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1.
Nanomaterials (Basel) ; 11(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34578574

RESUMO

Water-soluble nanoclusters, which are facilely enrichable without changes in the original properties, are highly demanded in many disciplines. In this contribution, a new class of gold nanoclusters (AuNCs) was synthesized using glutathione disulfide (GSSG) as a reducing and capping agent under intermittent heating mode. The as-prepared GSSG-AuNCs had a higher quantum yield (4.1%) compared to the conventional glutathione-protected AuNCs (1.8%). Moreover, by simply introducing the GSSG-AuNC solution to acetonitrile at a volume ratio of 1:7, a new bottom phase was formed, in which GSSG-AuNCs could be 400-fold enriched without changes in properties, with a percentage recovery higher than 99%. The enrichment approach did not need additional instruments and was potentially suitable for large-scale enrichment of nanoclusters. Further, density functional theory calculations indicated that the hydrogen bonding between GSSG and acetonitrile plays a key role for the bottom phase formation. Our work suggests that the highly emissive GSSG-AuNCs possess great potential not only in fluorescent measurements but also in other scenarios in which high-concentration AuNCs may be needed, such as catalysis, drug delivery, and electronic and optical industries.

2.
J Med Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

3.
Mediators Inflamm ; 2021: 5576596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194284

RESUMO

Background: Suppressor of tumorigenicity 2 (ST2) is a key biomarker in inflammation and cardiovascular diseases, but limited data is available on its role in allergic rhinitis (AR). Objective: The aim of this study is to explore the role of serum soluble ST2 (sST2) in evaluating disease severity and predicting the efficacy of sublingual immunotherapy (SLIT) in house dust mite- (HDM-) induced AR patients. Methods: Eighty healthy controls (HC group) and 160 HDM-induced AR patients, including 40 mild patients (MAR group) and 120 moderate-severe patients (MSAR group), were recruited in this study. Serum was collected from all participants and levels of sST2 were determined by ELISA and the relationship between sST2 levels and disease severity was assessed. In the MSAR group, 109 patients received 3 years of SLIT, and the relationship between serum levels of sST2 and efficacy of SLIT was exampled. Results: Serum sST2 levels were increased in HDM-induced AR patients compared to the HC group (P < 0.001), and the concentrations were higher in the MSAR group than in the MAR group and HC group (all P < 0.05). Moreover, sST2 levels positively correlated with the total nasal symptom score (TNSS), visual analogue scale (VAS), and specific IgE levels (P < 0.05). Seventy-eight MSAR patients accomplished SLIT, and they were divided into an effective group (n = 40) and an ineffective group (n = 38). The serum sST2 levels in the effective group were lower than those in the ineffective group (P < 0.001). In addition, patients in the effective group levels exhibited significantly lower sST2 levels post-SLIT than pre-SLIT (P < 0.001), but no statistic difference was observed in the ineffective group (P > 0.05). Receiver operating characteristic (ROC) curve showed promising accuracy for predicting clinical efficacy of SLIT in AR patients (area under the curve = 0.839, P < 0.001). Conclusion: Serum sST2 is a potential biomarker for assessing disease severity and may serve as a sensitive biomarker for predicting the therapeutic response of SLIT in HDM-induced AR patients.

4.
J Cancer Res Ther ; 17(3): 630-637, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34269292

RESUMO

Background: Small-cell carcinoma is a relatively infrequent pathological variety of esophageal cancer. In this study, a novel nomogram model was developed to evaluate the cancer-specific survival (CSS) and overall survival (OS) of patients with primary esophageal small-cell carcinoma (ESmCC). Materials and Methods: In total, 502 patients with primary ESmCC were identified based on data from 1973 to 2015 retrieved from the surveillance, epidemiology, and end results database. Clinical characteristics such as age at diagnosis, gender, race, site, tumor stage, surgery, radiotherapy, and chemotherapy were included for multivariate logistic analyses to predict CSS and OS. Nomogram models for the prediction of CSS and OS in ESmCC patients were tested with the concordance index (C-index) method and calibration curves. Results: From our multivariate analyses, race, stage, chemotherapy, and radiotherapy, but not surgery, were significantly associated with the CSS of ESmCC patients, while age at diagnosis, stage, chemotherapy, and radiotherapy were significantly associated with their OS. Nomograms were developed using age at diagnosis, race, gender, stage, surgery, radiotherapy, and chemotherapy to predict the two survival measures; these nomograms were verified as accurate in predicting OS and CSS in ESmCC patients, with C-index values of 0.736 and 0.731, respectively. Conclusions: By utilizing easily accessible clinicopathological information, we established a simple but useful tool for predicting the CSS and OS of ESmCC patients that could help to make personalized clinical decisions for patients with this rare malignancy. Cancer-specific survival, esophageal small-cell carcinoma, nomogram, overall survival, surveillance, epidemiology, and end results.

5.
PLoS Biol ; 19(5): e3001209, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33961621

RESUMO

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.


Assuntos
Anticorpos Neutralizantes/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/metabolismo , Epitopos/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Testes de Neutralização , Pandemias , Ligação Proteica , Domínios Proteicos , Receptores Virais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
6.
Cell Death Dis ; 12(3): 253, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692332

RESUMO

Hepatocellular carcinoma (HCC) is a devastating malignancy without targeted therapeutic options. Our results indicated that the histone demethylase GASC1 signature is associated with later tumor stage and poorer survival in HCC patients. GASC1 depletion led to diminished HCC proliferation and tumor growth. A distinct heterogeneity in GASC1 levels was observed among HCC cell populations, predicting their inherent high or low tumor-initiating capacity. Mechanistically, GASC1 is involved in the regulation of several components of the Rho-GTPase signaling pathway including its downstream target ROCK2. GASC1 demethylase activity ensured the transcriptional repression of FBXO42, a ROCK2 protein-ubiquitin ligase, thereby inhibiting ROCK2 degradation via K63-linked poly-ubiquitination. Treatment with the GASC1 inhibitor SD70 impaired the growth of both HCC cell lines and xenografts in mice, sensitizing them to standard-of-care chemotherapy. This work identifies GASC1 as a malignant-cell-selective target in HCC, and GASC1-specific therapeutics represent promising candidates for new treatment options to control this malignancy.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Hepáticas/enzimologia , Quinases Associadas a rho/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Estabilidade Enzimática , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Meia-Vida , Células Hep G2 , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Proteólise , Carga Tumoral , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cell Biochem ; 476(6): 2253-2267, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33570734

RESUMO

Circular RNAs (circRNAs) play vital roles in various types of cancer and chemosentivity. In the progression of carcinogenesis, exosomes are messengers for intercellular communication. The aim of this study was to explore the role of exosomal circRNA phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (circ_PIP5K1A) in non-small cell lung cancer (NSCLC) progression and cisplatin sensitivity. The expression levels of circ_PIP5K1A, miR-101 and ATP binding cassette subfamily C member 1 (ABCC1) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 assay was used to detect cell viability and 50% inhibitory concentration value of cisplatin. Cell migration, invasion, proliferation, and apoptosis were determined by wound healing assay, transwell assay, colony formation assay, and flow cytometry, respectively. A xenograft tumor model was established to explore the role of circ_PIP5K1A in vivo. Exosomes were detected using transmission electron microscopy analysis. The interaction between miR-101 and circ_PIP5K1A or ABCC1 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay and RNA pull-down assay. Circ_PIP5K1A and ABCC1 were overexpressed and miR-101 was downregulated in NSCLC tissues, serum samples, and cells. Knockdown of exosomal circ_PIP5K1A inhibited NSCLC cell proliferation, migration, and invasion and promoted apoptosis and cisplatin sensitivity. Likewise, circ_PIP5K1A downregulation inhibited tumor growth. MiR-101 was a direct target of circ_PIP5K1A, and its knockdown reversed the effects of circ_PIP5K1A silence on inhibition of NSCLC progression and promotion of cisplatin sensitivity. Moreover, ABCC1 was a downstream target of miR-101, and miR-101 overexpression inhibited the progression of NSCLC cells and increased cisplatin sensitivity by targeting ABCC1. Besides, circ_PIP5K1A positively regulated ABCC1 expression by sponging miR-101. Exosomal circ_PIP5K1A knockdown inhibited NSCLC progression and promoted cisplatin sensitivity by regulating miR-101/ABCC1 axis, providing a novel avenue for treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Exossomos/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Circular/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Exossomos/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética , Transdução de Sinais/genética
8.
Adv Sci (Weinh) ; 7(21): 2001018, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33173725

RESUMO

The transcription factor SOX9 is frequently amplified in diverse advanced-stage human tumors. Its stability has been shown to be tightly controlled by ubiquitination-dependent proteasome degradation. However, the exact underlying molecular mechanisms remain unclear. This work reports that SOX9 protein abundance is regulated by the Cullin 3-based ubiquitin ligase KEAP1 via proteasome-mediated degradation. Loss-of-function mutations in KEAP1 compromise polyubiquitination-mediated SOX9 degradation, leading to increased protein levels, which facilitate tumorigenesis. Moreover, the loss of critical ubiquitination residues in SOX9, by either a SOX9 (ΔK2) truncation or K249R mutation, leads to elevated protein stability. Furthermore, it is shown that the KEAP1/SOX9 interaction is modulated by CKIγ-mediated phosphorylation. Importantly, it is demonstrated that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the KEAP1/SOX9 interaction and its consequent degradation. Collectively, herein the findings uncover a novel molecular mechanism through which SOX9 protein stability is negatively regulated by KEAP1 to control tumorigenesis. Thus, these results suggest that mitigating SOX9 resistance to KEAP1-mediated degradation can represent a novel therapeutic strategy for cancers with KEAP1 mutations.

9.
Sci Rep ; 10(1): 20217, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214659

RESUMO

Mammalian oocytes represent impaired quality after undergoing a process of postovulatory aging, which can be alleviated through various effective ways such as reagent treatment. Accumulating evidences have revealed the beneficial effects of astaxanthin (Ax) as a potential antioxidant on reproductive biology. Here, porcine matured oocytes were used as a model to explore whether Ax supplement can protect against oocyte aging in vitro and the underlying mechanism, and therefore they were cultured with or without 2.5 µM Ax for an additional 24 h. Aged oocytes treated with Ax showed improved yield and quality of blastocysts as well as recovered expression of maternal genes. Importantly, oxidative stress in aged oocytes was relieved through Ax treatment, based on reduced reactive oxygen species and enhanced glutathione and antioxidant gene expression. Moreover, inhibition in apoptosis and autophagy of aged oocyte by Ax was confirmed through decreased caspase-3, cathepsin B and autophagic activities. Ax could also maintain spindle organization and actin expression, and rescue functional status of organelles including mitochondria, endoplasmic reticulum, Golgi apparatus and lysosomes according to restored fluorescence intensity. In conclusion, Ax might provide an alternative for ameliorating the oocyte quality following aging in vitro, through the mechanisms mediated by its antioxidant properties.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Feminino , Oócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Suínos , Xantofilas/farmacologia
10.
Org Lett ; 22(18): 7197-7201, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32877190

RESUMO

In order to prepare more efficiently key 1,3-diol fragments, we have devised a base-promoted redox-neutral condensation of ketones with alcohols. This diastereoselective alcohol-aldolization enables bypassing the classical oxidation and reduction steps necessary for the preparation of this crucial backbone by an overall redox-neutral formal borrowing hydrogen process. The starting alcohols constitute both the precursors of the in situ generated reactive aldehydes and the hydride source necessary for the chemoselective reduction of the aldol adduct intermediates.

11.
J Cancer Res Ther ; 16(2): 269-275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474512

RESUMO

Background: Hypoxia-inducible factor 1α (HIF-1α), p53, and vascular endothelial growth factor (VEGF) are important factors that facilitate tumor progression. The aims of our study were to investigate the expression of HIF-1α, p53, and VEGF in esophageal squamous cell carcinoma (ESCC) treated by curative surgery and to analyze their association with clinicopathological parameters and clinical outcome. Materials and Methods: The surgical specimens from 120 patients who had undergone potentially curative resection for ESCC were immunohistochemically assessed using monoclonal antibodies against HIF-1α, p53, and VEGF. Results: Positive rates of HIF-1α, p53, and VEGF expression were 61.7%, 56.7%, and 78.3%, respectively. No significant relationship was found between HIF-1α, p53, VEGF expression, and the analyzed clinicopathological parameters. There was no significant correlation between the expression of HIF-1α, p53, and VEGF. Univariate analysis revealed that overexpression of HIF-1α was associated with poor disease-free and overall survival (P = 0.023 and 0.01, respectively). Multivariate analysis demonstrated that upregulation of HIF-1α is an independent predictor for poor overall survival (P = 0.044). Conclusions: HIF-1α was a useful independent prognostic factor for surgically treated ESCC. Further studies with larger sample size are required to determine the relationship between the expression of HIF-1α, p53, VEGF, and clinicopathological parameters.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Humanos , Hipóxia/patologia , Metástase Linfática , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Taxa de Sobrevida
12.
Theriogenology ; 152: 8-17, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32361306

RESUMO

As the immature oocytes are submitted to cryopreservation, their surrounding cumulus cells (CCs) will inevitably suffer, which may have some adverse effects on subsequent oocyte maturation and development. So far, little is known about the molecular differences in CCs of immature oocytes after vitrification. The aim of this study therefore was to analyze the protein profile of CCs derived from vitrified porcine immature oocytes following in vitro maturation, using TMT-based quantitative proteomic approach. A total of 5910 proteins were identified, and 88 of them presented significant difference, with 46 up-regulated and 42 down-regulated proteins. Gene Ontology enrichment analysis revealed that cell cycle phase transition, mitotic cell cycle phase transition, positive regulation of cell differentiation and regulation of oogenesis were significantly down-regulated within the biological process. After Kyoto Encyclopedia of Genes and Genomes pathway analysis, some up-regulated proteins were significantly enriched in TGF-beta signaling pathway and 4 pathways related to steroid hormones. Furthermore, 10 selected proteins were quantified and verified by a parallel reaction monitoring technique, indicating a high reliability of the TMT results. In conclusion, vitrification affects protein profile of CCs as well as their biological functions, which will offer a new perspective to understand the reasons for decline in maturation quality of vitrified immature oocytes.


Assuntos
Células do Cúmulo/metabolismo , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/fisiologia , Proteômica/métodos , Suínos , Animais , Regulação da Expressão Gênica , Transcriptoma , Vitrificação
13.
Talanta ; 216: 120926, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32456892

RESUMO

Bioimaging probes for monitoring intracellular reactive oxygen species have important implications for cell biology research. Herein, we developed peptide-capped silver/gold nanoclusters (peptide@Ag/Au NCs) for lysosome-targeted imaging of hypochlorite (ClO-). The peptide@Ag/Au NCs were synthesized via a one-pot method using peptide as both a template and a reducing agent. The fluorescence intensity and absolute quantum yield of peptide@Ag/Au NCs were much higher than those of peptide-capped gold nanoclusters and silver nanoclusters. In the presence of ClO-, the fluorescence of peptide@Ag/Au NCs was quenched, accompanied by a redshift due to ClO--induced oxidation of the peptide ligand and decreased Ag content in Ag/Au NCs. The relative fluorescence intensity F0/F had favourable linearity for ClO- concentrations in the range 0.1-100 µmol/L (R2 = 0.9954), with a detection limit (LOD) of 80 nmol/L. The lysosome-targeted peptide@Ag/Au NCs were applied to detect ClO- in lysosomes in living cells via fluorescence imaging.


Assuntos
Fluorescência , Ácido Hipocloroso/análise , Lisossomos/química , Nanopartículas Metálicas/química , Imagem Óptica , Peptídeos/química , Ouro/química , Células Hep G2 , Humanos , Microscopia de Fluorescência , Prata/química , Células Tumorais Cultivadas
14.
Aging (Albany NY) ; 12(6): 4757-4777, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32209727

RESUMO

Non-small cell lung cancer (NSCLC), which consists mainly of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), are the leading cause of cancer deaths worldwide. In this study, we performed a comprehensive analysis of the tumor microenvironmental and genetic factors to identify prognostic biomarkers for NSCLC. We evaluated the immune and stromal scores of patients with LUAD and LUSC using data from The Cancer Genome Atlas database with the ESTIMATE algorithm. Based on these scores, the differentially expressed genes were obtained and immune-related prognostic genes were identified. Functional analysis and protein-protein interaction network further revealed the immune-related biological processes in which these genes participated. Additionally, 22 subsets of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment were analyzed with the CIBERSORT algorithm. Finally, we validated these valuable genes using an independent cohort from the Gene Expression Omnibus database. The associations of the immune and stromal scores with patients' clinical characteristics and prognosis were positive in LUAD but negative in LUSC and the correlations of TIICs with clinical characteristics were clarified. Several differentially expressed genes were identified to be potential immune-related prognostic genes. This study comprehensively analyzed the tumor microenvironment and presented immune-related prognostic biomarkers for NSCLC.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/imunologia , Feminino , Expressão Gênica/genética , Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Masculino , Prognóstico
15.
Front Neurol ; 11: 549331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33584489

RESUMO

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is a rare neurometabolic disorder caused by mutations of the SLC2A1 gene. Paroxysmal exercise-induced dyskinesia is regarded as a representative symptom of Glut1-DS. Paroxysmal non-kinesigenic dyskinesia is usually caused by aberrations of the MR1 and KCNMA1 genes, but it also appears in Glut1-DS. We herein document a patient with Glut1-DS who suffered first from paroxysmal exercise-induced dyskinesia and subsequently paroxysmal non-kinesigenic dyskinesia and experienced a recent worsening of symptoms accompanied with a low fever. The lumbar puncture result showed a decreased glucose concentration and increased white blood cell (WBC) count in cerebrospinal fluid (CSF). The exacerbated symptoms were initially suspected to be caused by intracranial infection due to a mild fever of <38.0°C, decreased CSF glucose, and increased CSF WBC count. However, the second lumbar puncture result indicated a decreased glucose concentration and normal WBC count in CSF with no anti-infective agents, and the patient's symptoms were not relieved apparently. The continuous low glucose concentration attracted our attention, and gene analysis was performed. According to the gene analysis result, the patient was diagnosed with Glut1-DS finally. This case indicates that the complex paroxysmal dyskinesia in Glut1-DS may be confusing and pose challenges for accurate diagnosis. Except intracranial infection, Glut1-DS should be considered as a differential diagnosis upon detection of a low CSF glucose concentration and dyskinesia. The case presented here may encourage clinicians to be mindful of this atypical manifestation of Glut1-DS in order to avoid misdiagnosis.

16.
Onco Targets Ther ; 12: 2495-2503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040692

RESUMO

Objective: The main aim of this study was to investigate the association of polymorphisms in long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population. Methods: A total of 245 ESCC patients and 490 gender- and age-matched cancer-free controls were genotyped for four tag single nucleotide polymorphisms (SNPs) of MALAT1 (rs3200401 C > T, rs1122709 C > G, rs664589 C > G, and rs619586 A > G). Statistical analyses including chi-squared test and logistic regression were performed to identify the association between the tag SNPs and risk of ESCC, and false discovery rate (FDR) <25% was applied to adjust for multiple comparisons. Results: We found that rs3200401 C > T polymorphism of MALAT1 was significantly associated with increased risk of ESCC (CT vs CC: adjusted OR =1.59, 95% CI =1.07-2.35, P=0.021; TT vs CC: adjusted OR =2.27, 95% CI =1.04-4.96, P=0.039; dominant model [CT+TT vs CC]: adjusted OR =1.68, 95% CI =1.16-2.43, P=0.006). In the stratified analysis, rs3200401 TT and CT/TT genotypes were associated with increased risk of ESCC compared with CC genotype in subgroup of never drinking (TT vs CC: adjusted OR =2.34, 95% CI =1.02-5.34, P=0.044; CT/TT vs CC: adjusted OR =1.52, 95% CI =1.02-2.26, P=0.041). However, compared with AA genotype, MALAT1 rs619586 GG was associated with decreased risk of ESCC in ever drinking subgroup (GG vs AA: adjusted OR =0.38, 95% CI =0.15-0.99, P=0.049). The results remained significant after FDR adjustment (FDR value <0.25) except for the comparison between rs619586 GG and AA genotype in ever drinking subgroup. Conclusion: Taken together, our findings proposed that polymorphism rs3200401 C > T in MALAT1 gene is associated with increased risk of ESCC. Since the association between rs619586 A > G polymorphism and ESCC risk was not significant after FDR adjustment, there was a minor possibility that rs619586 A > G might be a protective factor for ESCC.

17.
Elife ; 82019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31120418

RESUMO

A small subset of interneurons that are generated earliest as pioneer neurons are the first cohort of neurons that enter the neocortex. However, it remains largely unclear whether these early-generated interneurons (EGIns) predominantly regulate neocortical circuit formation. Using inducible genetic fate mapping to selectively label EGIns and pseudo-random interneurons (pRIns), we found that EGIns exhibited more mature electrophysiological and morphological properties and higher synaptic connectivity than pRIns in the somatosensory cortex at early postnatal stages. In addition, when stimulating one cell, the proportion of EGIns that influence spontaneous network synchronization is significantly higher than that of pRIns. Importantly, toxin-mediated ablation of EGIns after birth significantly reduce spontaneous network synchronization and decrease inhibitory synaptic formation during the first postnatal week. These results suggest that EGIns can shape developing networks and may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit.


Assuntos
Animais Recém-Nascidos , Interneurônios/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Córtex Somatossensorial/crescimento & desenvolvimento , Animais , Camundongos
18.
Biomed Pharmacother ; 114: 108794, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30947017

RESUMO

Glycine is a proteinogenic amino acid that serves as a precursor for several proteins. The anti-cataract effects of lysine and other amino acid mixtures in animal models have been reported. Normal rats were administered saline and formed the normal control group (group I). Diabetic rats were administered streptozotocin and were the diabetic control group (group II). Rats were administered glycine (250 mg and 500 mg/kg of body weight) formed groups III and IV, respectively. Diabetic rats were administered sorbinil and were served as positive control (group V). The body weight changes, serum glucose, plasma insulin, total protein, glutathione (GSH) content, and mRNA and protein levels of aldose reductase were determined. Glycine treatment increased body weight gain, reduced blood glucose, and increased plasma insulin levels compared to diabetic control rats, and also increased GSH content and decreased mRNA and protein levels of aldose reductase compared to their respective controls. In summary, glycine supplementation effectively inhibited aldose reductase enzyme activity in experimental diabetic rats.


Assuntos
Catarata/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Glicina/farmacologia , Substâncias Protetoras/farmacologia , Estreptozocina/farmacologia , Aldeído Redutase/metabolismo , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Catarata/sangue , Catarata/etiologia , Catarata/metabolismo , Complicações do Diabetes/sangue , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Glutationa/metabolismo , Insulina/sangue , Masculino , Ratos
19.
Epilepsy Behav ; 94: 198-203, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30974347

RESUMO

OBJECTIVES: The objective of this study was to report seizure characteristics, long-term outcome, and potential factors associated with persistent seizures in patients with autoimmune synaptic encephalitis (ASE). METHOD: Clinical data and courses of 52 patients with ASE who presented with seizures at the Department of Neurology of the First Hospital of Jilin University from January 2015 to August 2017 were reviewed. Seizure outcomes were assessed with a median follow-up duration of 30 months (8-40 months). RESULTS: Most patients (71.2%) presented with seizure at initial consultation; focal to bilateral tonic-clonic seizures (50.0%) were the most common type. The temporal lobe (73.5%) was the prominent region of seizure origin, which was incident with hippocampal lesions on magnetic resonance imaging (MRI) in 62.1% of the patients. Status epilepticus, subclinical seizures, and nonepileptic events were observed in 28.9%, 36.8%, and 28.9% of the patients, respectively. Twenty-seven out of the 43 followed-up patients (62.8%) exhibited seizure remission after initial immunotherapy. Others (37.2%) developed persistent seizures to different extents. Six out of 9 patients experienced additional seizure freedom because of antiepileptic drugs (AEDs); however, the seizures of the other three patients, with serious conditions, showed poor response. Patients with anti-N-methyl-d-aspartate receptor antibodies had a lower risk of developing persistent seizures than those with anti-leucine-rich glioma-inactivated 1 (LGI1) or anti-γ-aminobutyric acid receptor type B receptor (GABABR) antibodies (P = 0.001). CONCLUSIONS: A complex of clinical and subclinical seizures, and nonepileptic events characterize ASE. Patients with anti-LGI1 or anti-GABABR antibodies have a higher risk of developing persistent seizures; AEDs are suitable for achieving additional seizure freedom, but not for patients with serious conditions. A few patients present with super-refractory epilepsy despite multiple treatments.


Assuntos
Encefalite/fisiopatologia , Encefalite/terapia , Doença de Hashimoto/fisiopatologia , Doença de Hashimoto/terapia , Convulsões/fisiopatologia , Convulsões/terapia , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/terapia , Encefalite/diagnóstico por imagem , Epilepsia Tônico-Clônica/fisiopatologia , Epilepsia Tônico-Clônica/terapia , Feminino , Seguimentos , Doença de Hashimoto/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Imunoterapia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de GABA/imunologia , Estado Epiléptico/etiologia , Estado Epiléptico/terapia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia , Resultado do Tratamento , Adulto Jovem
20.
Anal Chem ; 91(7): 4301-4306, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30829471

RESUMO

Nitric oxide (NO) and glutathione (GSH) have interplaying roles in oxidant-antioxidant balance. In this work, we developed the first example of a single fluorescent probe that displayed a turn-on fluorescence response toward NO and GSH from dual emission channels. The probe was synthesized by introducing 4-amino-3-(methylamino)-phenol to a BODIPY scaffold. Specifically, the NO-mediated transformation of diamine into a triazole triggered the fluorescence in the green channel, and the GSH-induced SNAr substitution reaction led to the red-shifted emission in the red channel. The probe was successfully applied to detect the exogenous and endogenous NO and GSH in macrophage cells. More importantly, the probe revealed that NO induced by interferon-γ (IFN-γ), lipopolysaccharide (LPS), and l-arginine (l-Arg) could also elicit the augmentation of intracellular GSH. We anticipate the probe would hold great potential for investigating the redox balance in biological processes.


Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Glutationa/análise , Óxido Nítrico/análise , Fenilenodiaminas/química , Animais , Arginina/farmacologia , Compostos de Boro/toxicidade , Teoria da Densidade Funcional , Corantes Fluorescentes/toxicidade , Glutationa/metabolismo , Interferon gama/farmacologia , Limite de Detecção , Lipopolissacarídeos/farmacologia , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Modelos Químicos , Óxido Nítrico/metabolismo , Fenilenodiaminas/toxicidade , Células RAW 264.7
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