Specific intracellular retention of circSKA3 promotes colorectal cancer metastasis by attenuating ubiquitination and degradation of SLUG.

Our previous study demonstrated that tumor-suppressor circular RNAs (circRNAs) can be specifically secreted outside of colorectal cancer (CRC) cells within exosomes to maintain tumor cell fitness. However, whether tumor-driving circRNAs can be specifically retained in cells to facilitate tumor progression remains unknown. In this study, circRNA-seq showed that circSKA3 was significantly upregulated in CRC tissues but downregulated in serum samples from CRC patients. In addition, circSKA3 promoted CRC progression in vitro and in vivo and was retained in CRC cells via a specific cellmotif element. Interestingly, the cellmotif element was also the site of interaction of circSKA3 with SLUG, which inhibited SLUG ubiquitination degradation and promoted CRC epithelial-mesenchymal transition (EMT). Moreover, FUS was identified as a key circularization regulator of circSKA3 that bound to the key element. Finally, we designed and synthesized specific antisense oligonucleotides (ASOs) targeting circularization and cellmotif elements, which repressed circSKA3 expression, abolished the SLUG-circSKA3 interaction, and further inhibited CRC EMT and metastasis in vitro and in vivo.

Methylation-Mediated Silencing of RBP7 Promotes Breast Cancer Progression through PPAR and PI3K/AKT Pathway.

Retinoid-binding protein7 (RBP7) is a member of the cellular retinol-binding protein (CRBP) family, which is involved in the pathogenesis of breast cancer. The study aims to illustrate the prognostic value and the potential regulatory mechanisms of RBP7 expression in breast cancer. Bioinformatics analysis with the TCGA and CPTAC databases revealed that the mRNA and protein expression levels of RBP7 in normal were higher compared to breast cancer tissues. Survival analysis displayed that the lower expression of RBP7, the worse the prognosis in ER-positive (ER+) breast cancer patients. Genomic analysis showed that low expression of RBP7 correlates with its promoter hypermethylation in breast cancer. Functional enrichment analysis demonstrated that downregulation of RBP7 expression may exert its biological influence on breast cancer through the PPAR pathway and the PI3K/AKT pathway. In summary, we identified RBP7 as a novel biomarker that is helpful for the prognosis of ER+ breast cancer patients. Promoter methylation of RBP7 is involved in its gene silencing in breast cancer, thus regulating the occurrence and development of ER+ breast cancer through the PPAR and PI3K/AKT pathways.

XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment.

Background: The activation of X-box binding protein 1 (XBP1) plays an essential role in the unfolded protein response (UPR) of the endoplasmic reticulum (ER). XBP1 is commonly expressed in various tumors and is closely related to tumorigenesis and progression. However, the role of XBP1 in lung adenocarcinoma (LUAD), especially the prognostic value of its alternative splicing isoforms, remains largely unknown. Methods: The LUAD datasets were retrieved from the The Cancer Genome Atlas, ArrayExpress and Gene Expression Omnibus. GEPIA2 and meta-analysis were employed to explore the prognostic value, and bioinformatics analysis with the TIMER2.0 database was used to investigate immune cell infiltration. We performed single-cell analyses to identify cell types with high XBP1 expression. In addition, polymerase chain reaction (PCR) and DNA sequencing were performed to verify the authenticity of the new spliceosome. Results: In this study, we found that high expression of XBP1 was significantly associated with a good prognosis, and XBP1 expression was significantly positively correlated with B cell infiltration in LUAD. In addition, we found that high-level expression of a novel splicing isoform, XBP1 (XBP1-003), improved the prognosis of LUAD. Protein structural analysis demonstrated that XBP1-003 has several specific protein domains that are different from those of other XBP1 isoforms, indicating a unique function of this isoform in LUAD. Conclusion: All these results suggest that XBP1 plays an antitumorigenic role in LUAD through alternative splicing, which may be related to the adaptation of plasma cells. This sheds new light on the potential strategy for LUAD prognosis evaluation and immunotherapy.

Identification of heptapeptides targeting a lethal bacterial strain in septic mice through an integrative approach.

Effectively killing pathogenic bacteria is key for the treatment of sepsis. Although various anti-infective drugs have been used for the treatment of sepsis, the therapeutic effect is largely limited by the lack of a specific bacterium-targeting delivery system. This study aimed to develop antibacterial peptides that specifically target pathogenic bacteria for the treatment of sepsis. The lethal bacterial strain Escherichia coli MSI001 was isolated from mice of a cecal ligation and puncture (CLP) model and was used as a target to screen bacterial binding heptapeptides through an integrative bioinformatics approach based on phage display technology and high-throughput sequencing (HTS). Heptapeptides binding to E. coli MSI001 with high affinity were acquired after normalization by the heptapeptide frequency of the library. A representative heptapeptide VTKLGSL (VTK) was selected for fusion with the antibacterial peptide LL-37 to construct the specific-targeting antibacterial peptide VTK-LL37. We found that, in comparison with LL37, VTK-LL37 showed prominent bacteriostatic activity and an inhibitive effect on biofilm formation in vitro. In vivo experiments demonstrated that VTK-LL37 significantly inhibited bacterial growth, reduced HMGB1 expression, alleviated lesions of vital organs and improved the survival of mice subjected to CLP modeling. Furthermore, membrane DEGP and DEGQ were identified as VTK-binding proteins by proteomic methods. This study provides a novel strategy for targeted pathogen killing, which is helpful for the treatment of sepsis in the era of precise medicine.

Identification of Radiotherapy-Associated Genes in Lung Adenocarcinoma by an Integrated Bioinformatics Analysis Approach.

Radiotherapy (RT) plays an important role in the prognosis of lung adenocarcinoma (LUAD) patients, but the radioresistance (RR) of LUAD is still a challenge that needs to be overcome. The current study aimed to investigate LUAD patients with RR to illuminate the underlying mechanisms. We utilized gene set variation analysis (GSVA) and The Cancer Immunome Atlas (TCIA) database to characterize the differences in biological functions and neoantigen-coding genes between RR and radiosensitive (RS) patients. Weighted Gene co-expression network analysis (WGCNA) was used to explore the relationship between RT-related traits and hub genes in two modules, i.e., RR and RS; two representative hub genes for RR (MZB1 and DERL3) and two for RS (IFI35 and PSMD3) were found to be related to different RT-related traits. Further analysis of the hub genes with the Lung Cancer Explorer (LCE), PanglaoDB and GSVA resources revealed the differences in gene expression levels, cell types and potential functions. On this basis, the Tumor and Immune System Interaction Database (TISIDB) was used to identify the potential association between RR genes and B cell infiltration. Finally, we used the Computational Analysis of Resistance (CARE) database to identify specific gene-associated drugs for RR patients and found that GSK525762A and nilotinib might be promising candidates for RR treatment. Taken together, these results demonstrate that B cells in TME may have a significant impact on the RT and that these two drug candidates, GSK525762A and nilotinib, might be helpful for the treatment of RR patients.

TMBIM6, a potential virus target protein identified by integrated multiomics data analysis in SARS-CoV-2-infected host cells.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we collected open access data to analyze the mechanisms associated with SARS-CoV-2 infection. Gene set enrichment analysis (GSEA) revealed that apoptosis-related pathways were enriched in the cells after SARS-CoV-2 infection, and the results of differential expression analysis showed that biological functions related to endoplasmic reticulum stress (ERS) and lipid metabolism were disordered. TMBIM6 was identified as a potential target for SARS-CoV-2 in host cells through weighted gene coexpression network analysis (WGCNA) of the time course of expression of host and viral proteins. The expression and related functions of TMBIM6 were subsequently analyzed to illuminate how viral proteins interfere with the physiological function of host cells. The potential function of viral proteins was further analyzed by GEne Network Inference with Ensemble of trees (GENIE3). This study identified TMBIM6 as a target protein associated with the pathogenesis of SARS-CoV-2, which might provide a novel therapeutic approach for COVID-19 in the future.

COVID-19 Dynamic Computed Tomography (CT) Performance and Observation of Some Laboratory Indicators.

BACKGROUND Chest CT has an essential role in the detection and evaluation of novel coronary pneumonia (COVID-19) and has be regarded as a critical supplement for RT-PCR. This study explored the dynamic CT manifestations of COVID-19 at different times and the value of some laboratory indicators for clinical guidance. MATERIAL AND METHODS This retrospective review included 44 patients who were infected with COVID-19. The dynamic chest CT and laboratory findings were obtained from electronic medical records. The intervals between onset and CT scans and the dynamic changes of the lesions were recorded. The above data were reviewed, sorted, and analyzed by using SPSS 21.0 software. RESULTS From the time of onset, the dynamic image of the lungs became more complete. Fibrous cord shadow absorption in the lungs were observed. Experimental indicators, biochemical indicators of lymphocytes, and protein series were decreased to varying degrees, while erythrocyte sedimentation, fibrinogen, and D-dimer were increased to varying degrees. CONCLUSIONS The dynamic changes of CT images of lungs of COVID-19 patients, combined with the clinical manifestations and laboratory indicators of patients, can help guide clinical diagnosis and treatment.

Depression and anxiety in children with benign childhood epilepsy with centrotemporal spikes (BCECTS).

BACKGROUND: Elevated rates of affective disturbance in children with benign childhood epilepsy with centrotemporal spikes (BCECTS) have been reported. However, it remains unclear how anxiety and depression are related to epilepsy, and it is unknown whether these mood disorders are influenced by the use of antiepileptic drugs. In the present report, we performed a prospective study designed to evaluate affective disorders (anxiety and depression) without the bias of antiepileptic drug treatment in 89 children with BCECTS, based on self-reporting. Furthermore, we sought to determine whether clinical factors, such as age, disease course, seizure frequency, and spike wave index (SWI), were related to the psychological profiles. METHODS: Patients with BCECTS (n = 89) and healthy matched controls (n = 75) were included in this study. The Depression Self-Rating Scale for Children (DSRSC) and the Screen for Child Anxiety-Related Emotional Disorders (SCARED) were completed by the children. RESULTS: None of the children met criteria for clinically significant anxiety or depression. However, the children with BCECTS had significantly higher depression and anxiety scores compared with children in the control group. We found no significant differences in depression or anxiety between the left, right, and bilateral lobe groups. The DSRSC scores were similar between the children with partial seizures and those with secondarily generalized seizures. Similarly, there were no significant differences in the SCARED scores between these two groups. However, the DSRSC and SCARED scores were positively correlated with age, seizure frequency, SWI, and disease course. CONCLUSIONS: The children with BCECTS had an increased likelihood of depression and anxiety, and these higher rates were unrelated to seizure type or epileptic focus, but were positively correlated with age, seizure frequency, SWI, and disease course.

Establishment of rat pneumococcal meningitis models: a histopathological analysis.

The aim of this study was to perform a preliminary investigation of the pathogenesis of bacterial meningitis-induced brain injury by establishing rat pneumococcal meningitis models. Infant Wistar rats were intracranially inoculated with different concentrations of Streptococcus pneumoniae. Rats were sacrificed at different time points to observe clinical symptoms and pathological changes in brain tissues. Twenty-four hours after intracranial inoculation with Streptococcus pneumoniae, regardless of high or low concentrations of bacterial inoculation, all rats developed bacterial meningitis with manifestations such as lethargy and seizures. Pathological changes in brain tissues included subarachnoid and intraventricular inflammation, vasodilation and vascular congestion, and cortical neuronal necrosis. The number of rats with seizures, the degree of cerebral vascular disease, and the extent of neuronal damage were associated with the concentration of bacterial inoculum. Thirty days after infection, brain tissue weight significantly reduced. The pathological changes induced by inoculation with pneumococcal meningitis in Wistar rats were similar to those seen in the human brain. The possible mechanisms of brain damage caused by meningitis are cerebrovascular inflammation and disruption of regional cerebral blood flow.

Risk Factors on Health-Related Quality of Life in Children With Epilepsy.

The goal of this study was to evaluate how epilepsy affected the health-related quality of life (HRQOL) in children with epilepsy, as well as the risk factors for poor HRQOL. Parents of epileptic children (n = 223) and parents of healthy children (n = 216) were enrolled. The Child Epilepsy Questionnaire-Parental form was given to all parents. Children with epilepsy had significantly lower HRQOL scores for overall QOL and all subscales. Seizure types were not associated with HRQOL, but the age of the child with epilepsy, disease courses and seizure frequency did influence the quality of life. Epilepsy has a severe impact on children's HRQOL, and age, increased seizure frequency and longer duration of epilepsy are associated with poor HRQOL.

Analysis of nucleotide-binding oligomerization domain proteins in a murine model of pneumococcal meningitis.

BACKGROUND: The innate immune system recognizes pathogens via its pattern recognition receptors. The objective of this study was to investigate the role of the nucleotide-binding oligomerization domain (NOD) proteins, a family of the novel bacterial pattern recognition receptors, in host responses to the gram-positive bacteria Streptococcus pneumoniae. METHODS: Sprague-Dawley rats were infected via intracisternal injections of viable S. pneumoniae, and rats in the control group were injected with sterile saline. After infection, real-time PCR was performed to determine the presence of mRNAs encoding NOD1 and NOD2. Quantitative analyses of the NOD1, NOD2 and NF-kB proteins were also performed western blotting following challenge infections with viable S. pneumoniae. The TNF-α and IL-6 levels in brain homogenates were evaluated using enzyme-linked immunosorbent assays (ELISAs). RESULTS: The results revealed up-regulations of the mRNA and protein levels of NOD2 within the CNS of rats with S. pneumoniae meningitis. Moreover, the activation of NF-κB in the brain tissues following infection with live S. pneumoniae was also significantly increased, which indicates that NOD2 mediated NF-κB activation in experimental pneumococcal meningitis. Similarly, TNF-α and IL-6 levels were increased in the brain following in vivo S. pneumoniae administration. CONCLUSIONS: These results suggest that NOD2 is involved in the host response to the gram-positive bacteria S. pneumoniae in the CNS and that NOD2 might play an important role in the initiation and/or progression of CNS inflammation associated with pneumococcal meningitis.

Efficacy of GM6001 as an adjuvant to ceftriaxone in a neonatal rat model of Streptococcus pneumoniae meningitis.

Evidence has demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis; therefore, MMP inhibitors may be a neuroprotective treatment for brain injury caused by meningitis because of their antiinflammatory effects. The objective of this study was to evaluate the effect of the MMP inhibitor GM6001 in a rat model of S. pneumoniae meningitis. For these experiments, 7-day-old Sprague-Dawley rats were randomly divided into an uninfected group, meningitis group, antibiotic group and GM6001+antibiotic group. Uninfected animals were sham infected with sterile saline. Rats in the other three groups were inoculated with S. pneumoniae and left untreated, treated with ceftriaxone, or treated with ceftriaxone combined with GM6001. Rats in the meningitis group were severely ill, and MMP-9 was significantly up-regulated. The change in brain water content was consistent with the MMP-9 level. A significant loss of neurons and impaired learning function were observed in the meningitis group. Treatment with the antibiotic and GM6001 significantly down-regulated the level of MMP-9, decreased the brain water content, attenuated neuronal injury and improved learning. Conclusions: GM6001 protected the brain from damage caused by S. pneumoniae, and this effect may occur via downregulating MMP-9 and decreasing brain water content.

Cognition in Chinese children with benign childhood epilepsy with centrotemporal spikes (BCECTS).

Most studies about cognitive functions in children with benign childhood epilepsy with centrotemporal spikes (BCECTS) have been conducted with alphabetic writing background subjects, however deficits observed might therefore potentially differ in a Chinese language environment. This study was designed to evaluate the intelligence quotient (IQ) profiles, especially the language abilities, in Chinese children with BCECTS and to investigate whether there is a relationship between clinical factors and disorders of cognitive functions. There are selective cognitive deficits in Chinese children with BCECTS, although the Full Scale Intelligence Quotient is within the normal range. There was a correlation between spike wave index (SWI) and language deficits in children with BCECTS, but the deficits are not dependent on age of onset, disease course, seizure frequency, spike location or seizure type. It is important that children with typical BCECTS undergo regular clinical investigations about language performance in order to start necessary interventions as early as possible.

Dexamethasone regulation of matrix metalloproteinase expression in experimental pneumococcal meningitis.

Accumulating evidences have demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis. MMPs facilitate leukocyte extravasation and brain edema by degradation of extracellular matrix components. Dexamethasone as adjunctive therapy to antibiotics has shown to have beneficial effects on pathophysiological changes and neurological outcome in children with meningitis and in animal models. However, the role of dexamethasone in the pathophysiology of pneumococcal meningitis is still unknown. The effects of antibiotics on MMPs in bacterial meningitis have not been evaluated so far. We have therefore intended to investigate the induction and expression of MMPs with special emphasis on the regulation of MMPs by dexamethasone and antibiotics in therapy of pneumococcal meningitis. In the present study, the expression of MMP-9 and MMP-2 mRNA in the brain of rats and the activity of MMP-9 and MMP-2 in the CSF of rats have been determined during the course of experimental bacterial meningitis and after treatment with an antibiotic plus dexamethasone. In the brain tissue of rats with Streptococcus pneumococcal meningitis, MMP-9 mRNA was obviously up-regulated after inoculation for 24 h (p<0.01) and then declined but was still greater than that in the brains of control rats after inoculation for 4 days (p<0.05) while the expression of MMP-2 remained at basal level. The expression of MMP-9 in the brains of rats inoculated with Streptococcus pneumoniae and treated by antibiotic was dose-dependent, up-regulated (p<0.01) but down-regulated after treatment with an antibiotic plus dexamethasone (p<0.01). However, the expression of MMP-9 mRNA did not change in the rats inoculated with sterile saline and treated with an antibiotic. The zymographic activity of MMP-9 and MMP-2 showed similar changes. The results indicated that the expression of MMP-9 mRNA and its activity might be increased after antibiotic treatment and inhibited after treatment with antibiotics plus dexamethasone; dexamethasone might have a beneficial effect on bacterial meningitis via down-regulation of the expression of MMP-9.