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1.
Pol J Pathol ; 70(2): 127-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556563

RESUMO

We tested the association between HOXB13 G84E (rs138213197) germline mutation and PC risk in Polish men. DNA from 103 consecutive, newly diagnosed patients hospitalised because of PC and DNA from 103 men: volunteers, healthy at the time of the study. The G84E mutation was genotyped using Sanger sequencing. The HOXB13 G84E germline mutation was detected in 2.9% of PC men (3/103) and not detected in any healthy man. Two mutation carriers originated from two of 25 families fulfilling hereditary prostate cancer criteria (HPC) and one mutation carrier from one family among 78 families without HPC (PC frequency: 8% vs. 1.3%, OR = 6.70, p = 0.13). In two of three mutation carriers, disease was detected above 60 years of age. There was a trend for a lower probability of 5-year survival in patients with G84E than in patients without it (66.7% vs. 94.0%, p = 0.08). The HOXB13 G84E germline mutation is associated with increased prostate cancer risk in Polish men, with hereditary form of the disease, and probably with older age at PC onset (> 60 years of age) and shorter survival. However, it is not associated with PSA level, or PC stage or grade at the time of diagnosis.


Assuntos
Mutação em Linhagem Germinativa , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polônia , Antígeno Prostático Específico/sangue , Fatores de Risco
2.
Gene ; 718: 144048, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421189

RESUMO

Main conclusion Among 247 RsAP2/ERF identified, the majority of the 21 representatives were preferably expressed under drought and heat while suppressed under heavy metals, indicating their potential roles in abiotic stress responses and tolerance. APETALA2/Ethylene-Responsive factor (AP2/ERF) transcription factor (TF) is one of the largest gene families in plants that play a fundamental role in growth and development as well as biotic and/or abiotic stresses responses. Although AP2/ERFs have been extensively characterized in many plant species, little is known about this family in radish, which is an important root vegetable with various medicinal properties. The available genome provides valuable opportunity to identify and characterize the global information on AP2/ERF TFs in radish. In this study, a total of 247 ERF family genes were identified from the radish genome, and sequence alignment and phylogenetic analyses classified the AP2/ERF superfamily into five groups (AP2, ERF, DREB, RAV and soloist). Motif analysis showed that other than AP2/ERF domains, other conserved regions were selectively distributed among different clades in the phylogenetic tree. Chromosome location analysis showed that tandem duplication may result in the expansion of RsAP2/ERF gene family. The RT-qPCR analysis confirmed that a proportion of AP2/ERF genes were preferably expressed under drought and heat stresses, whereas they were suppressed under the ABA and heavy metal stresses. These results provided valuable information for further evolutionary and functional characterization of RsAP2/ERF genes, and contributed to genetic improvement of stress tolerances in radish and other root vegetable crops.


Assuntos
Evolução Molecular , Proteínas de Homeodomínio , Metais Pesados/toxicidade , Família Multigênica , Proteínas Nucleares , Filogenia , Proteínas de Plantas , Raphanus , Estresse Fisiológico/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raphanus/genética , Raphanus/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Medicine (Baltimore) ; 98(27): e16314, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277174

RESUMO

The Ladybird Homeobox 1 (LBX1) gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). The association between LBX1 gene polymorphisms and AIS has been investigated in several studies. However, these findings have yield contradictory results rather than conclusive evidence.This study is to provide a meta-analysis of the published case-control studies on the association between LBX1 gene polymorphisms and AIS in Asian and Caucasian populations.This meta-analysis conformed to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We conducted a literature research on PubMed, Embase, Web of Science, and Cochrane Library until February 10, 2018. We included all case-control or cohort studies about association between LBX1 gene polymorphisms and AIS. The Risk Of Bias In Non-randomised Studies-of Interventions and Critical Appraisal Skills Programme were used to evaluate the risk of bias and study quality. We assessed the strength of association by pooled odds ratios (ORs) and 95% confidence intervals (CIs) in all genetic models under a fixed-effect model or random-effect model. We further performed subgroup analysis by ethnicity and sex. Sensitivity analysis and publication bias were also undertaken.A total of 10 studies (11,411 cases and 26,609 controls) were included in this meta-analysis. The pooled results showed a statistically significant association between LBX1 gene polymorphisms and AIS (for rs11190870, T vs C, OR = 1.54, 95% CI = 1.48-1.61, P < .00001; for rs625039, G vs A, OR = 1.50, 95% CI: 1.38-1.62; P < .00001; for rs678741, G vs A, OR = 0.74, 95% CI: 0.63-0.86; P < .0001; for rs11598564, G vs A, OR = 1.41, 95% CI: 1.31-1.51; P < .0001). For stratified analyses by ethnicity and sex, robust significant associations were detected in Asian and Caucasian populations, and in women and men under all genetic models.T allele of rs11190870 and G alleles of rs625039 and rs11598564 represent risk factors for AIS, but G allele of rs678741 may play a protective role in the occurrence of AIS. Further research is needed to confirm this finding and to understand its implications.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Homeodomínio/genética , Polimorfismo Genético/genética , Escoliose/genética , Fatores de Transcrição/genética , Adolescente , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Razão de Chances , Escoliose/etnologia
4.
J Agric Food Chem ; 67(28): 7898-7907, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282664

RESUMO

This study aimed to explore the effects of silencing HB12 and TT8 genes on protein utilization characteristics of alfalfa. Ground samples of 11 HB12-silenced (HB12i), 5 TT8-silenced (TT8i) and 4 wild type (WT) were incubated in a Daisy II incubator with N15 labeled ammonium sulfate for 0, 4, 8, 12, and 24 h. CP degradation and degradational kinetics, microbial nitrogen fractions, and protein metabolic profiles were determined. Moreover, relationships between protein profiles and FTIR spectral parameters were estimated. Results showed that transgenic alfalfa had lower CP degradation, microbial protein, and total available protein compared with WT, especially for HB12i. In addition, CP degradation and protein metabolic profiles were closely correlated with FTIR spectral parameters and thereby could be predicted from spectral parameters. In conclusion, silencing of HB12 and TT8 genes in alfalfa decreased protein degradational and metabolic profiles, which were predictable with FTIR spectral parameters.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Inativação Gênica , Proteínas de Homeodomínio/genética , Medicago sativa/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Rúmen/metabolismo , Ração Animal/análise , Animais , Bactérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Bovinos , Digestão , Proteínas de Homeodomínio/metabolismo , Cinética , Medicago sativa/química , Medicago sativa/metabolismo , Proteínas de Plantas/química , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Proteólise , Rúmen/química , Rúmen/microbiologia
5.
BMC Plant Biol ; 19(1): 312, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307379

RESUMO

BACKGROUND: The WOX (WUSCHEL-RELATED HOMEOBOX) gene family encodes a class of transcription factors that are unique to green plants, where they are involved in regulating the development of plant tissues and organs by determining cell fate. Although the importance of the WOX gene is well known, there are few studies describing their functions in cotton. RESULTS: In this study, 32 WOX genes were found in Gossypium hirsutum. Phylogenetic analysis showed that WOX proteins of cotton can be divided into three clades: the ancient, intermediate, and WUS clades. The number of WOX proteins in the WUS clade was greater than the sum of the proteins in the other two clades. Our analysis revealed that 20 GhWOX genes are distributed on 16 cotton chromosomes and that duplication events are likely to have contributed to the expansion of the GhWOX family. All GhWOX genes have introns, and each GhWOX protein contains multiple motifs. RNA-seq data and real-time PCR showed that GhWOX13 gene subfamily is specifically expressed at a high level in cotton fibers. We also identified putative GA, NAA, and BR response elements in the promoter regions of the GhWOX13 genes and GhWOX13 transcripts were significantly induced by GA, NAA, and BR. CONCLUSIONS: Our data provides a useful resource for future studies on the functional roles of cotton WOX genes and shows that the GhWOX13 genes may influence cotton fiber development. Our results also provide an approach for identifying and characterizing WOX protein genes in other species.


Assuntos
Fibra de Algodão , Genes de Plantas , Gossypium/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Gossypium/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Filogenia , Reguladores de Crescimento de Planta/fisiologia , Proteínas de Plantas/genética
6.
Nat Commun ; 10(1): 2913, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266935

RESUMO

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia/metabolismo , Família Multigênica , Animais , Proliferação de Células , Epigênese Genética , Feminino , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Leucemia/genética , Leucemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Modelos Genéticos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo
7.
Life Sci ; 232: 116664, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325426

RESUMO

AIMS: MicroRNAs have been demonstrated to be involved in the development of atherosclerosis. The present study aimed to evaluate the effect of miR-99a-5p and its target gene Homeobox A1 (HOXA1) in atherosclerosis. MAIN METHODS: The biological functions of miR-99a-5p on human aortic smooth muscle cells (ASMCs) were assessed by MTT, wound healing and transwell assays. The target genes of microRNAs were predicted by TargetScan and miRDB. The binding of miR-99a-5p and HOXA1 was confirmed by luciferase reporter assay. In the in vivo study, high-fat diet-induced atherosclerosis model was established in Apolipoprotein E knockout mice. Hematoxylin-eosin (H&E), oil Red O and Masson trichrome staining were performed for determination of atherosclerotic lesion. The levels of miR-99a-5p and HOXA1 mRNA were detected by real-time PCR. HOXA1 and migration-associated protein levels were detected by western blot or immunohistochemistry analysis. KEY FINDINGS: MiR-99a-5p inhibited HOXA1 expression by targeting 3'UTR of HOXA1 mRNA. Enforced HOXA1 significantly promoted the proliferation, migration, and invasion of ASMCs. Furthermore, miR-99a-5p overexpression inhibited the proliferation, migration, and invasion of ASMCs stimulated by HOXA1, whereas miR-99a-5p inhibition reversed the effects of HOXA1 knockdown on these behaviours of ASMCs. In vivo, the specific overexpression of miR-99a-5p significantly abated atherosclerotic lesions formatted, accompanied with a significant down-regulation of HOXA1 mRNA and protein expression levels. SIGNIFICANCE: We demonstrate for first time that miR-99a-5p may serve as a potential inhibitor of the atherosclerosis, and miR-99a-5p plays its role partially through targeting HOXA1.


Assuntos
Aterosclerose/prevenção & controle , Regulação da Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/genética , MicroRNAs/fisiologia , Fatores de Transcrição/genética , Regiões 3' não Traduzidas , Animais , Aterosclerose/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Proteínas de Homeodomínio/fisiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fatores de Transcrição/fisiologia
8.
Plant Physiol Biochem ; 141: 250-258, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195255

RESUMO

The homeodomain-leucine zipper (HD-Zip) gene family plays an important role in plant growth and environmental responses. At present, research on the HD-Zip gene family of barley is incomplete. In this study, 32 HD-Zip genes (HvHD-Zip 1-32) were identified from the barley genome and were subsequently divided into four subfamilies according to conserved structure and motif analysis. Whole genome replication events in barley and Arabidopsis, rice, and wheat HD-Zip gene families were analyzed, yielding 3, 14 and 25 gene pairs, respectively, but no segmental or tandem duplication events were identified in the barley HD-Zip gene family. Subsequently, quantitative real-time PCR (qRT-PCR) analysis revealed that the HvHD-Zip gene is sensitive to drought stress and that members of the HD-Zip I and HD-Zip IV subfamilies are generally more sensitive to abiotic stresses. Our results suggest a relationship between barley resistance and the potential key HvHD-Zip gene, which lay the foundation for further functional studies.


Assuntos
Hordeum/genética , Família Multigênica , Estresse Fisiológico , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Biologia Computacional , Duplicação Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genoma , Genoma de Planta , Proteínas de Homeodomínio/genética , Oryza/genética , Filogenia , Domínios Proteicos , Triticum/genética
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 637-640, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204910

RESUMO

OBJECTIVE: To explore the clinical features and therapeutic efficacy in adult ALL patients with t (1; 19) (E2A-PBX1). METHODS: The clinic data of 19 adult ALL patients with t (1; 19) (E2A-PBX1) in our hospital from Nov. 22, 2010 to Apr. 4, 2018 were collected. The clinical features,complete remission (CR) rate, overall survival (OS) rate and relapse-free survival (RFS) rate of patients received chemotherapy and chemotherapy+HSCT were analyzed. RESULTS: In all the 19 patients, the median age was 24 (14-66), median WBC count was 16.47×109 (1.8-170.34)/L, median Hb level was 98 (65-176) g/L, median Plt count was 50 (15-254)×109/L. Pre B-ALL were 17 cases (89.5%), and common B-ALL were 2 cases (10.5%). Patients received the induction therapy, the overall CR rate was 94.7%, one course CR rate was 94.7%, 4 year OS rate was 47.1% and RFS rate was 43.3%. The OS rate and RFS rate of patients received transplantation were slightly higher than those of patients not received transplantation (OS: 62.5% vs 36.7%) (P=0.188);RFS (62.5% vs 38.9%) (P=0.166). CONCLUSION: Most adult ALL patients with t (1; 19) (E2A-PBX1) is Pre B-ALL by Immunophenotyping, as compared with the pediatric patients, the therapeutic efficacy for adult patients with t (1; 19) (E2A-PBX1) is worsen, therefore, stem cell transplantation is still acquired for better long term survival.


Assuntos
Proteínas de Homeodomínio/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Humanos , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 735-740, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204924

RESUMO

OBJECTIVE: RAG1 plays important roles in lymphopoiesis and immune system, its dysfunction may result in the malignancies of hemopoietic system. The aim of this study was to investigate the characteristics of RAG1 expression in adult B-cell acute lymphoblastic leukemia (B-ALL), and to analyze the clinical significances. METHODS: Quantitative PCR (q-PCR) was performed to evaluate the expression of RAG1 in 104 newly diagnosed, 22 relapsed adult B-ALL patients and 30 normal controls, the clinical significances of RAG1 expression were analyzed. RESULTS: Compared with normal controls, newly diagnosed and relapsed adult B-ALL patients showed higher RAG1 expression level (3.94 vs 1.23) (P<0.01), (5.86 vs 1.23) (P<0.01). The analysis of paired simples from 6 cases of newly diagnosed and relapsed B-ALL showed that the expression level of RAG1 at relapse was significantly higher than that at new diagnosis (13.65 vs 2.31) (P<0.01). The RAG1 expression level in IK6 positive patients was higher than that in IK6 negative patients (5.30 vs 2.11) (P<0.05). The ratio of patients with LDH>1 000 U/L in RAG1 high expression group was higher than that in RAG1 low expression group (42.2% vs 20.5%) (P<0.05). CONCLUSION: RAG1 up-regulation may play an important role in the development of adult B-ALL especially when relapsed, which may also take part in the formation of Ik6. Monitoring RAG1 expression may provide a new method to evaluate the prognosis of adult B-ALL patients.


Assuntos
Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adulto , Linfócitos B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico
11.
Gastroenterology ; 157(3): 838-850.e6, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163177

RESUMO

BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.


Assuntos
Anexina A2/metabolismo , Orientação de Axônios , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Gânglios Espinais/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Pancreáticas/metabolismo , Semaforinas/metabolismo , Animais , Anexina A2/deficiência , Anexina A2/genética , Orientação de Axônios/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Comunicação Celular , Gânglios Espinais/patologia , Regulação Neoplásica da Expressão Gênica , Genes p53 , Genes ras , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Crescimento Neuronal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Semaforinas/genética , Transdução de Sinais , Transativadores/genética , Células Tumorais Cultivadas
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 357-361, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167696

RESUMO

Objective To investigate the clinical significance of plasma cell free DNA (cfDNA) methylation in short stature homeobox 2 (SHOX2) and prostaglandin E receptor 4 (PTGER4) for diagnosing pulmonary nodule patients. Methods We collected 10 mL venous blood from patients. And the plasma DNA was extracted. Real-time quantitative PCR was performed to amplify the DNA after bisulfite conversion. Valid Ct values were input into specialized software to analyze the methylation status of SHOX2 and PTGER4. Histological classification of lung malignant tissues was carried out by immunohistochemistry. Results The 22 of 57 patients were positive and 35 were negative for SHOX2 and PTGER4 DNA methylation detection. Computed tomography (CT) indicated that 31 of 57 patients were diagnosed with pulmonary nodules, among which 19 patients were positive for DNA methylation; 3 of 16 patients with inflammation on CT were positive for DNA methylation; 10 patients with normal or ground glass CT images were negative for DNA methylation. Significant differences in SHOX2 and PTGER4 DNA methylation were observed in the patients with different CT findings. The highest positive rate of CT nodular lesions was 61.3%. The 20 patients with pulmonary nodules were pathologically diagnosed with lung cancer, of which 18 were positive for SHOX2 and PTGER4 DNA methylation, with a positive rate of 90%. Only 1 case of benign pulmonary nodules was positive. Significant difference in SHOX2 and PTGER4 methylation status was observed between benign and malignant pulmonary nodules. The positive rate of SHOX2 and PTGER4 methylation were both 100% in squamous cell lung carcinoma and small cell lung carcinoma, while 75% in adenocarcinoma. Conclusion SHOX2 and PTGER4 methylation detection in blood plasma has certain value in the early diagnosis of lung cancer and can be a complementary tool of CT in diagnosing pulmonary nodule patients.


Assuntos
Metilação de DNA , Proteínas de Homeodomínio/genética , Neoplasias Pulmonares/diagnóstico , Receptores de Prostaglandina E Subtipo EP4/genética , Biomarcadores Tumorais , Diagnóstico Diferencial , Proteínas de Homeodomínio/sangue , Humanos , Neoplasias Pulmonares/genética , Receptores de Prostaglandina E Subtipo EP4/sangue
13.
Nat Immunol ; 20(7): 890-901, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209400

RESUMO

Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Infecção/etiologia , Análise de Célula Única , Animais , Biomarcadores , Imunoprecipitação da Cromatina , Epigênese Genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Infecção/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fatores de Tempo , Transcriptoma
14.
BMC Med Genet ; 20(1): 105, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185933

RESUMO

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Anormalidades do Olho/etnologia , Oftalmopatias Hereditárias/etnologia , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Adulto Jovem
15.
Nature ; 571(7764): 270-274, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207604

RESUMO

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Transcrição Genética
16.
Medicine (Baltimore) ; 98(23): e15953, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169720

RESUMO

BACKGROUND: Studies showed the controversial results about the effect of common genetic polymorphisms on the atrial fibrillation (AF) recurrence. We performed the systematic review and meta-analysis to qualify the association between common genetic polymorphisms and AF recurrence. METHODS: Articles were systematically retrieved PubMed, Web of Science, EMBASE, Wanfang, and CNKI database and 9 studies including 3204 patients were enrolled in our meta-analysis. RESULTS: Results showed that the associations were significant under rs2200733 3 genetic models (TT vs CC: odds ratio [OR] [confidence interval [CI]] = 1.336 [1.061-1.683], P = .014; CT vs CC: OR [CI] = 0.759 [0.614-0.937], P = .01; TT vs CT + CC: OR [CI] = 2.308 [1.440-3.700], P = .001). The association was significant under rs10033464 genetic model (TT vs GG: OR [CI] = 1.517 [1.165-1.976], P = .002). CONCLUSIONS: Rs13376333 on chromosome 1q21 (in KCNN3), rs7193343 and rs2106261 on chromosome 16q22 (in ZFHX3) were not associated with AF recurrence in our meta-analysis. In total, our meta-analysis found that rs2200733 and rs10033464 on chromosome 4q25 (near PITX2) were associated with the risk of AF recurrence.


Assuntos
Fibrilação Atrial/genética , Cromossomos Humanos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Recidiva , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Fatores de Transcrição/genética
17.
DNA Cell Biol ; 38(7): 678-687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188017

RESUMO

Staging and pathological grading systems are convenient, but imperfect predictors of recurrence of head and neck squamous cell carcinoma. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of the promoter of Sal-like protein 2 (SALL2). SALL2 mRNA expression was absent in 8/9 (88.9%) University of Michigan squamous cell carcinoma cell lines, whereas two nonmalignant cell lines had stable expression. The normalized methylation value of SALL2 in cancer cell lines was significantly higher than in normal cell lines. SALL2 methylation found in 74 of 233 (31.8%) tumor specimens was correlated with the methylation status of both SALL1 and SALL3. SALL2 methylation was not associated with any difference in disease-free survival (DFS). Therefore, the presence of SALL2 methylation was statistically correlated with a decrease in DFS in patients with oral cancer (log-rank test, p = 0.032). Furthermore, it was associated with disease recurrence in 36.2% of oral cancer cases, with an odds ratio of 2.922 (95% confidence interval = 1.198-7.130; p = 0.018) by multivariate Cox proportional hazard regression analysis. This study suggests that cytosine-phosphate- guanosine (CpG) hypermethylation is a likely mechanism of SALL2 inactivation and supports the hypothesis that SALL2 could serve as an important clinical risk assessment.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Metilação de DNA , Neoplasias Bucais/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição/metabolismo
18.
Anticancer Res ; 39(5): 2289-2298, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092420

RESUMO

BACKGROUND/AIM: We previously identified that promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) and homeobox only protein homeobox (HOPX) were both cancer specific, and have a clinical potential as prognostic biomarkers in breast cancer (BC). The present study compared the differential prognostic relevance of methylation status of the CDO1 and HOPX genes in BC. MATERIALS AND METHODS: Methylation levels (TaqMethVs) were quantified in 7 BC cell lines and 133 BC patients by TaqMan methylation-specific PCR and functional traits were explored for CDO1. RESULTS: TaqMethVs were associated between CDO1 and HOPX (r2=0.072, p=0.002). Multivariate Cox proportional hazards model could identify CDO1 hypermethylation as well as Ki-67 as independent prognostic factors related to disease-specific survival (p=0.016, p<0.001). Overexpression of CDO1 decreased the anchorage-independent growth capacity in BC cell lines. CONCLUSION: CDO1 is a definite tumor suppressor gene, while its prognostic relevance was more than expected in the context of its functional relevance.


Assuntos
Neoplasias da Mama/genética , Cisteína Dioxigenase/genética , Metilação de DNA/genética , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais
19.
Nat Mater ; 18(6): 627-637, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31114073

RESUMO

Cells are transplanted to regenerate an organs' parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/ß-catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure-mechanical equivalency to native dentin. Thus, the Alx3-Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.


Assuntos
Proteínas de Homeodomínio/metabolismo , Tecido Parenquimatoso/fisiologia , Dente/citologia , Dente/embriologia , Adolescente , Animais , Feminino , Proteínas de Homeodomínio/genética , Humanos , Incisivo/citologia , Incisivo/embriologia , Camundongos Endogâmicos , Dente Serotino/citologia , Técnicas de Cultura de Órgãos , Tecido Parenquimatoso/citologia , Gravidez , Regiões Promotoras Genéticas , Regeneração , Células Estromais/fisiologia , Suínos , Fator A de Crescimento do Endotélio Vascular/genética , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo
20.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060342

RESUMO

The prospero homeobox 1 (PROX1) transcription factor is a product of one of the lymphangiogenesis master genes. It has also been suggested to play a role in carcinogenesis, although its precise role in tumour development and metastasis remains unclear. The aim of this study was to gain more knowledge on the PROX1 function in thyroid tumorigenesis. Follicular thyroid cancer-derived cells-CGTH-W-1-were transfected with PROX1-siRNA (small interfering RNA) and their proliferation, cell cycle, apoptosis and motility were then analysed. The transcriptional signature of PROX1 depletion was determined using RNA-Sequencing (RNA-Seq) and the expression of relevant genes was further validated using reverse transcriptase quantitative PCR (RT-qPCR), Western blot and immunocytochemistry. PROX1 depletion resulted in a decreased cell motility, with both migratory and invasive potential being significantly reduced. The cell morphology was also affected, while the other studied cancer-related cell characteristics were not significantly altered. RNA-seq analysis revealed significant changes in the expression of transcripts encoding genes involved in both motility and cytoskeleton organization. Our transcriptional analysis of PROX1-depleted follicular thyroid carcinoma cells followed by functional and phenotypical analyses provide, for the first time, evidence that PROX1 plays an important role in the metastasis of thyroid cancer cells by regulating genes involved in focal adhesion and cytoskeleton organization in tumour cells.


Assuntos
Adenocarcinoma Folicular/genética , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genética , Adenocarcinoma Folicular/patologia , Apoptose/genética , Biomarcadores Tumorais , Biópsia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , RNA Interferente Pequeno/genética , Transcriptoma
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