RESUMO
OBJECTIVES: To identify the 5' untranslated region of Zika virus (ZIKV 5'UTR) RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site (IRES) located in ZIKV 5'UTR and virus production. METHODS: Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining. Subsequently, liquid chromatography-tandem mass spectrometry (LC-MS/MS), bioinformatics analysis, and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR. Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production, respecitvely. RESULTS: tRSA RNA pull-down assay, LC-MS/MS, and Western blot analysis showed that polypyrimidine tract-binding protein (PTB) bound to the ZIKV 5'UTR. Furthermore, dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV (t = 10.220, P < 0.001), while PTB knockdown had the opposite effect (t = 4.897, P < 0.01). Additionally, virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer (t = 6.400, P < 0.01), whereas reducing PTB expression level weakened virus infectivity (t = 5.055, P < 0.01). CONCLUSIONS: PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production.
Assuntos
Regiões 5' não Traduzidas , Sítios Internos de Entrada Ribossomal , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Zika virus , Zika virus/genética , Zika virus/metabolismo , Zika virus/fisiologia , Regiões 5' não Traduzidas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Sítios Internos de Entrada Ribossomal/genética , Humanos , Biossíntese de Proteínas , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Infecção por Zika virus/genética , Ligação ProteicaRESUMO
Cryptosporidium is an important opportunistic intestinal pathogen for immunocompromised individuals and a common cause of diarrhea in young children in developing countries. Gastrointestinal epithelial cells play a central role in activating and orchestrating host immune responses against Cryptosporidium infection, but underlying molecular mechanisms are not fully understood. We report in this paper that C. parvum infection causes significant alterations in long noncoding RNA (lncRNA) expression profiles in murine intestinal epithelial cells. Transcription of a panel of lncRNA genes, including NR_045064, in infected cells is controlled by the NF-κB signaling. Functionally, inhibition of NR_045064 induction increases parasite burden in intestinal epithelial cells. Induction of NR_045064 enhances the transcription of selected defense genes in host cells following C. parvum infection. Epigenetic histone modifications are involved in NR_045064-mediated transcription of associated defense genes in infected host cells. Moreover, the p300/MLL-associated chromatin remodeling is involved in NR_045064-mediated transcription of associated defense genes in intestinal epithelial cells following C. parvum infection. Expression of NR_045064 and associated genes is also identified in intestinal epithelium in C57BL/6J mice following phosphorothioate oligodeoxynucleotide or LPS stimulation. Our data demonstrate that lncRNAs, such as NR_045064, play a role in regulating epithelial defense against microbial infection.
Assuntos
Criptosporidiose/genética , Cryptosporidium parvum/fisiologia , Mucosa Intestinal/fisiologia , RNA Longo não Codificante/genética , Animais , Anti-Infecciosos , Linhagem Celular , Criptosporidiose/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Imunidade/genética , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismoRESUMO
Random screening suggested that the EtOH extract of Artemisia myriantha (Asteraceae) and its EtOAc fraction had cytotoxicity against HepG2 cells with inhibitory ratios of 30.6% and 53.5% at 50.0 µg/mL. Bioassay-guided isolation of the most active fractions (Fr. C and Fr. D) afforded 19 new sesquiterpenolides, artemyrianolides A-S (1-19), involving 13 germacranolides (1-13), four guaianolides (14-17), and two eudesmanolides (18 and 19), together with 16 known sesquiterpenoids (20-35). The new compounds were characterized by physical data analyses (HRESIMS, IR, 1D and 2D NMR, ECD), and the absolute configurations of compounds 1, 2, and 11 were determined by X-ray crystallography. Structurally, compounds 2 and 11-13 maintain an uncommon cis-fused 10/5 bicyclic system and compound 12 possesses an unusual (7S) configuration. Twenty of the compounds exhibited cytotoxicity against HepG2, Huh7, and SMMC-7721 cell lines. Compound 9 showed cytotoxic activity on both HepG2 and Huh7 cells with IC50 values of 8.6 and 8.8 µM, and compounds 8 and 33 showed cytotoxicity to the three human hepatoma cell lines with IC50 values of 4.9 and 7.4 µM (HepG2), 4.3 and 7.8 µM (Huh7), and 3.1 and 9.8 µM (SMMC-7721), respectively.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Artemisia/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios XRESUMO
Cryptosporidium, a protozoan parasite that infects the gastrointestinal epithelium and other mucosal surfaces in humans and animals, is an important opportunistic pathogen in AIDS patients and one of the most common enteric pathogens affecting young children in developing regions. This parasite is referred to as a "minimally invasive" mucosal pathogen, and epithelial cells play a central role in activating and orchestrating host immune responses. We previously demonstrated that Cryptosporidium parvum infection stimulates host epithelial cells to release exosomes, and these released exosomes shuttle several antimicrobial peptides to carry out anti-C. parvum activity. In this study, we detected the upregulation of inflammatory genes in the liver and spleen following C. parvum intestinal infection in neonatal mice. Interestingly, exosomes released from intestinal epithelial cells following C. parvum infection could activate the nuclear factor kappa B signaling pathway and trigger inflammatory gene transcription in isolated primary splenocytes. Several epithelial cell-derived proteins and a subset of parasite RNAs were detected in the exosomes released from C. parvum-infected intestinal epithelial cells. Shuttling of these effector molecules, including the high mobility group box 1 protein, was involved in the induction of inflammatory responses in splenocytes induced by the exosomes released from infected cells. Our data indicate that exosomes released from intestinal epithelial cells upon C. parvum infection can activate immune cells by shuttling various effector molecules, a process that may be relevant to host systemic responses to Cryptosporidium infection.
Assuntos
Criptosporidiose/imunologia , Criptosporidiose/parasitologia , Cryptosporidium parvum/fisiologia , Células Epiteliais/imunologia , Exossomos/imunologia , Intestinos/imunologia , Baço/citologia , Animais , Criptosporidiose/genética , Células Epiteliais/parasitologia , Exossomos/genética , Feminino , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/imunologia , Humanos , Intestinos/parasitologia , Fígado/imunologia , Fígado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/imunologia , Baço/imunologia , Baço/parasitologiaRESUMO
Epidermal growth factor-like protein 6 (EGFL6) serves as an exocrine protein promoting proliferation and migration during carcinogenesis in ovarian cancer. However, its function and mechanisms in colorectal cancer (CRC) have not been completely explored. To investigate the role of EGFL6 in CRC cell growth, in vitro CCK8, colony formation assays, flow cytometric analysis of the cell cycle and apoptosis, and an in vivo tumor xenograft model were utilized. Additionally, Western blotting and luciferase reporter assays were used to investigate the underlying mechanisms of EGFL6 function on the WNT/ß-catenin signaling pathway. Immunohistochemical staining showed that EGFL6 is overexpressed in CRCs and this overexpression was highly correlated with advanced T classification, N classification, distant metastasis, and poor survival. Knocking down EGFL6 in CRC cell lines induced the inhibition of cell growth, cell cycle arrest at the G0/G1 phase, and apoptosis. Further, knockdown of EGFL6 blocked WNT/ß-catenin signaling as measured by Western blotting and luciferase reporter assay. Results also showed that recombinant EGFL6 (rEGFL6) induced ß-catenin in a concentration- and time-dependent manner. Further experiments showed that administration of rEGFL6 to cell cultures with EGFL6 knocked down or treated with the WNT/ß-catenin inhibitor ICG-001 increased ß-catenin and its downstream protein CyclinD1. The CCK8 assay showed that EGFL6 promoted CRC cell growth partly by the promotion of TCF7L2 expression. These findings suggest that EGFL6 plays a crucial role in the progression of CRC by regulation of the WNT/ß-catenin signaling pathway.
Assuntos
Neoplasias Colorretais/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Via de Sinalização Wnt , Animais , Células CACO-2 , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Prognóstico , Análise de Sobrevida , Regulação para CimaRESUMO
Intestinal infection by Cryptosporidium is known to cause epithelial cell migration disorder but the underlying mechanisms are unclear. Previous studies demonstrated that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected epithelial cells. Using multiple models of intestinal cryptosporidiosis, we report here that C. parvum infection induces expression and release of the dickkopf protein 1 (Dkk1) from intestinal epithelial cells. Delivery of parasite Cdg7_FLc_1030 RNA to intestinal epithelial cells triggers transactivation of host Dkk1 gene during C. parvum infection. Release of Dkk1 is involved in C. parvum-induced inhibition of cell migration of epithelial cells, including noninfected bystander cells. Moreover, Dkk1-mediated suppression of host cell migration during C. parvum infection involves inhibition of Cdc42/Par6 signaling. Our data support the hypothesis that attenuation of intestinal epithelial cell migration during Cryptosporidium infection involves parasite Cdg7_FLc_1030 RNA-mediated induction and release of Dkk1 from infected cells.
Assuntos
Cryptosporidium parvum/metabolismo , Células Epiteliais/parasitologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/citologia , RNA de Protozoário/farmacologia , Animais , Linhagem Celular , Cryptosporidium parvum/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Ativação TranscricionalRESUMO
To counteract host immunity, Cryptosporidium parvum has evolved multiple strategies to suppress host antimicrobial defense. One such strategy is to reduce the production of the antimicrobial peptide beta-defensin 1 (DEFB1) by host epithelial cells but the underlying mechanisms remain unclear. Recent studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of intestinal cryptosporidiosis, in this study, we analyzed the expression profile of host beta-defensin genes in host cells following infection. We found that C. parvum infection caused a significant downregulation of the DEFB1 gene. Interestingly, downregulation of DEFB1 gene was associated with host delivery of Cdg7_FLc_1000 RNA transcript, a C. parvum RNA that has previously demonstrated to be delivered into the nuclei of infected host cells. Knockdown of Cdg7_FLc_1000 in host cells could attenuate the trans-suppression of host DEFB1 gene and decreased the parasite burden. Therefore, our data suggest that trans-suppression of DEFB1 gene in intestinal epithelial cells following C. parvum infection involves host delivery of parasite Cdg7_FLc_1000 RNA, a process that may be relevant to the epithelial defense evasion by C. parvum at the early stage of infection.
Assuntos
Criptosporidiose/genética , Cryptosporidium parvum , Mucosa Intestinal/parasitologia , RNA de Protozoário/fisiologia , beta-Defensinas/genética , Animais , Linhagem Celular , Criptosporidiose/imunologia , Criptosporidiose/parasitologia , Cryptosporidium parvum/genética , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , CamundongosRESUMO
Intestinal infection by Cryptosporidium parvum causes inhibition of epithelial turnover, but underlying mechanisms are unclear. Previous studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected epithelial cells. Using in vitro and in vivo models of intestinal cryptosporidiosis, we report here that host delivery of parasite Cdg7_FLc_1000 RNA results in inhibition of epithelial cell migration through suppression of the gene encoding sphingomyelinase 3 (SMPD3). Delivery of Cdg7_FLc_1000 into infected cells promotes the histone methyltransferase G9a-mediated H3K9 methylation in the SMPD3 locus. The DNA-binding transcriptional repressor, PR domain zinc finger protein 1, is required for the assembly of Cdg7_FLc_1000 into the G9a complex and associated with the enrichment of H3K9 methylation at the gene locus. Pathologically, nuclear transfer of Cryptosporidium parvum Cdg7_FLc_1000 RNA is involved in the attenuation of intestinal epithelial cell migration via trans-suppression of host cell SMPD3.
Assuntos
Movimento Celular , Criptosporidiose/patologia , Cryptosporidium parvum/patogenicidade , Regulação para Baixo , Células Epiteliais/fisiologia , RNA de Protozoário/metabolismo , Esfingomielina Fosfodiesterase/biossíntese , Animais , Linhagem Celular , Modelos Animais de Doenças , Epigênese Genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Enteropatias/patologia , Metilação , Camundongos , Processamento de Proteína Pós-TraducionalRESUMO
Long intergenic noncoding RNAs (lincRNAs) can regulate the transcription of inflammatory genes and thus may represent a new group of inflammatory mediators with a potential pathogenic role in inflammatory diseases. Here, our genome-wide transcriptomic data show that TNF-α stimulation caused up-regulation of 171 lincRNAs and down-regulation of 196 lincRNAs in murine intestinal epithelial cells in culture. One of the up-regulated lincRNAs, lincRNA-Cox2, is an early-responsive lincRNA induced by TNF-α through activation of the NF-ĸB signaling pathway. Knockdown of lincRNA-Cox2 resulted in reprogramming of the gene expression profile in intestinal epithelial cells in response to TNF-α stimulation. Specifically, lincRNA-Cox2 silencing significantly (P < 0.05) enhanced the transcription of Il12b, a secondary late-responsive gene induced by TNF-α. Mechanistically, lincRNA-Cox2 promoted the recruitment of the Mi-2/nucleosome remodeling and deacetylase (Mi-2/NuRD) repressor complex to the Il12b promoter region. Recruitment of the Mi-2/NuRD complex was associated with decreased H3K27 acetylation and increased H3K27 dimethylation at the Il12b promoter region, which might contribute to Il12b trans-suppression by lincRNA-Cox2. Thus, our data demonstrate a novel mechanism of epigenetic modulation by lincRNA-Cox2 on Il12b transcription, supporting an important role for lincRNAs in the regulation of intestinal epithelial inflammatory responses.
Assuntos
Interleucina-12/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , RNA Longo não Codificante/genética , Fator de Necrose Tumoral alfa/metabolismo , Acetilação , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Epigenômica/métodos , Células Epiteliais/metabolismo , Histonas/genética , Interleucina-12/metabolismo , Mucosa Intestinal/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nucleossomos/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Transcrição Gênica , Ativação Transcricional , Fator de Necrose Tumoral alfa/genética , Regulação para CimaRESUMO
Background and aims Magnifying endoscopy with narrow-band imaging (M-NBI) has been widely used in the differential diagnosis of deep submucosal colorectal cancers (dSMCs) from superficial submucosal cancers (sSMCs) and intramucosal neoplasms. We aimed to pool the diagnostic efficacy of M-NBI and compare it with that of magnifying chromoendoscopy (M-CE) in diagnosing colorectal dSMC. Methods PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies. Meeting abstracts were also searched. A bivariate mixed-effects binary regression model was used in the meta-analysis to calculate the pooled diagnostic efficacy of M-NBI and compare it with that of M-CE in the diagnosis of dSMC. Subgroup analyses and meta-regression were conducted to explore sources of heterogeneity. Results We included 17 studies: 14 full texts and 3 meeting abstracts. The pooled sensitivity, specificity, and area under the summary receiver operating characteristic curve (AUC) with 95â% confidence intervals (CIs) in diagnosing dSMC were 74â% (66â%â-â81â%; I2â=â84.6â%), 98â% (94â%â-â99â%; I2â=â94.4â%), and 0.91 (0.88â-â0.93), respectively, for M-NBI. The pooled sensitivity, specificity and AUC (95â%CI) were 84â% (76â%â-â89â%; I2â=â76.9â%), 97â% (94â%â-â99â%; I2â=â90.2â%), and 0.97 (0.95â-â0.98), respectively, for M-CE. M-NBI had lower sensitivity (Pâ<â0.01) than M-CE with similar specificity (Pâ=â0.32). Subgroup analyses and meta-regression indicated that endoscopic diagnostic criteria, study type, endoscope type, risk of index test bias, and histopathological diagnostic criteria might be the sources of heterogeneity. Conclusions M-NBI and M-CE had comparable specificities in diagnosing dSMC, but the sensitivity of M-NBI was slightly lower than that of M-CE.
Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico por imagem , Mucosa Intestinal/diagnóstico por imagem , Imagem de Banda Estreita , Área Sob a Curva , Cor , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Humanos , Mucosa Intestinal/patologia , Curva ROCRESUMO
BACKGROUND: Artematrolide A (AR-A), a guaianolide dimer isolated from Artemisia atrovirens, demonstrated significant inhibitory effect on three human hepatoma cell lines (HepG2, Huh7 and SMMC7721). The anti-cervical cancer effect and mechanism of this compound have yet to be explored. This study is to reveal the role and mechanisms of artematrolide A on cervical cancer cells, and provide the pharmacological understanding of artematrolide A. PURPOSE: To investigate the function and possible mechanism of artematrolide A on cervical cancer cells in vitro. METHODS: HeLa S3 and SiHa cells were treated with artematrolide A at various concentrations. In this study, MTT, colony formation, cell migration and invasion, cell cycle analysis, cell apoptosis, reactive oxygen species (ROS) detection, western blotting, enzyme activity, and lactate production of artematrolide A were evaluated. RESULTS: Artematrolide A inhibited cell viability, proliferation, migration and invasion in a dose-dependent manner, caused cell cycle arrest in G2/M phase, and induced cell apoptosis via Bcl-2/PARP-1. The mechanism of action of artematrolide A included two aspects: artematrolide A suppressed cell proliferation by activating ROS/ERK/mTOR signaling pathway and promoted glucose metabolism from aerobic glycolysis to mitochondrial respiration by activating pyruvate dehydrogenase complex (PDC) and oxoglutarate dehydrogenase complex (OGDC) via inhibiting the activity of alkaline phosphatases (ALP). CONCLUSION: Artematrolide A exhibited a significant cytotoxic activity on cervical cancer cells, induced G2/M cell cycle arrest and apoptosis by activating ROS/ERK/mTOR signaling pathway and promoting metabolic shift from aerobic glycolysis to mitochondrial respiration, which suggested artematrolide A might be a potential agent for the treatment of cervical cancer.
Assuntos
Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Espécies Reativas de Oxigênio , Serina-Treonina Quinases TOR , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologiaRESUMO
The monitoring of deferasirox (DEF) has important clinical roles in patients who need iron excretion. However, analytical methods with practicability and simplicity are limited. Moreover, ratiometric fluorescence strategies based on Förster resonance energy transfer (FRET) from carbon dots (CDs) as a donor are rarely reported as a drug monitor. In this work, CDs with an appropriate emitting wavelength at 480 nm and excitation around 370 nm were prepared by hydrothermal approach and HCl post-treatment. O-Phenylenediamine (OPD) can be oxidized by Cu2+ to produce yellow fluorescent 2,3-diaminophenazine (oxOPD) in the system of Cu2+ and OPD (Cu-OPD). Correspondingly, a remarkable FRET from CDs to oxOPD in the system of CDs, Cu2+ and OPD (CDs-Cu-OPD) was fabricated with the quenching illustration of CDs, but emitting property of oxOPD. Attributed to the chelation ability of DEF on Cu2+, the inhibitory effects of DEF on the Cu2+-triggered oxidative capability reduced the FRET system by the decreased oxOPD. Thus, the recovered CDs at F 480 and decreased oxOPD at F 560 were found through a ratiometric mode by the addition of DEF in CDs-Cu-OPD for the DEF assay. The FRET behavior of CDs and oxOPD in CDs-Cu-OPD was proved clearly through the calculation of the association constant, binding constant, number of binding sites, and the distance between the donor and acceptor. Furthermore, this ratiometric method exhibited promising analytical performance for DEF with the application in real samples. The implementation of this work expands the application field of CDs and OPD oxidation in drug monitoring, and even other biological analyses through ratiometric strategy.
RESUMO
Interferon (IFN) signaling is key to mucosal immunity in the gastrointestinal tract, but cellular regulatory elements that determine interferon gamma (IFN-γ)-mediated antimicrobial defense in intestinal epithelial cells are not fully understood. We report here that a long noncoding RNA (lncRNA), GenBank accession no. XR_001779380, was increased in abundance in murine intestinal epithelial cells following infection by Cryptosporidium, an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children. Expression of XR_001779380 in infected intestinal epithelial cells was triggered by TLR4/NF-κB/Cdc42 signaling and epithelial-specific transcription factor Elf3. XR_001779380 primed epithelial cells for IFN-γ-mediated gene transcription through facilitating Stat1/Swi/Snf-associated chromatin remodeling. Interactions between XR_001779380 and Prdm1, which is expressed in neonatal but not adult intestinal epithelium, attenuated Stat1/Swi/Snf-associated chromatin remodeling induced by IFN-γ, contributing to suppression of IFN-γ-mediated epithelial defense in neonatal intestine. Our data demonstrate that XR_001779380 is an important regulator in IFN-γ-mediated gene transcription and age-associated intestinal epithelial antimicrobial defense. IMPORTANCE Epithelial cells along the mucosal surface provide the front line of defense against luminal pathogen infection in the gastrointestinal tract. These epithelial cells represent an integral component of a highly regulated communication network that can transmit essential signals to cells in the underlying intestinal mucosa that, in turn, serve as targets of mucosal immune mediators. LncRNAs are recently identified long noncoding transcripts that can regulate gene transcription through their interactions with other effect molecules. In this study, we demonstrated that lncRNA XR_001779380 was upregulated in murine intestinal epithelial cells following infection by a mucosal protozoan parasite Cryptosporidium. Expression of XR_001779380 in infected cells primed host epithelial cells for IFN-γ-mediated gene transcription, relevant to age-dependent intestinal antimicrobial defense. Our data provide new mechanistic insights into how intestinal epithelial cells orchestrate intestinal mucosal defense against microbial infection.
Assuntos
Criptosporidiose/imunologia , Cryptosporidium parvum/fisiologia , Interferon gama/imunologia , Mucosa Intestinal/imunologia , RNA Longo não Codificante/imunologia , Fatores Etários , Animais , Criptosporidiose/genética , Criptosporidiose/parasitologia , Cryptosporidium parvum/genética , Células Epiteliais/imunologia , Células Epiteliais/parasitologia , Humanos , Imunidade nas Mucosas , Interferon gama/genética , Mucosa Intestinal/parasitologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , RNA Longo não Codificante/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
Background: There existed limited evidence about prognosis of young-onset early colorectal cancer (ECRC). In the present study, we aimed to compare prognosis between patients with young-onset ECRCs and patients with conventional ECRCs. Method: Patients with surgically resected, histologically diagnosed ECRCs were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Young-onset ECRC was defined as ECRC occurring in patients aged <50 years. Five-years relative survival was calculated at the time of diagnosed year and linear regression was performed to analyze the association between 5-years relative survival and age. The multivariate Cox regression, multivariate competing risk model, and propensity score matching (PSM) and univariate analysis weighted by the inverse probability of treatment weight (IPTW) were used to compare overall survival (OS) between young-onset ECRCs and conventional ECRCs. Results: A total of 51,197 ECRCs were retrieved from SEER database, including 4,634 young-onset ECRCs and 46,563 conventional ECRCs. Five-years relative survival was found to be moderately associated with different age groups (R = -0.725, P = 0.0034). Patients with young-onset ECRCs (96.7%) had similar 5-years relative survival compared with conventional ECRCs (96.3%). However, multivariate Cox regression [HR (hazard ratio), 0.18; 95% CI: 0.16-0.20; P < 0.001] showed better OS in young-onset ECRCs. After PSM, we still found favored prognosis for young-onset ECRCs under univariate Cox regression (HR, 0.18; 95% CI: 0.16-0.21; P < 0.001). Similar results could also be found in the univariate Cox regression weighted by IPTW (HR, 0.17; 95% CI: 0.17-0.18; P < 0.001). Conclusions: Patients with young-onset ECRCs had similar relative survival but better OS compared with conventional ECRCs.
RESUMO
With the wide application of endoscopic resection for early gastric cancer (EGC) by not only Asian endoscopists but also those from Western countries, reviews on standardized treatment processes before and after endoscopic resection are nevertheless lacking. In this article we provide a narrative review of studies on the selection of appropriate EGC for endoscopic resection and the follow-up strategies for those with histologically confirmed EGC after endoscopic resection. EGC should be comprehensively assessed before endoscopic resection, including its exact margin, invasive depth and risk of lymph node metastasis (LNM). While the curative resection status of EGC may be evaluated after endoscopic resection based on the newly developed eCura system, although this needs to be further verified. Surveillance with endoscopy and computed tomography scan is necessary for patients with an EGC level A or B. An additional endoscopic resection is recommended for patients with a level-C1 EGC. For patients with a level-C2 EGC, close follow-up is suggested for low-risk tumors of level C2 and additional surgery for those at high risks. Further postoperative strategy is suggested based on comprehensive assessment of the risk of LNM, patient's quality of life and wishes.
Assuntos
Gastroscopia/métodos , Neoplasias Gástricas/cirurgia , Diferenciação Celular , Detecção Precoce de Câncer/métodos , Ressecção Endoscópica de Mucosa/métodos , Humanos , Metástase Linfática , Recidiva Local de Neoplasia/diagnóstico , Vigilância da População/métodos , Neoplasias Gástricas/patologiaRESUMO
OBJECTIVE: Sessile serrated adenoma/polyps (SSA/P) are recognized as precancerous lesions in the colon and resemble hyperplastic polyps (HP). Definite endoscopic features under narrow band imaging (NBI) with or without magnification may help differentiate these two lesions. Our study aimed to identify specific endoscopic features of SSA/P by NBI. METHODS: A total of 199 patients with histopathologically proven colorectal SSA/P or HP after a polypectomy were enrolled. Magnifying and non-magnifying NBI pictures of 206 matching lesions were evaluated by one expert and two non-expert endoscopists using various endoscopic characteristics retrospectively. RESULTS: Multivariate analysis indicated that a clouded surface (odds ratio [OR] 6.48, 95% confidence interval [CI] 2.72-15.44, P = 0.000) and dilated and branching vessels (DBV) (OR 7.95, 95% CI 3.71-17.02, P = 0.000) were significant endoscopic features for diagnosing SSA/P compared with HP. The combination of these two features could improve diagnostic specificity to 96%, and the area under the receiver operating characteristic curve was 0.749. However, it seemed that the presence of dark spots (OR 1.93, 95% CI 0.94-4.00, P = 0.075) was not a definite feature in differentiating these two lesions. Neither a mucus cap nor CP-II meshed capillary vessels showed statistical significance in differentiating SSA/P from HP (P = 0.590 and 0.293, respectively). CONCLUSIONS: A clouded surface and DBV were two indicators for diagnosing SSA/P. Combining these two factors together under NBI with or without magnification achieved better diagnostic performance than when they were used alone.
Assuntos
Adenoma/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Imagem de Banda Estreita/métodos , Lesões Pré-Cancerosas/diagnóstico , Adenoma/diagnóstico por imagem , Adenoma/patologia , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/diagnóstico por imagem , Pólipos Adenomatosos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/patologia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Humanos , Aumento da Imagem , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/patologia , Estudos Retrospectivos , Adulto JovemRESUMO
Multiple studies have shown that cancer-specific alternative splicing (AS) alterations are associated with clinical outcome. In this study, we aimed to profile prognostic AS signatures for pancreatic ductal adenocarcinoma (PDAC). We integrated the percent-spliced-in (PSI) data of AS in 140 PDAC patients based on the Cancer Genome Atlas (TCGA) dataset. We identified overall survival (OS)-associated AS events using univariate Cox regression analysis. Then, prognostic AS signatures were constructed for OS and chemoresistance prediction using the least absolute shrinkage and selection operator (LASSO) method. We also analyzed splicing factors (SFs) regulatory networks by Pearson's correlation. We detected 677 OS-related AS events in 485 genes by profiling 10,354 AS events obtained from 140 PDAC patients. Gene functional enrichment analysis demonstrated the pathways enriched by survival-associated AS. The AS signatures constructed with significant survival-associated AS events revealed high performance in predicting PDAC survival and gemcitabine chemoresistance. The area under the receiver operator characteristic curve was 0.937 in training cohort and 0.748 in validation cohort at 2000 days of OS. Furthermore, we identified prognostic SFs (e.g., ESRP1 and HNRNPC) to build the AS regulatory network. We constructed AS signatures for OS and gemcitabine chemoresistance in PDAC patients, which may provide clues for further experiment-based mechanism study.