by microglia and peripheral macrophages using hTau transgenic mice, which do not exhibit microglial activation/pathology or macrophage engraftment. To assess the direct impact of microglia on tau pathology we developed a protocol for long-term microglial depletion in Cx3cr1CreER R26DTA mice and crossed them with hTau mice. We then depleted microglia up to 3 months in both young and old mice, but no net change in forebrain soluble oligomeric tau or total or phosphorylated levels of aggregated tau was recorded. To investigate the consequence of peripherally-derived parenchymal macrophages on tau aggregation we partially repopulated the hTau microglial pool with peripheral macrophages, but this also did not affect levels of tau oligomers or insoluble aggregates. Our study questions the direct involvement of microglia or peripheral macrophages in the development of tau pathology in the hTau model.

Transitional B cells involved in autoimmunity and their impact on neuroimmunological diseases.

Transitional B cells (TrB cells) represent a crucial link between immature B cells in the bone marrow and mature peripheral B cells. Although TrB cells represent one of the regulatory B cell subpopulations in healthy individuals, the frequency of CD24hiCD38hi TrB cells in circulation may be altered in individuals with autoimmune diseases, such as multiple sclerosis, neuromyelitisoptica spectrum disorders, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, and juvenile dermatomyositis. Although TrB cells play regulatory roles under inflammatory conditions, consequences of their functional impairment vary across autoimmune diseases. Since the origin, development, and function of TrB cells, especially in humans, remain unclear and controversial, this review aimed to discuss the characteristics of TrB cells at steady state and explore their role in various immune diseases, including autoimmune rheumatic diseases and neuroimmunological diseases.

Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis.

Background: Multiple sclerosis (MS) is a demyelinating and disabling inflammatory disease of the central nervous system. MS is triggered by complex environmental factors which mostly affect genetically the susceptible young people. Emerging data has suggested that changes of homocysteine (Hcy), Vitamin B12 and folate serum levels may be associated with MS. However, previous findings are not always consistent. Methods: In this study, we aimed to investigate the relationships between MS and Hcy, Vitamin B12 and folate with updated available data (until September, 2019). The diagnosis of MS was performed based on international criteria for the diagnosis of MS, including magnetic resonance imaging and cerebrospinal fluid tests. We searched the databases including PubMed, EMBASE, Cochrane Library and ScienceDirect. After data collection, separate analyses based on random-effect models were used to test for relationships between MS and Hcy, Vitamin B12 or folate blood levels. The effective sizes were estimated by the combined standardized mean difference (SMD) and associated 95% confidence interval (CI). Results: Based on the inclusion criteria, a total of 21 original studies with 1738 MS patients and 1424 controls were included in this study. There were 17 studies for measuring Hcy, 16 studies for measuring Vitamin B12 and 13 studies for measuring folate in patients with MS, respectively. Specifically, patients with MS had higher serum levels of Hcy (SMD: 0.64; 95% CI:0.33, 0.95; P <0.0001) compared with control groups. There were no significant differences of SMD for Vitamin B12 (SMD: -0.08; 95% CI: -0.35, 0.20; P=0.58) or folate (SMD: 0.07; 95% CI: -0.14, 0.28; P=0.52) between MS and controls. Subgroup analysis demonstrated that there was statistically significant difference for Hcy between relapsing-remitting MS (RRMS) patients and controls with a SMD of 0.67 (95% CI: 0.21, 1.13; P=0.004). However, no significant difference of Hcy serum levels between secondary progressive MS patients or primary progressive MS patients and controls was noted in this study. In addition, there was no significant difference of Hcy levels in females (SMD: 0.22; 95% CI: -0.16, 0.60; P=0.25) or males (SMD: 0.56; 95% CI: -0.13, 1.26; P=0.11) between MS patients and controls. Conclusions: Higher serum levels of Hcy were noted in patients with MS when compared with control groups. And the difference was especially significant between RRMS patients and controls. Hcy may play an important role in the pathogenesis of MS. Functional studies are required to assess the effects of Hcy on patients with MS at the molecular level.

Astragaloside IV suppresses transforming growth factor-ß1-induced epithelial-mesenchymal transition through inhibition of Wnt/ß-catenin pathway in glioma U251 cells.

Astragaloside IV (AS#IV) has previously demonstrated antitumoractivity. We investigated the effect and mechanisms of AS#IV in relation to epithelial-mesenchymal transition (EMT), viainterference with the Wnt/ß-catenin signaling pathway in gliomaU251 cells. Induction of glioma U251 cells by transforming growthfactor (TGF)#ß1 activated EMT, including switching E#cadherin toN-cadherin and altering the expression of Wnt/ß-catenin signalingpathway components such as vimentin, ß-catenin, and cyclin-D1.AS-IV inhibited the viability, invasion, and migration of TGF-ß1-induced glioma U251 cells. AS-IV also interfered with the TGF#ß1-induced Wnt/ß-catenin signaling pathway in glioma U251 cells.These findings indicate that AS#IV prohibits TGF#ß1-induced EMTby disrupting the Wnt/ß-catenin pathway in glioma U251 cells. AS#IV may thus be a potential candidate agent for treating glioma andother central nervous system tumors.

Overexpression of gene DEP domain containing 1 and its clinical prognostic significance in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly seen malignancies worldwide, yet its regulatory mechanisms still need to be further illuminated. Abundant evidence revealed that aberrant expression of cancer-related genes contributes to CRC progression. DEP domain containing 1 (DEPDC1) has been found to play a crucial role in the carcinogenesis and development of malignancies. Nevertheless, limited studies have been concerned with the role of DEPDC1 in CRC. This study aimed to investigate the relationship between DEPDC1 expression and CRC clinicopathological parameters. METHODS: Solid CRC tissues and adjacent noncancerous tissues (ANCTs) (n = 150) were chosen randomly to detect the mRNA expression levels of DEPDC1 by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Formalin-fixed, paraffin-embedded (FFPE) blocks of CRC tissues and ANCTs (n = 150) were acquired to examine DEPDC1 protein expression levels by immunohistochemistry (IHC). RESULTS: DEPDC1 was significantly overexpressed in CRC tissues than that in ANCTs (P < .05). High protein expression of DEPDC1 was associated with poorer TNM stage and recurrence (P < .001 and P = .003, respectively). Kaplan-Meier survival analysis showed significantly shorter overall survival (OS) and disease-free survival (DFS) in DEPDC1 protein high-expression group compared with low-expression group (P < .05). Univariate analysis demonstrated that DEPDC1 protein expression was correlated with DFS (P = .005) and OS (P = .006). Multivariate analysis revealed that the combination of DEPDC1 protein expression and TNM stage has statistical significance in CRC prognosis prediction (P = .024 and P = .009, respectively). CONCLUSIONS: DEPDC1 may act as a potential biomarker for CRC detection as well as a prognostic predictor concerning the survival of CRC patients.