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1.
Oncol Res ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998794

RESUMO

Wnt molecules play crucial roles in development and adult homeostasis through their receptors Frizzled proteins (Fzds). Fzds mediate canonical ß-catenin pathway and various non-canonical ß-catenin-independent pathways. Aberrant Fzd signaling is involved in many diseases including cancer. Wnt/ß-catenin is a well-established oncogenic pathway involved in almost every aspects of tumor development. However, Fzd-mediated non-canonical Wnt pathways function as both tumor promoters and tumor suppressors depending on cellular context. Fzd-targeted therapies have proven to be effective on cultured tumor cells, tumor cell xenografts, mouse tumor models and patient-derived xenografts (PDX). Moreover, Fzd-targeted therapies synergize with chemotherapy in preclinical models. However, the occurrence of fragility fractures in patients treated with Fzd-targeted agents such as OMP-54F28 and OMP-18R5 limits the development of this combination. Along with new insights on signaling, roles, and modulation mechanisms of Fzds in human tumors, more Fzd-related therapeutic targets will be developed.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33004280

RESUMO

OBJECTIVE: Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1ß). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1ß, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model. METHODS: The TAD rat model was induced by ß-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague-Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1ß, and BAPN + IL-1ß antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1ß, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing. RESULTS: During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p < .001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1ß group (p = .007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1ß antibody group (p = .023 compared with BAPN group and p < .001 compared with the BAPN + IL-1ß group). IL-1ß treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1ß treatment. In BAPN + IL-1ß group, stress and strain parameters were decreased by 13.5%-53.5% and elastin content was decreased by 14%, and IL-1ß, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1ß antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1ß treatment. CONCLUSION: IL-1ß plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1ß reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future.

3.
Virol Sin ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001388

RESUMO

Nosocomial infections are common in pediatric patients and can be fatal in infants and immunocompromised patients. In September 2018, a high positive rate of human adenovirus HAdV was occurred among hospitalized children in the Children's Hospital Affiliated to the Capital Institute of Paediatrics in Beijing. To investigate whether this outbreak of HAdV was related to nosocomial infections or the result of community infections, we collected respiratory specimens from patients with acute respiratory infections in a respiratory ward during June to December 2018, and screened for respiratory viruses. Among 1,840 cases included, 95 (5.2%, 95/1840) were positive for HAdV and 81 were genotyped based on phylogenetic analysis, including seven as HAdV-1 (8.6%), 30 HAdV-3 (37.0%), two HAdV-6 (2.5%), and 42 HAdV-7 (51.9%). More HAdV-positive samples were collected in August (4.7%, 12/255), September (15.0%, 41/274) and October (6.9%, 17/247), with a peak in September 2018. By combining the results of HAdV phylogenetic analysis with clinical data of patients, there were 77 cases (4.2%, 77/1840; 81.1%, 77/95) excluded from nosocomial infections, eight cases representing possible infections transmitted by visitors or attending parents, three cases without sequences that might have been due to infection transmitted by roommates positive for HAdV, one case of a roommate without an HAdV sequence, and six cases that shared highly homologous sequences with those of their roommates, for which nosocomial infections might be considered. In conclusion, genotyping of HAdVs based on phylogenetic analysis combined with clinical information provides a powerful method to distinguish nosocomial infections from community acquired infection, especially when tracing the origins of nosocomial infections.

4.
Ann N Y Acad Sci ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009679

RESUMO

Aeromonas veronii is an important zoonotic and aquatic pathogen. An increasing number of reports indicate that it has caused substantial economic losses in the aquaculture industry, in addition to threatening human health. However, little is known about its pathogenesis. Exploration of new virulence factors of A. veronii would be helpful for further understanding its pathogenesis. Hence, we comparatively analyzed the proteomes of virulent, attenuated, and avirulent strains of A. veronii using tandem mass tag (TMT) protein labeling and found numerous proteins either up- or downregulated in the virulent strain. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that these differentially expressed proteins (DEPs) were involved mainly in pathways associated with bacterial chemotaxis and microbial metabolism in diverse environments. Furthermore, the expression levels of lysine decarboxylase, endoribonuclease, maltoporin, pullulanase, and aerolysin were positively correlated with the virulence of the strains, suggesting that their function may be closely related to the virulence of A. veronii. The results of qRT-PCR and multiple reaction monitoring for some DEPs were consistent with the results of TMT protein labeling. These results suggest that these DEPs may be novel potential virulence factors and will help to further understand the pathogenesis of A. veronii.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33026625

RESUMO

China's rapid economic development is unavoidably characterized by environmental pitfalls, especially the carbon dioxide emissions of greenhouse gases from the use of energy. Since there is a relationship between economic growth, energy consumption, and carbon emission, it is important to note that the continuous improvement and application of solar energy technology will play an active role in carbon emission reduction. Therefore, this paper uses the Kuznets curve to probe the relationship between economic growth, solar energy technology, and carbon emissions. The results show that solar energy technology, economic development level, and carbon emissions are all integrated at the second order with a long-run cointegration relationship. In the long-run, the relationship between economic growth and carbon emissions is inverted "U," which suggest that there is a turning point of carbon emissions, where the carbon emissions first increase with economic growth and then gradually decrease, which is reflected in the image as an inverted "U" curve. Also, the impact of economic factors on carbon emissions and the innovation of solar technology can negatively influence carbon emissions, and enhancing the innovation of solar technology has a positive effect on reducing carbon dioxide emissions.

6.
Cell Syst ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33038298

RESUMO

The need to derive and culture diverse cell or tissue types in vitro has prompted investigations on how changes in culture conditions affect cell states. However, the identification of the optimal conditions (e.g., signaling molecules and growth factors) required to maintain cell types or convert between cell types remains a time-consuming task. Here, we developed EpiMogrify, an approach that leverages data from ∼100 human cell/tissue types available from ENCODE and Roadmap Epigenomics consortia to predict signaling molecules and factors that can either maintain cell identity or enhance directed differentiation (or cell conversion). EpiMogrify integrates protein-protein interaction network information with a model of the cell's epigenetic landscape based on H3K4me3 histone modifications. Using EpiMogrify-predicted factors for maintenance conditions, we were able to better potentiate the maintenance of astrocytes and cardiomyocytes in vitro. We report a significant increase in the efficiency of astrocyte and cardiomyocyte differentiation using EpiMogrify-predicted factors for conversion conditions.

7.
Artigo em Chinês | MEDLINE | ID: mdl-33040516

RESUMO

Perilymphatic fistula(PLF) is defined as an abnormal communication between the fluid(perilymph) -filled space of the inner ear and the air-filled space of the middle ear and mastoid, or cranial spaces. At present the diagnostic criteria for perilymphatic fistula is the fistula hole confirmed by the microscope and endoscope between the middle ear and inner ear, the hole is located in the round or oval window, fractured bony labyrinth, microfissures, anomalous footplate, and can occur after head trauma or barotrauma, chronic inflammation, or in otic capsule dehiscence. Recently, the cochlin-tomoprotein(CTP) detected from the middle ear. CTP, the shortest isoform of cochlin encoded by the COCH gene, has been proven to be a perilymph-specific protein which is not expressed in blood, cerebrospinal fluid and saliva but is highly expressed in lymphatic fluid of the inner ear and is used as a diagnostic biochemical marker for perilymph fistula. The CTP test based on ELISA was performed on the lavage fluid of patients with suspected perilymph fistula to obtain comparatively accurate test results. This paper reviewed the diagnostic value of CTP in perilymphatic fistula.


Assuntos
Fístula , Doenças Vestibulares , Proteínas da Matriz Extracelular , Fístula/diagnóstico , Humanos , Perilinfa , Saliva , Crânio
8.
Microbiologyopen ; : e1125, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058518

RESUMO

Synthetic Cry1Ab/Ac proteins expressed by genetically modified (GM) crops have a high potential to control insect pests without utilizing large amounts of chemical insecticides. Before these crops are used in agriculture, the environmental fate and interactions in the soil must be understood. Stable isotope-labeled Cry1Ab/Ac protein is a highly useful tool for collecting such data. We developed a protocol to produce 13 C/15 N single-labeled Cry proteins. The artificially synthesized gene Cry1Ab/Ac of Bt rice Huahui No. 1, which has been certified by the Chinese government to be safe for human consumption, was subcloned into pUC57, and the expression vector pET-28a-CryAb/Ac was constructed and transformed into Escherichia coli BL21 (DE3) competent cells. Next, 0.2 mM isopropyl thiogalactoside (IPTG) was added to these cells and cultured at 37°C for 4 h to induce the synthesis and formation of inclusion bodies in M9 growth media containing either [U-13 C] glucose (5% 13 C-enriched) or [15 N] ammonium chloride (5% 15 N-enriched). Then, Cry inclusion bodies were dissolved in urea and purified by affinity chromatography under denaturing conditions, renatured by dialysis, and further detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. The purities of 13 C/15 N-labeled Cry proteins reached 99% with amounts of 12.6 mg/L and 8.8 mg/L, respectively. The δ 13 C and ä 15 N values of 13 C-labeled Cry protein and 15 N-labeled Cry protein were 3,269‰ and 2,854‰, respectively. A bioassay test revealed that the labeled Cry1Ab/Ac proteins had strong insecticidal activity. The stable isotope-labeled insecticidal Cry proteins produced for the first time in this study will provide an experimental basis for future metabolic studies on Cry proteins in soil and the characteristics of nitrogen (N) and carbon (C) transformations. Our findings may also be employed as a reference for elucidating the environmental behavior and ecological effects of BT plants and expressed products.

9.
Sensors (Basel) ; 20(19)2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33027897

RESUMO

Metamaterials, artificially engineered structures with extraordinary physical properties, offer multifaceted capabilities in interdisciplinary fields. To address the looming threat of stealthy monitoring, the detection and identification of metamaterials is the next research frontier but have not yet been explored. Here, we show that the crypto-oriented convolutional neural network (CNN) makes possible the secure intelligent detection of metamaterials in mixtures. Terahertz signals were encrypted by homomorphic encryption and the ciphertext was submitted to the CNN directly for results, which can only be decrypted by the data owner. The experimentally measured terahertz signals were augmented and further divided into training sets and test sets using 5-fold cross-validation. Experimental results illustrated that the model achieved an accuracy of 100% on the test sets, which highly outperformed humans and the traditional machine learning. The CNN took 9.6 s to inference on 92 encrypted test signals with homomorphic encryption backend. The proposed method with accuracy and security provides private preserving paradigm for artificial intelligence-based material identification.

10.
Ear Nose Throat J ; : 145561320966072, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048587

RESUMO

Myiasis is a type of parasitosis caused by the larvae of diptera. It commonly occurs in tropical and subtropical zones. The infestation of nose and ears can be extremely dangerous if the larvae destroy the bone and penetrate into the brain, in which case the fatality rate is reported to be as high as 8%. Here, we report a case of aural myiasis in a patient with congenital mental retardation. Twelve maggots were removed mechanically, and the patient was treated with appropriate antibiotics.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33052846

RESUMO

Accumulating efforts have been made to discover effective solutions for fatigue recovery with the ultimate aim of reducing adverse consequences of mental fatigue in real life. The previously-reported behavioral benefits of physical exercise on mental fatigue recovery prompted us to investigate the restorative effect and reveal the underlying neural mechanisms. Specifically, we introduced an empirical method to investigate the beneficial effect of physical exercise on the reorganization of EEG functional connectivity (FC) in a two-session experiment where one session including a successive 30-min psychomotor vigilance task (PVT) (No-intervention session) compared to an insertion of a mid-task 15-min cycling exercise (Intervention session). EEG FC was obtained from 21 participants and quantitatively assessed via graph theoretical analysis and a classification framework. The findings demonstrated the effectiveness of exercise intervention on behavioral performance as shown in improved reaction time and response accuracy. Although we found significantly altered network alterations towards the end of experiment in both sessions, no significant differences between the two sessions and no interaction between session and time were found in EEG network topology. Further interrogation of functional connectivity through classification analysis showed decreased FC in distributed brain areas, which may lead to the significant reduction of network efficiency in both sessions. Moreover, we showed distinct patterns of FC alterations between the two sessions, indicating different information processing strategies adopted in the intervention session. In sum, these results provide some of the first quantitative insights into the complex neural mechanism of exercise intervention for fatigue recovery and lead a new direction for further application research in real-world situations.

12.
Essays Biochem ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33078197

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

13.
Eur J Med Chem ; 209: 112906, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33049607

RESUMO

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.

14.
BMC Complement Med Ther ; 20(1): 309, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054760

RESUMO

BACKGROUND: Ulcerative colitis, characterized by diarrhea, bloody stools and abdominal pain, is a chronic, idiopathic inflammatory disease of the colonic mucosa. In recent years, the incidence of ulcerative colitis presents an increasing trend year by year. Acupuncture, as a potential effective treatment for ulcerative colitis, is widely used in clinical practice. METHODS: We searched PubMed, the Cochrane Library, Chinese CBM Database, China National Knowledge Infrastructure, Chinese VIP Information, and Wanfang Database from the date of the establishment of each database up to March, 2019. We included randomized controlled clinical trials (RCT) comparing acupuncture versus conventional conventional medicine or comparing acupuncture combined with conventional medicine versus conventional medicine in participants with ulcerative colitis. Two authors screened all references, assessed the risk of bias and extracted data independently. We summarized data using risk ratios (RR) with 95% confidence intervals (CI) for binary outcomes. We performed meta-analyses using random effects model. We assessed overall quality of evidence using GRADE. RESULTS: We included 13 RCTs (1030 participants, 515 in the acupuncture group and 515 in the control group). Only one study tested head acupuncture, and the other 12 tested body acupuncture. The treatment duration ranged from 14 to 60 days. Seven trials compared acupuncture alone versus conventional medicine, and six compared acupuncture combined with conventional medicine versus conventional medicine. Acupuncture combined with mesalazine showed better clinical effect (improved clinical symptoms, colonoscopy results and stool examination results) (RR 1.25, 95% CI 1.19 to 1.41; 232 participants; 4 trials; low quality evidence) and better colonoscopy curative effect (RR 1.33, 95% CI 1.04 to 1.71; 108 participants; 2 trials; moderate quality evidence) compared to mesalazine. Acupuncture showed better clinical effect compared to the combination of metronidazole and sulfasalazine (RR 1.21, 95%CI 1.10, 1.34; 318 participants; 3 trials; moderate quality evidence). There was no significant difference in the incidence of adverse events between groups. CONCLUSIONS: Both acupuncture alone and acupuncture combined with conventional medicine may be effective in treating ulcerative colitis compared to conventional medicine. Our findings must be interpreted with caution due to high or unclear risk of bias of the included trials.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33017926

RESUMO

The study of working memory (WM) is a hot topic in recent years and accumulating literatures underlying the achievement and neural mechanism of WM. However, the effect of WM training on cognitive functions were rarely studied. In this study, nineteen healthy young subjects participated in a longitudinal design with one week N-back training (N=1,2,3,4). Experimental results demonstrated that training procedure could help the subjects master more complex psychological tasks when comparing the pre-training performance with those post-training. More specifically, the behavior accuracy increased from 68.14±9.34%, 45.09±14.90%, 39.12±12.71%, and 32.11±10.98% for 1-back, 2-back, 3-back and 4-back respectively to 73.52±4.01%, 69.14±5.28%, 69.09±6.41% and 64.41±5.12% after training. Furthermore, we applied electroencephalogram (EEG) power and functional connectivity to reveal the neural mechanisms of this beneficial effect and found that the EEG power of δ, θ and α band located in the left temporal and occipital lobe increased significantly. Meanwhile, the functional connectivity strength also increased obviously in δ and θ band. In sum, we showed positive effect of WM training on psychological performance and explored the neural mechanisms. Our findings may have the implications for enhancing the performance of participants who are prone to cognitive.

16.
J Hum Genet ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33040084

RESUMO

Long continuous stretches of homozygosity (LCSH) are associated with risk of recessive disorders. Though LCSH can be detected by SNP microarrays, additional testing is necessary to clarify the clinical significance. This study is to assess the yield of additional exome sequencing (ES) after LCSH detection and inform the likelihood of eventual diagnosis. In 2226 patients referred to SNP microarrays, 35 patients met the criteria of indicative LCSH. These patients were recruited and went through additional ES. The diagnostic yield was analyzed, and the LCSH pattern was compared between eventually diagnosed cases and those undiagnosed. The results showed additional ES attained a diagnostic yield of 31.4% (11/35), but only one-third of the yield (11.4%, 4/35) was relevant to LCSH. In contrast, two-thirds of the diagnostic variants (20%, 7/35) were de novo or dominantly inherited, irrelevant to the original LCSH finding. No particular LCSH pattern, including the chromosomal coverage or LCSH size, was found to associate with the diagnostic outcome. We concluded that additional ES after LCSH detection could reveal diagnostic variants, but it is strongly recommended to consider all possible inheritance mode, as the diagnostic variants may be irrelevant to the original LCSH finding.

17.
Brain Imaging Behav ; 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33040258

RESUMO

OBJECTIVES: Although laboratory parameters have long been recognized as indicators of outcome of traumatic brain injury (TBI), it remains a challenge to predict the recovery of disorder of consciousness (DOC) in severe brain injury including TBI. Recent advances have shown an association between alterations in brain connectivity and recovery from DOC. In the present study, we developed a prognostic model of DOC recovery via a combination of laboratory parameters and resting-state functional magnetic resonance imaging (fMRI). METHODS: Fifty-one patients with DOC (age = 52.3 ± 15.2 y, male/female = 31/20) were recruited from Hangzhou Hospital of Zhejiang CAPR and were sub-grouped into conscious (n = 34) and unconscious (n = 17) groups based upon their Glasgow Outcome Scale-Extended (GOS-E) scores at 12-month follow-ups after injury. Resting-state functional connectivity, network nodal measures (centrality), and laboratory parameters were obtained from each patient and served as features for support vector machine (SVM) classifications. RESULTS: We found that functional connectivity was the most accurate single-domain model (ACC: 70.1% ± 4.5%, P = 0.038, 1000 permutations), followed by degree centrality, betweenness centrality, and laboratory parameters. The stacked multi-domain prognostic model (ACC: 73.4% ± 3.1%, P = 0.005, 1000 permutations) combining all single-domain models yielded a significantly higher accuracy compared to that of the best-performing single-domain model (P = 0.002). CONCLUSION: Our results suggest that laboratory parameters only contribute to the outcome prediction of DOC patients, whereas combining information from neuroimaging and clinical parameters may represent a strategy to achieve a more accurate prognostic model, which may further provide better guidance for clinical management of DOC patients.

18.
Clin Epigenetics ; 12(1): 149, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33069246

RESUMO

BACKGROUND: Growing evidence shows that epigenetic modifications play a role in Alzheimer's disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples. RESULTS: Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina© Infinium MethylationEPIC BeadChip. Five and 14 differentially methylated positions (DMPs) associated with pathology (i.e., Braak stage) with p value less than Bonferroni correction threshold of 6.79 × 10-8 in the STG and IFG were identified, respectively. These cytosine-phosphate-guanine (CpG) sites included promoter associated cg26263477 annotated to ABCA7 in the STG (p = 1.21 × 10-11), and cg14058329 annotated to the HOXA5/HOXA3/HOXA-AS3 gene cluster (p = 1.62 × 10-9) and cg09448088 (p = 3.95 × 10-9) annotated to MCF2L in the IFG. These genes were previously reported to harbor DMPs and/or differentially methylated regions (DMRs). Previously reported DMPs annotated to RMGA, GNG7, HOXA3, GPR56, SPG7, PCNT, RP11-961A15.1, MCF2L, RHBDF2, ANK1, PCNT, TPRG1, and RASGEF1C were replicated (p < 0.0001). One hundred twenty-one and 173 DMRs associated with pathology in the STG and IFG, respectively, were additionally identified. Of these, DMRs annotated to 30 unique genes were also identified as significant DMRs in the same brain region in a recent meta-analysis, while additional DMRs annotated to 12 genes were reported as DMRs in a different brain region or in a cross-cortex meta-analysis. The significant DMRs were enriched in promoters, CpG islands, and exons in the genome. Gene set enrichment analysis of DMPs and DMRs showed that gene sets involved in neuroinflammation (e.g., microglia differentiation), neurogenesis, and cognition were enriched (false discovery rate (FDR) < 0.05). CONCLUSIONS: Twenty-two DMPs and 30 DMRs associated with pathology were replicated, and novel DMPs and DMRs were discovered.

19.
Brief Bioinform ; 21(5): 1818-1824, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978617

RESUMO

: Unsupervised clustering of high-throughput gene expression data is widely adopted for cancer subtyping. However, cancer subtypes derived from a single dataset are usually not applicable across multiple datasets from different platforms. Merging different datasets is necessary to determine accurate and applicable cancer subtypes but is still embarrassing due to the batch effect. CrossICC is an R package designed for the unsupervised clustering of gene expression data from multiple datasets/platforms without the requirement of batch effect adjustment. CrossICC utilizes an iterative strategy to derive the optimal gene signature and cluster numbers from a consensus similarity matrix generated by consensus clustering. This package also provides abundant functions to visualize the identified subtypes and evaluate subtyping performance. We expected that CrossICC could be used to discover the robust cancer subtypes with significant translational implications in personalized care for cancer patients. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available at GitHub (https://github.com/bioinformatist/CrossICC) and Bioconductor (http://bioconductor.org/packages/release/bioc/html/CrossICC.html) under the GPL v3 License.

20.
Gynecol Oncol ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32980127

RESUMO

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) is lethal mainly due to extensive metastasis. Cancer cell stem-like properties are responsible for HGSOC metastasis. LGR4, a G-protein-coupled receptor, is involved in the maintenance of stem cell self-renewal and activity in some human organs. METHODS: TCGA and CCLE databases were interrogated for gene mRNA in ovarian cancer tissues and cell lines. Gain and loss of functions of LGR4, ELF3, FZD5 and WNT7B were performed to identify their roles in ovarian cancer cell epithelial phenotype and stem-like properties. In vivo experiments were performed to observe the effect of LGR4 on ovarian cancer cell growth and peritoneal seeding. The binding of ELF3 to LGR4 gene promoter was investigated by dual-luciferase reporter assays and ChIP. RESULTS: LGR4 was shown to be overexpressed in HGSOCs and maintain the epithelial phenotype of HGSOC cells. LGR4 knockdown suppressed POU5F1, SOX2, PROM1 (CD133) and ALDH1A2 expression. Furthermore, LGR4 knockdown reduced CD133+ and ALDH+ subpopulations and impaired tumorisphere formation. To the contrary, LGR4 overexpression enhanced POU5F1 and SOX2 expression and tumorisphere formation capacity. LGR4 knockdown inhibited HGSOC cell growth and peritoneal seeding in xenograft models. Mechanistically, LGR4 and ELF3, an epithelium-specific transcription factor, formed a reciprocal regulatory loop, which was positively modulated by WNT7B/FZD5 ligand-receptor pair. Consistently, knockdown of ELF3, WNT7B, and FZD5, respectively, disrupted HGSOC cell epithelial phenotype and stem-like properties. CONCLUSION: Together, these data demonstrate that WNT7B/FZD5-LGR4/ELF3 axis maintains HGSOC cell epithelial phenotype and stem-like traits; targeting this axis may prevent HGSOC metastasis.

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