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1.
Mol Psychiatry ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051547

RESUMO

Methamphetamine (METH) is a potent stimulant that induces a euphoric state but also causes cognitive impairment, neurotoxicity and neurodevelopmental deficits. Yet, the molecular mechanisms by which METH causes neurodevelopmental defects have remained elusive. Here we utilized human cerebral organoids and single-cell RNA sequencing (scRNA-seq) to study the effects of prenatal METH exposure on fetal brain development. We analyzed 20,758 cells from eight untreated and six METH-treated cerebral organoids and found that the organoids developed from embryonic stem cells contained a diverse array of glial and neuronal cell types. We further identified transcriptionally distinct populations of astrocytes and oligodendrocytes within cerebral organoids. Treatment of organoids with METH-induced marked changes in transcription in multiple cell types, including astrocytes and neural progenitor cells. METH also elicited novel astrocyte-specific gene expression networks regulating responses to cytokines, and inflammasome. Moreover, upregulation of immediate early genes, complement factors, apoptosis, and immune response genes suggests a neuroinflammatory program induced by METH regulating neural stem cell proliferation, differentiation, and cell death. Finally, we observed marked METH-induced changes in neuroinflammatory and cytokine gene expression at the RNA and protein levels. Our data suggest that human cerebral organoids represent a model system to study drug-induced neuroinflammation at single-cell resolution.

2.
Alzheimers Dement ; 16(1): 118-130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914217

RESUMO

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

3.
IEEE Trans Cybern ; 50(2): 503-513, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30273171

RESUMO

Exploiting semantic interactions between the source and target linguistic items at different levels of granularity is crucial for generating compact vector representations for bilingual phrases. To achieve this, we propose alignment-supervised bidimensional attention-based recursive autoencoders (ABattRAE) in this paper. ABattRAE first individually employs two recursive autoencoders to recover hierarchical tree structures of bilingual phrase, and treats the subphrase covered by each node on the tree as a linguistic item. Unlike previous methods, ABattRAE introduces a bidimensional attention network to measure the semantic matching degree between linguistic items of different languages, which enables our model to integrate information from all nodes by dynamically assigning varying weights to their corresponding embeddings. To ensure the accuracy of the generated attention weights in the attention network, ABattRAE incorporates word alignments as supervision signals to guide the learning procedure. Using the general stochastic gradient descent algorithm, we train our model in an end-to-end fashion, where the semantic similarity of translation equivalents is maximized while the semantic similarity of nontranslation pairs is minimized. Finally, we incorporate a semantic feature based on the learned bilingual phrase representations into a machine translation system for better translation selection. Experimental results on NIST Chinese-English and WMT English-German test sets show that our model achieves substantial improvements of up to 2.86 and 1.09 BLEU points over the baseline, respectively. Extensive in-depth analyses demonstrate the superiority of our model in learning bilingual phrase embeddings.

4.
BMC Gastroenterol ; 19(1): 219, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852444

RESUMO

BACKGROUND: Alternate-day fasting (ADF) is a novel diet therapy that may achieve reduction in body weight and improvement of dyslipidaemia, but the impact of this diet on patients with non-alcoholic fatty liver disease (NAFLD) remains unknown. The aim of this study was to evaluate the effects of ADF on the body weight and lipid profile of individuals with NAFLD. METHODS: NAFLD patients (n = 271) were randomised to the ADF group, time-restricted feeding (TRF) group, or the control group and subjected to the respective diet for 12 weeks. Anthropometric measurements (body weight, fat mass/fat-free mass) were performed, and plasma lipids were analysed enzymatically. RESULTS: Within 4 weeks, the body weight decreased significantly (P < 0.001) in the ADF group by 4.56 ± 0.41 kg (6.1 ± 0.5%) and the TRF group by 3.62 ± 0.65 kg (4.83 ± 0.9%) compared to the control group, and it decreased even more after 12 weeks in both groups (ADF: - 4.04 ± 0.54 kg, 5.4 ± 0.7%; TRF: - 3.25 ± 0.67 kg, 4.3 ± 0.9%). Fat mass was significantly reduced by ADF (- 3.49 ± 0.37 kg; 11 ± 1.2%) and TRF (- 2.91 ± 0.41 kg; 9.6 ± 1.3%), with ADF leading to a further reduction in fat mass after 12 weeks (- 3.48 ± 0.38 kg; 11 ± 1.2%). Total cholesterol was significantly decreased at both time points in the ADF group (- 0.91 ± 0.07 mmol/L; 18.5 ± 1.5%) compared to the control and TRF groups. Both ADF (- 0.64 ± 0.06 mmol/L; 25 ± 1.9%) and TRF (0.58 ± 0.07 mmol/L; 20 ± 1.7%) achieved a significant reduction in serum triglycerides (P < 0.001) after 12 weeks. Changes in fat free mass, HDL, LDL, fasting insulin, glucose, liver stiffness, and systolic or diastolic blood pressure did not differ between the groups. CONCLUSIONS: ADF appears to be an effective diet therapy for individuals with NAFLD that can achieve weight loss and improvement of dyslipidaemia within a relatively short period of time (4 to 12 weeks). Potential preventive effects of ADF on cardiovascular disease need to be confirmed by future investigations. TRIAL REGISTRATION: ChiCTR1900024411, this trial was retrospectively registered on July 10, 2019.

5.
Harmful Algae ; 89: 101666, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31672231

RESUMO

Harmful algal blooms caused by Chattonella marina recently have caused severe negative effect on coastal economy worldwide, with increased occurrence frequency and scale. It is therefore vital to establish new methods for rapid detection of this alga. In this study, the internal transcribed spacer (ITS) sequence was used as the target gene for molecular detection of C. marina. First, four loop-mediated isothermal amplification (LAMP) primers were designed based on the six regions of ITS, and the LAMP reaction system was established using these primers. Next, a probe was designed to detect the LAMP products by lateral-flow dipstick (LFD). Finally, a new method for rapid and sensitive detection of C. marina that is referred to as LAMP-LFD was established. The LAMP reaction system, amplification time, and amplification temperature were particularly optimized. The optimal parameters are as follows: Mg2+ concentration, 10 mM;dNTP concentration, 1.2 mM;ratio of internal primer concentration to outer primer concentration, 8:1;reaction time, 60 min;and reaction temperature, 60 °C. Both specificity and sensitivity were tested using the optimized LAMP reaction system in combination with LFD (LAMP-LFD). The established LAMP-LFD displayed good specificity and no cross reaction was detected with non-target algal species. The detection limit of LAMP-LFD was 3.4 × 10-4 ng µL-1 (3.4 × 10-4 ng per reaction) for the genomic DNA of target algae, and 1.3 copies µL-1 (1.3 copies per reaction) for the plasmid DNA containing the target ITS. Sensitivity tests using genomic DNA and plasmid DNA as templates consistently revealed that LAMP-LFD is 100 times more sensitive than regular PCR. The established LAMP-LFD was applied to analyze the simulated samples and the results showed that the detection limit of LAMP-LFD could reach 1 cell mL-1. LAMP-LFD also demonstrated good specificity and sensitivity in the analysis of natural samples. The whole procedure of LAMP-LFD could be completed within 1.5 h. Taken together, the LAMP-LFD assay developed here is characterized by simplicity, high specificity and sensitivity, and rapidity and therefore is promising for rapid detection of C. marina.

6.
Fish Physiol Biochem ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31612298

RESUMO

Cadmium (Cd) is the most abundant heavy metal in aquatic environments and is easily detected on a global scale. Carassius auratus gibelio is a common aquaculture species. The aim of this study was to explore the toxic effects of 1, 2, and 4 mg/L Cd on the energy metabolism, growth performance, and neurological responses of C. gibelio. After 30 days of exposure, Cd concentrations in the liver and brain were significantly increased in Cd-exposed groups. Low-level Cd exposure (1 mg/L) increased weight and length gains, as well as food intake, in the fish. Acetylcholinesterase activity decreased significantly in the Cd-exposed groups. Energy metabolism levels (as reflected by oxygen consumption, ammonia excretion rate, and swimming activity), as well as serum T3 and T4 levels, increased significantly in the fish exposed to 1 mg/L Cd. However, energy metabolism and serum T3/T4 levels decreased significantly in the 4-mg/L Cd group. Neuropeptide gene expression levels in brain were consistent with the observed changes in food intake. In the Cd-exposed groups, the expression levels of neuropeptide Y (NPY), apelin, and metallothionein (MT) increased significantly, while those of pro-opinmelanocortin (POMC), ghrelin, and corticotrophin-releasing factor (CRF) decreased significantly. Our data suggested that in fish, low doses of Cd might increase food intake, as well as weight and length gains, but high doses of Cd might have the opposite effect. These effects might be a result of neurohumoral regulation. Long-term exposure to low doses of Cd might cause weight gain and affect food intake.

7.
Mol Pharm ; 16(12): 4826-4835, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31663764

RESUMO

Tumor-targeted ligand modification and nanosized coloaded drug delivery systems are promising for cancer therapy. In this study, we showed that coix seed oil and tripterine coloaded microemulsions with a transferrin modification (Tf-CT-MEs) could improve the treatment of cervical cancer. Tf-CT-MEs exhibited good stability in serum and a notably synergistic antiproliferation effect. In the HeLa xenograft tumor-bearing mouse model, Tf-CT-MEs accumulated at tumor sites and penetrated deeply in tumor tissues. Tf-CT-MEs had superior anticancer efficacy in vivo, which greatly slowed the growth of tumors (***p < 0.001 vs saline). We also found that Tf-CT-MEs inhibited tumor cell proliferation, enhanced antiangiogenesis, and induced apoptosis by regulating bax/bcl-2 and the activating caspase-3 pathway. Tf-CT-MEs decreased by 27.7, 26.9, 61.2, and 42.5% of concentrations of TGF-ß1, CCL2, TNF-α, and IL-6 in serum, respectively. In addition, Tf-CT-MEs showed little toxicity in vital organs. These results were due to the improved drug delivery efficiency. Collectively, Tf-CT-MEs enhance tumor-targeting, facilitate deep penetration of drugs, and have promising potential as an efficient treatment for cervical cancer.

8.
EMBO Mol Med ; 11(11): e10698, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602788

RESUMO

Tumor-associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long-chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en-route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate-induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro-tumoral myeloid cells on a metabolic level.

9.
Cell Death Dis ; 10(9): 658, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506425

RESUMO

Nitidine chloride (NC) has been demonstrated to have an anticancer effect in hepatocellular carcinoma (HCC). However, the mechanism of action of NC against HCC remains largely unclear. In this study, three pairs of NC-treated and NC-untreated HCC xenograft tumour tissues were collected for circRNA sequencing analysis. In total, 297 circRNAs were differently expressed between the two groups, with 188 upregulated and 109 downregulated, among which hsa_circ_0088364 and hsa_circ_0090049 were validated by real-time quantitative polymerase chain reaction. The in vitro experiments showed that the two circRNAs inhibited the malignant biological behaviour of HCC, suggesting that they may play important roles in the development of HCC. To elucidate whether the two circRNAs function as "miRNA sponges" in HCC, we identified circRNA-miRNA and miRNA-mRNA interactions by using the CircInteractome and miRwalk, respectively. Subsequently, 857 miRNA-associated differently expressed genes in HCC were selected for weighted gene co-expression network analysis. Module Eigengene turquoise with 423 genes was found to be significantly related to the survival time, pathology grade and TNM stage of HCC patients. Gene functional enrichment analysis showed that the 423 genes mainly functioned in DNA replication- and cell cycle-related biological processes and signalling cascades. Eighteen hubgenes (SMARCD1, CBX1, HCFC1, RBM12B, RCC2, NUP205, ECT2, PRIM2, RBM28, COPS7B, PRRC2A, GPR107, ANKRD52, TUBA1B, ATXN7L3, FUS, MCM8 and RACGAP1) associated with clinical outcomes of HCC patients were then identified. These findings showed that the crosstalk between hsa_circ_0088364 and hsa_circ_0090049 and their competing mRNAs may play important roles in HCC, providing interesting clues into the potential of circRNAs as therapeutic targets of NC in HCC.

11.
Curr Gene Ther ; 19(4): 264-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31549954

RESUMO

Novel gene therapy strategies have changed the prognosis of many inherited diseases in recent years. New development in genetic tools and study models has brought us closer to a complete cure for hemophilia. This review will address the latest gene therapy research in hemophilia A and B including gene therapy tools, genetic strategies and animal models. It also summarizes the results of recent clinical trials. Potential solutions are discussed regarding the current barriers in gene therapy for hemophilia.

12.
mBio ; 10(5)2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551335

RESUMO

A major challenge in finding a cure for HIV-1/AIDS is the difficulty in identifying and eradicating persistent reservoirs of replication-competent provirus. Long noncoding RNAs (lncRNAs, >200 nucleotides) are increasingly recognized to play important roles in pathophysiology. Here, we report the first genome-wide expression analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs). We identified an lncRNA, which we named HIV-1-enhanced lncRNA (HEAL), that is upregulated by HIV-1 infection of MDMs, microglia, and T lymphocytes. Peripheral blood mononuclear cells of HIV-1-infected individuals show elevated levels of HEAL Importantly, HEAL is a broad enhancer of multiple HIV-1 strains because depletion of HEAL inhibited X4, R5, and dual-tropic HIV replications and the inhibition was rescued by HEAL overexpression. HEAL forms a complex with the RNA-binding protein FUS, which facilitates HIV replication through at least two mechanisms: (i) HEAL-FUS complex binds the HIV promoter and enhances recruitment of the histone acetyltransferase p300, which positively regulates HIV transcription by increasing histone H3K27 acetylation and P-TEFb enrichment on the HIV promoter, and (ii) HEAL-FUS complex is enriched at the promoter of the cyclin-dependent kinase 2 gene, CDK2, to enhance CDK2 expression. Notably, HEAL knockdown and knockout mediated by RNA interference (RNAi) and CRISPR-Cas9, respectively, prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment in vitro Our results suggest that silencing of HEAL or perturbation of the HEAL-FUS ribonucleoprotein complex could provide a new epigenetic silencing strategy to eradicate viral reservoirs and effect a cure for HIV-1/AIDS.IMPORTANCE Despite our increased understanding of the functions of lncRNAs, their potential to develop HIV/AIDS cure strategies remains unexplored. A genome-wide analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs) was performed, and 1,145 differentially expressed lncRNAs were identified. An lncRNA named HIV-1-enhanced lncRNA (HEAL) is upregulated by HIV-1 infection and promotes HIV replication in T cells and macrophages. HEAL forms a complex with the RNA-binding protein FUS to enhance transcriptional coactivator p300 recruitment to the HIV promoter. Furthermore, HEAL knockdown and knockout prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment, suggesting HEAL as a potential therapeutic target to cure HIV-1/AIDS.

13.
FASEB J ; 33(11): 12164-12174, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31370707

RESUMO

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.

14.
Nature ; 572(7769): 373-377, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31261374

RESUMO

Net anthropogenic emissions of carbon dioxide (CO2) must approach zero by mid-century (2050) in order to stabilize the global mean temperature at the level targeted by international efforts1-5. Yet continued expansion of fossil-fuel-burning energy infrastructure implies already 'committed' future CO2 emissions6-13. Here we use detailed datasets of existing fossil-fuel energy infrastructure in 2018 to estimate regional and sectoral patterns of committed CO2 emissions, the sensitivity of such emissions to assumed operating lifetimes and schedules, and the economic value of the associated infrastructure. We estimate that, if operated as historically, existing infrastructure will cumulatively emit about 658 gigatonnes of CO2 (with a range of 226 to 1,479 gigatonnes CO2, depending on the lifetimes and utilization rates assumed). More than half of these emissions are predicted to come from the electricity sector; infrastructure in China, the USA and the 28 member states of the European Union represents approximately 41 per cent, 9 per cent and 7 per cent of the total, respectively. If built, proposed power plants (planned, permitted or under construction) would emit roughly an extra 188 (range 37-427) gigatonnes CO2. Committed emissions from existing and proposed energy infrastructure (about 846 gigatonnes CO2) thus represent more than the entire carbon budget that remains if mean warming is to be limited to 1.5 degrees Celsius (°C) with a probability of 66 to 50 per cent (420-580 gigatonnes CO2)5, and perhaps two-thirds of the remaining carbon budget if mean warming is to be limited to less than 2 °C (1,170-1,500 gigatonnes CO2)5. The remaining carbon budget estimates are varied and nuanced14,15, and depend on the climate target and the availability of large-scale negative emissions16. Nevertheless, our estimates suggest that little or no new CO2-emitting infrastructure can be commissioned, and that existing infrastructure may need to be retired early (or be retrofitted with carbon capture and storage technology) in order to meet the Paris Agreement climate goals17. Given the asset value per tonne of committed emissions, we suggest that the most cost-effective premature infrastructure retirements will be in the electricity and industry sectors, if non-emitting alternatives are available and affordable4,18.

15.
iScience ; 16: 155-161, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31174177

RESUMO

We present an accessible, fast, and customizable network propagation system for pathway boosting and interpretation of genome-wide association studies. This system-NAGA (Network Assisted Genomic Association)-taps the NDEx biological network resource to gain access to thousands of protein networks and select those most relevant and performative for a specific association study. The method works efficiently, completing genome-wide analysis in under 5 minutes on a modern laptop computer. We show that NAGA recovers many known disease genes from analysis of schizophrenia genetic data, and it substantially boosts associations with previously unappreciated genes such as amyloid beta precursor. On this and seven other gene-disease association tasks, NAGA outperforms conventional approaches in recovery of known disease genes and replicability of results. Protein interactions associated with disease are visualized and annotated in Cytoscape, which, in addition to standard programmatic interfaces, allows for downstream analysis.

16.
Cell Rep ; 27(12): 3473-3485.e5, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216469

RESUMO

Reprogramming somatic cells to pluripotency by Oct4, Sox2, Klf4, and Myc represent a paradigm for cell fate determination. Here, we report a combination of Jdp2, Jhdm1b, Mkk6, Glis1, Nanog, Essrb, and Sall4 (7F) that reprogram mouse embryonic fibroblasts or MEFs to chimera competent induced pluripotent stem cells (iPSCs) efficiently. RNA sequencing (RNA-seq) and ATAC-seq reveal distinct mechanisms for 7F induction of pluripotency. Dropout experiments further reveal a highly cooperative process among 7F to dynamically close and open chromatin loci that encode a network of transcription factors to mediate reprogramming. These results establish an alternative paradigm for reprogramming that may be useful for analyzing cell fate control.

17.
Cell Rep ; 27(12): 3618-3628.e5, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216479

RESUMO

Zika virus (ZIKV) infection is implicated in severe fetal developmental disorders, including microcephaly. MicroRNAs (miRNAs) post-transcriptionally regulate numerous processes associated with viral infection and neurodegeneration, but their contribution to ZIKV pathogenesis is unclear. We analyzed the mRNA and miRNA transcriptomes of human neuronal stem cells (hNSCs) during infection with ZIKV MR766 and Paraiba strains. Integration of the miRNA and mRNA expression data into regulatory interaction networks showed that ZIKV infection resulted in miRNA-mediated repression of genes regulating the cell cycle, stem cell maintenance, and neurogenesis. Bioinformatics analysis of Argonaute-bound RNAs in ZIKV-infected hNSCs identified a number of miRNAs with predicted involvement in microcephaly, including miR-124-3p, which dysregulates NSC maintenance through repression of the transferrin receptor (TFRC). Consistent with this, ZIKV infection upregulated miR-124-3p and downregulated TFRC mRNA in ZIKV-infected hNSCs and mouse brain tissue. These data provide insights into the roles of miRNAs in ZIKV pathogenesis, particularly the microcephaly phenotype.

18.
Medicine (Baltimore) ; 98(14): e14979, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946324

RESUMO

BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a widely studied tumor marker for diagnosing malignant pleural mesothelioma (MPM). This study discussed the diagnostic value of SMRPs in pleural effusion (PE) for MPM. METHODS: Medline, Embase, Web of Science, and Cochrane library system were systematically searched on the data of SMRPs in PE for MPM diagnosis. Pooled diagnostic sensitivity, specificity, and symmetric receiver operating characteristic curve were calculated. RESULTS: Thirteen studies fulfilled the inclusion criteria and a total of 3359 cases including 759 MPM cases, 1061 non-MM (malignant mesothelioma) malignant PE, and 1539 benign PE were brought into this meta-analysis. The pooled results of SMRPs in PE for diagnosing MPM were as follows: sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.68 (95% confidence interval [CI]: 0.64-0.72), 0.91 (95% CI: 0.86-0.94), 7.8 (95% CI: 5.0-12.0), 0.35 (95% CI: 0.31-0.40), and 22 (95% CI: 14-35), respectively. The area under the summary receiver operating characteristic curves (AUC) was 0.75 (95% CI: 0.72-0.80). Subgroup analyzes revealed that the AUC of cohort group using histological diagnosis could be improved to 0.86 (95% CI: 0.83, 0.89). The Deek's funnel plot asymmetry test showed no publication bias. CONCLUSION: Although the sensitivity of SMRPs was low, PE-SMRPs can be a good indicator of the existence of MPM.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Derrame Pleural/metabolismo , Biomarcadores Tumorais/metabolismo , Exsudatos e Transudatos/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Mesotelioma/diagnóstico , Mesotelioma/patologia , Derrame Pleural/diagnóstico , Derrame Pleural/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Sensibilidade e Especificidade
19.
ACS Nano ; 13(5): 5091-5102, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30986342

RESUMO

Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.

20.
EMBO J ; 38(8)2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918008

RESUMO

Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca2+ signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.


Assuntos
Regulação da Expressão Gênica , Imunidade Inata/imunologia , Inflamação/imunologia , Macrófagos/imunologia , RNA Longo não Codificante/metabolismo , Infecções Estreptocócicas/microbiologia , Receptores Toll-Like/metabolismo , Células Cultivadas , Citocinas/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Genoma Humano , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Humanos , Inflamação/genética , Inflamação/microbiologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Substrato Quinase C Rico em Alanina Miristoilada/genética , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/isolamento & purificação , Receptores Toll-Like/genética
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