Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 139
Filtrar
1.
Nat Commun ; 12(1): 5285, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489442

RESUMO

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Genoma , Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Transcrição Genética , Animais , Cromatina/química , Cromatina/metabolismo , Ilhas de CpG , DNA/genética , DNA/metabolismo , Metilases de Modificação do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ontologia Genética , Histonas/genética , Histonas/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Anotação de Sequência Molecular , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-34380082

RESUMO

BACKGROUND: Previous sleep electroencephalography studies have detected abnormalities in sleep architecture and sleep spindle deficits in schizophrenia (SCZ), but the consistency of these results was not robust, which might be due to the small sample size and the influence of clinical factors such as the various medication therapies and symptom heterogeneity. This study aimed to regard auditory verbal hallucinations (AVHs) as a pointcut to downscale the heterogeneity of SCZ and explore whether some sleep architecture and spindle parameters were more severely impaired in SCZ patients with AVHs compared with those without AVHs. METHODS: A total of 90 SCZ patients with AVHs, 92 SCZ patients without AVHs, and 91 healthy control subjects were recruited, and parameters of sleep architecture and spindle activities were compared between groups. The correlation between significant sleep parameters and clinical indicators was analyzed. RESULTS: Deficits of sleep spindle activities at prefrontal electrodes and intrahemispheric spindle coherence were observed in both AVH and non-AVH groups, several of which were more serious in the AVH group. In addition, deficits of spindle activities at central and occipital electrodes and interhemispheric spindle coherence mainly manifested accompanying AVH symptoms, most of which were retained in the medication-naive first-episode patients, and were associated with Auditory Hallucination Rating Scale scores. CONCLUSIONS: Our results suggest that the underlying mechanism of spindle deficits might be different between SCZ patients with and without AVHs. In the future, the sleep feature of SCZ patients with different symptoms and the influence of clinical factors, such as medication therapy, should be further illustrated.

4.
Bioorg Med Chem Lett ; 50: 128319, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34403728

RESUMO

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

5.
Nucleic Acids Res ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34432052

RESUMO

Genome-wide association studies (GWAS) have identified thousands of non-coding single-nucleotide polymorphisms (SNPs) associated with human traits and diseases. However, functional interpretation of these SNPs remains a significant challenge. Our recent study established the concept of 3' untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), which can be used to interpret ∼16.1% of GWAS SNPs and are distinct from gene expression QTLs and splicing QTLs. Despite the growing interest in 3'aQTLs, there is no comprehensive database for users to search and visualize them across human normal tissues. In the 3'aQTL-atlas (https://wlcb.oit.uci.edu/3aQTLatlas), we provide a comprehensive list of 3'aQTLs containing ∼1.49 million SNPs associated with APA of target genes, based on 15,201 RNA-seq samples across 49 human Genotype-Tissue Expression (GTEx v8) tissues isolated from 838 individuals. The 3'aQTL-atlas provides a ∼2-fold increase in sample size compared with our published study. It also includes 3'aQTL searches by Gene/SNP across tissues, a 3'aQTL genome browser, 3'aQTL boxplots, and GWAS-3'aQTL colocalization event visualization. The 3'aQTL-atlas aims to establish APA as an emerging molecular phenotype to explain a large fraction of GWAS risk SNPs, leading to significant novel insights into the genetic basis of APA and APA-linked susceptibility genes in human traits and diseases.

7.
J Microbiol Biotechnol ; 31(8): 1163-1174, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34226415

RESUMO

Casein-derived antioxidant peptides by using microbial proteases have gained increasing attention. Combination of two microbial proteases, Protin SD-NY10 and Protease A "Amano" 2SD, was employed to hydrolyze casein to obtain potential antioxidant peptides that were identified by LCMS/ MS, chemically synthesized and characterized in a oxidatively damaged HepG2 cell model. Four peptides, YQLD, FSDIPNPIGSEN, FSDIPNPIGSE, YFYP were found to possess high 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability. Evaluation with HepG2 cells showed that the 4 peptides at low concentrations (< 1.0 mg/ml) protected the cells against oxidative damage. The 4 peptides exhibited different levels of antioxidant activity by stimulating mRNA and protein expression of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as nuclear factor erythroid-2-related factor 2 (Nrf2), but decreasing the mRNA expression of Kelch-like ECH-associated protein 1 (Keap1). Furthermore, these peptides decreased production of reactive oxygen species (ROS) and malondialdehyde (MDA), but increased glutathione (GSH) production in HepG2 cells. Therefore, the 4 casein-derived peptides obtained by using microbial proteases exhibited different antioxidant activity by activating the Keap1-Nrf2 signaling pathway, and they could serve as potential antioxidant agents in functional foods or pharmaceutic preparation.

8.
Ann Surg ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132691

RESUMO

OBJECTIVE: We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY BACKGROUND DATA: Pre-treatment risk stratification is essential for offering individualized treatments to patients with pancreatic ductal adenocarcinoma (PDAC), but predicting recurrence following surgery remains clinically challenging. METHODS: We analyzed 210 plasma and serum specimens from four cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS: We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence (AUC: 0.81, 95% CI: 0.70-0.89) and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65-0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (HR: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS: We identified a novel, non-invasive exosomal miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.

9.
Nat Genet ; 53(7): 994-1005, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33986536

RESUMO

Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3'aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein-binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3'aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3'aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3'aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3'aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Herança Multifatorial , Poliadenilação , Locos de Características Quantitativas , RNA Mensageiro/genética , Regiões 3' não Traduzidas , Estudos de Associação Genética/métodos , Humanos , Poli A
10.
Food Funct ; 12(12): 5607-5620, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34018492

RESUMO

Diets of overloaded purine-rich foods for a long time are one of the important reasons to cause renal lesions. Eucommia ulmoides is one of the traditional Chinese medicine herbs, which has been used to recover functions of the kidney. However, its mechanism remains unclear. The aim of this study was to explore the effects and protective mechanism of Eucommia ulmoides extract on renal injury caused by long-term high purine diets in rats. SD rats underwent an intragastric adenine (200 mg kg-1 d-1) administration for 9 weeks and were treated for 15 weeks. The results demonstrated that Eucommia ulmoides extract significantly reduced serum Cre and BUN levels in rats. H&E and Masson's trichrome stains showed notable lowering of the infiltration of inflammatory cells, the formation of fibrous tissues and collagen fibers, and improvement in the pathological morphology of kidneys. It also suppressed the protein and mRNA expressions of TGF-ß1 and α-SMA and enhanced E-cadherin expression. Meanwhile, Eucommia ulmoides extract prominently inhibited the mRNA expression of Col I, Col III, Col IV, TIMP-1, and TIMP-2 and promoted expressions of MMP-1, MMP-2 and MMP-9. Through our study, it is the first time to prove that Eucommia ulmoides extract could ameliorate renal interstitial fibrosis and may involve in the regulation of the extracellular matrix (ECM) degradation enzyme (MMPs/TIMPs) system, promotion of the expression of E-cadherin, and suppression of expressions of TGF-ß1 and α-SMA. The results provide a significant implication for the utilization of Eunomia Ulmoides extract as functional foods to enhance renal functions and improve renal injury caused by high purine diets.


Assuntos
Eucommiaceae/química , Rim/efeitos dos fármacos , Rim/lesões , Extratos Vegetais/farmacologia , Purinas/administração & dosagem , Animais , Caderinas/metabolismo , Medicamentos de Ervas Chinesas , Rim Fundido/metabolismo , Rim Fundido/patologia , Rim/patologia , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Sprague-Dawley , Insuficiência Renal , Fator de Crescimento Transformador beta1/metabolismo
11.
Cell Biochem Biophys ; 79(4): 905-917, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34028638

RESUMO

In addition to nucleic acids, a variety of other biomolecules have also been found on the plasma membrane. Although researchers have realized that RNA has the ability to bind to membrane vesicles in vitro, little is known about whether and how RNA connects to the plasma membrane of the cell. The combination of high-throughput sequencing and in situ labeling methods provides an innovative approach for large-scale identification of subcellular RNAs. Here, we applied the recently published method APEX-seq and identified 75 RNAs related to the plasma membrane, in which lncRNA PMAR72 (plasma membrane-associated RNA AL121772.1) has a considerable affinity with sphingomyelin (SM) and localizes within distinct membrane foci. Our findings will provide some new evidence to elaborate the relationship between RNA and the plasma membrane of mammalian cells.

12.
Front Genet ; 12: 658352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889181

RESUMO

Single-cell Assay Transposase Accessible Chromatin sequencing (scATAC-seq) has been widely used in profiling genome-wide chromatin accessibility in thousands of individual cells. However, compared with single-cell RNA-seq, the peaks of scATAC-seq are much sparser due to the lower copy numbers (diploid in humans) and the inherent missing signals, which makes it more challenging to classify cell type based on specific expressed gene or other canonical markers. Here, we present svmATAC, a support vector machine (SVM)-based method for accurately identifying cell types in scATAC-seq datasets by enhancing peak signal strength and imputing signals through patterns of co-accessibility. We applied svmATAC to several scATAC-seq data from human immune cells, human hematopoietic system cells, and peripheral blood mononuclear cells. The benchmark results showed that svmATAC is free of literature-based markers and robust across datasets in different libraries and platforms. The source code of svmATAC is available at https://github.com/mrcuizhe/svmATAC under the MIT license.

13.
Bioinformatics ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830205

RESUMO

SUMMARY: JavaScript-based Circos libraries have been widely implemented to generate interactive Circos plots in web applications. However, these libraries require either local installation, which requires the compilation of extra libraries, or extra data processing procedures to prepare input and configuration for each track of plot, which limits the utility and capability of integration with powerful R packages. In this report, we present interacCircos, an R package for creating interactive Circos plots through the integration of JavaScript-based libraries. interacCircos can simply and flexibly implement 14 track-plot functions and 7 auxiliary functions for presenting large-scale genomic data in interactive Circos plots. AVAILABILITY AND IMPLEMENTATION: InteracCircos and its manual are freely available at https://github.com/mrcuizhe/interacCircos. The online documentation is available at https://mrcuizhe.github.io/interacCircos_documentation/index.html under the GPL license. We thank the teams of BioCircos.js, BioCircos.R, NGCircos and circosJS for sharing the code.

14.
Nat Commun ; 12(1): 400, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452255

RESUMO

Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.


Assuntos
Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Regiões Promotoras Genéticas/genética , Sequenciamento de Cromatina por Imunoprecipitação , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Aprendizado Profundo , Histonas , Humanos , RNA-Seq
15.
Biol Proced Online ; 23(1): 2, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413084

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. The wide distribution and multifunctional properties of ACE suggest it's involvement in various pathophysiological conditions. RESULTS: In this study, a novel visual detection method for ACE I/D polymorphisms was designed by integrating direct PCR without the need for DNA extraction using gold magnetic nanoparticles (GMNPs)-based lateral flow assay (LFA) biosensor. The entire detection procedure could enable the genotyping of clinical samples in about 80 min. The detection limit was 0.75 ng and results could be obtained in 5 min using the LFA device. Three hundred peripheral blood samples were analyzed using the direct PCR-LFA system and then verified by sequencing to determine accuracy and repeatability. A clinical preliminary study was then performed to analyze a total of 633 clinical samples. CONCLUSIONS: After grouping based on age, we found a significant difference between the genotypes and the age of patients in the CHD group. The introduction of this method into clinical practice may be helpful for the diagnosis of diseases caused by large fragment gene insertions/deletions.

16.
J Pathol ; 254(1): 57-69, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33512716

RESUMO

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

17.
Biomater Sci ; 9(5): 1795-1804, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33443505

RESUMO

The accumulation of bacteria at the margin of dental resin composites is the main reason for secondary caries, which may further cause failure of prosthodontics. Therefore, antibacterial activity is highly required. However, the addition of antibacterial agents or fillers weakens the mechanical or aesthetic properties of composites. In this work, regular-shaped SiO2-ZnO complex clusters (CCs) constructed by spray-drying technology can enhance the antibacterial activity while maintaining the mechanical and aesthetic properties of dental resin composites. The results show that the regular shape and closely packed structure of nanoparticle clusters were not corrupted by the introduction of ZnO particles. As compared to resin composites filled with SiO2 nanoparticle clusters, the comprehensive performances of composites containing SiO2-ZnO CCs were further improved, and the composites filled with 70 wt% Si66Zn4 (CCs composed of 66/70 SiO2 and 4/70 of ZnO) exhibited superior antibacterial capability (antibacterial ratio >99.9%) and acceptable depth of cure, degree of conversion, and biocompatibility. The cooperation of different fillers is highly essential for resin composites to achieve enhanced multifunctional performance.


Assuntos
Dióxido de Silício , Óxido de Zinco , Antibacterianos/farmacologia , Teste de Materiais , Propriedades de Superfície
18.
J Investig Med ; 69(1): 13-19, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004469

RESUMO

To investigate the predictive ability of serum matrix metalloproteinase-9 (MMP-9) in the acute phase of Kawasaki disease (KD) with coronary artery lesions (CALs). Patients with KD hospitalized in Lanzhou University Second Hospital, Northwest China, from November 2015 to January 2018 were retrospectively reviewed, and clinical trial indicators and peripheral blood specimens were collected before intravenous immunoglobulin therapy treatment. The independent risk factors were determined using multivariate regression analysis. The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to quantitatively evaluate the ability of MMP-9 to improve the efficiency of predicting KD with CALs. The white cell, neutrophil percentage, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were higher in patients with higher MMP-9, and the monocyte percentage was higher in patients with lower MMP-9. Logistic regression analysis revealed that long-term fever; elevated CRP, ESR, platelets (PLT), and MMP-9; and low albumin (ALB) levels were independent predictors of KD with CALs. A predictive model of KD with CALs using fever duration, CRP, ESR, PLT, and ALB showed significantly improved predictive ability when MMP-9 was added to the model (the area under the curve increased by 0.02; no change in sensitivity; specificity increased from 81.48% to 87.04%; NRI value: 13.46%; IDI value: 5.00%, p<0.05). Adding MMP-9 to traditional risk factors may improve prediction of CALs, the overall predictive ability of model 2 was increased by 5%.

19.
Int J Cancer ; 148(3): 769-779, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32895958

RESUMO

In patients with pancreatic ductal adenocarcinoma (PDAC), optimal treatment selection, including multimodality regimens such as neoadjuvant chemoradiotherapy (NACRT), can be clinically transformative. Unfortunately, currently no predictive biomarkers are available that can guide the use of NACRT in PDAC patients. Accordingly, herein we developed a novel gene signature that can preoperatively predict NACRT-sensitivity in PDAC patients. Herein, we evaluated the performance of a 10-gene panel in 749 PDAC cases, which included two public datasets (The Cancer Genome Atlas and International Cancer Genome Consortium; n = 276), and three clinical specimen cohorts (n = 417), and a pre-NACRT endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy cohort (n = 56). The potential predictive performance of this signature was evaluated and compared to CA-19-9 levels and key clinicopathological factors. We first evaluated the prognostic potential of a 10-gene panel which significantly predicted overall survival in both public datasets (P < .01, P < .01), and two in-house patient cohorts (P < .01, P = .04). In the pre-NACRT EUS-FNA cohort, we established a radio-sensitivity gene panel (RSGP) which yielded highly robust (area under the curve [AUC] = 0.91; 95% CI: 0.81-0.97) for predicting response to gemcitabine-based NACRT. Multivariate logistic regression analysis revealed that RSGP was an independent predictor for response to NACRT (OR = 2.70; 95% CI: 1.25-5.85), and this response-prediction was even more robust when CA-19-9 levels were included into the model. In conclusion, we have validated and developed a novel gene signature that is highly robust in predicting response to NACRT, even in preoperative settings, highlighting its clinical significance for optimizing and personalizing treatment strategies in PDAC patients.


Assuntos
Carcinoma Ductal Pancreático/terapia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Bases de Dados Genéticas , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos da radiação , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Análise de Sobrevida , Resultado do Tratamento
20.
Pain ; 162(1): 135-151, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773598

RESUMO

Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here, we demonstrated significant upregulation of PKG-I in ipsilateral L3 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I, in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.


Assuntos
Proteína Quinase Dependente de GMP Cíclico Tipo I , Neuralgia , Sensibilização do Sistema Nervoso Central , Gânglios Espinais , Humanos , Hiperalgesia/etiologia , Neuralgia/etiologia , Nociceptores
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...