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1.
BMC Genomics ; 25(1): 858, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271972

RESUMO

BACKGROUND: Melanin in the black-bone chicken's body is considered the material basis for its medicinal effects and is an economically important trait. Therefore, improving the melanin content is a crucial focus in the breeding process of black-bone chickens. Luning chickens are black-bone chickens, with black beaks, skin, and meat. To investigate the genetic diversity and molecular mechanisms of melanin deposition in Luning chickens, we conducted whole-genome resequencing to analyze their breeding history and identify candidate genes influencing their black phenotype, along with transcriptome sequencing of dorsal skin tissues of male Luning chickens. RESULTS: Population structure analysis revealed that Luning chickens tend to cluster independently and are closely related to Tibetan chickens. Runs of homozygosity analysis suggested potential inbreeding in the Luning chicken and Tibetan chicken population. By combining genetic differentiation index (Fst) and nucleotide diversity (θπ) ratios, we pinpointed selected regions associated with melanin deposition. Gene annotation identified 540 genes with the highest Fst value in LOC101750371 and LOC121108313, located on the 68.24-68.58 Mb interval of chromosome Z. Combining genomic and transcriptomic data, we identified ATP5E, EDN3, and LOC101750371 as candidate genes influencing skin color traits in black-bone chickens. CONCLUSIONS: This study characterized the evolutionary history of Luning chickens and preliminarily excavated candidate genes influencing the genetic mechanism of pigmentation in black-bone chickens, providing valuable insights for the study of animal melanin deposition.


Assuntos
Galinhas , Melaninas , Sequenciamento Completo do Genoma , Animais , Galinhas/genética , Galinhas/metabolismo , Melaninas/metabolismo , Melaninas/genética , Pigmentação da Pele/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
BMC Plant Biol ; 22(1): 513, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36324064

RESUMO

Genome variation not only plays an important role in plant phenotypic modeling and adaptive evolution, but also enhances population genetic diversity and regulates gene expression. The tea tree (Camellia sinensis) has a large genome (~ 3.0 Gb), making the identification of genome-wide variants time-consuming and expensive. With the continuous publication of a large number of different types of population sequencing data, there is a lack of an open platform to integrate these data and identify variants in the tea plant genome.To integrate the genetic variation confidence in the tea plant population genome, 238 whole-genome resequencing, 213 transcriptome sequencing, and 96 hybrid F1 individuals with a total of more than 20 Tb were collected for mutation site identification. Based on these variations information, we constructed the first tea tree variation web service database TeaPVs ( http://47.106.184.91:8025/ and http://liushang.top:8025/ ). It supports users to search all SNP, Indel, SV mutations and SSR/Polymorphic SSR sequences by location or gene ID. Furthermore, the website also provides the functions of gene expression search of different transcriptome, sequence blast, sequence extraction of CDS and mutation loci, etc.The features of the TeaPVs database make it a comprehensive tea plant genetic variation bioinformatics platform for researchers, and will also be helpful for revealing new functional mutations in the tea plant genome and molecular marker-assisted breeding.


Assuntos
Camellia sinensis , Camellia sinensis/genética , Melhoramento Vegetal , Genoma de Planta/genética , Chá , Genômica
3.
BMC Plant Biol ; 21(1): 280, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154536

RESUMO

Alternative splicing (AS) increases the diversity of transcripts and proteins through the selection of different splice sites and plays an important role in the growth, development and stress tolerance of plants. With the release of the reference genome of the tea plant (Camellia sinensis) and the development of transcriptome sequencing, researchers have reported the existence of AS in tea plants. However, there is a lack of a platform, centered on different RNA-seq datasets, that provides comprehensive information on AS.To facilitate access to information on AS and reveal the molecular function of AS in tea plants, we established the first comprehensive AS database for tea plants (TeaAS, http://www.teaas.cn/index.php ). In this study, 3.96 Tb reads from 66 different RNA-seq datasets were collected to identify AS events. TeaAS supports four methods of retrieval of AS information based on gene ID, gene name, annotation (non-redundant/Kyoto encyclopedia of genes and genomes/gene ontology annotation or chromosomal location) and RNA-seq data. It integrates data pertaining to genome annotation, type of AS event, transcript sequence, and isoforms expression levels from 66 RNA-seq datasets. The AS events resulting from different environmental conditions and that occurring in varied tissue types, and the expression levels of specific transcripts can be clearly identified through this online database. Moreover, it also provides two useful tools, Basic Local Alignment Search Tool and Generic Genome Browser, for sequence alignment and visualization of gene structure.The features of the TeaAS database make it a comprehensive AS bioinformatics platform for researchers, as well as a reference for studying AS events in woody crops. It could also be helpful for revealing the novel biological functions of AS in gene regulation in tea plants.


Assuntos
Processamento Alternativo , Camellia sinensis/genética , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , RNA de Plantas , RNA-Seq
4.
BMC Genomics ; 21(1): 162, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066369

RESUMO

BACKGROUND: Gang goose is a native species with gray plumage in Sichuan, China. As a result of overhunting, the number of gray Gang geese has decreased dramatically. To keep the species from extinction, conservation work for Gang geese was undertaken. In the process of pure breeding of gray Gang geese, approximately 2% of the offspring of each generation were white. This study aims to explain the genetic mechanism of this phenomenon and provide reliable molecular markers for goose-related plumage color breeding. RESULTS: We used the method of pooled whole genome sequencing and Fst (fixation statistics) to identify the differentiation degree of alleles between gray Gang geese and white Gang geese from their offspring. In this way, EDNRB2, a key gene that affects the migration of melanoblasts, was identified. Then, the transcriptome was sequenced for the two geese plumage color populations, and the DEGs (differentially expressed genes) were analyzed. The results indicated that EDNRB2, as a possible candidate gene, had a significantly differential mRNA expression. In addition, a 14-bp insertion (NW_013185915.1: g. 750,748-750,735 insertion. CACAGGTGAGCTCT) in exon 3 of EDNRB2 was analyzed and found to have a significant association between gray geese and Chinese white breeds (P = 0.00), while this mutation was not found in European geese. Meanwhile, the insertion was homozygous in all the white geese we detected and heterozygous in gray geese, indicating that this mutation is recessive. Furthermore, this 14-bp insertion leads to a frameshift mutation in the EDNRB2 coding region and nonsense-mediated mRNA decay. CONCLUSION: Our study strongly suggests that the 14-bp insertion in exon 3 of the EDNRB2 gene is associated with the white plumage phenotype in Chinese geese. This study is the first to investigate the relationship between EDNRB2 and white plumage in geese.


Assuntos
Gansos/genética , Mutagênese Insercional , Fenótipo , Pigmentação/genética , Receptores de Endotelina/genética , Animais , Expressão Gênica , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genoma , Genômica/métodos , Transcriptoma
5.
BMC Genomics ; 21(1): 511, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703156

RESUMO

BACKGROUND: Domesticated chickens have a wide variety of phenotypes, in contrast with their wild progenitors. Unlike other chicken breeds, Xichuan black-bone chickens have blue-shelled eggs, and black meat, beaks, skin, bones, and legs. The breeding history and the economically important traits of this breed have not yet been explored at the genomic level. We therefore used whole genome resequencing to analyze the breeding history of the Xichuan black-bone chickens and to identify genes responsible for its unique phenotype. RESULTS: Principal component and population structure analysis showed that Xichuan black-bone chicken is in a distinct clade apart from eight other breeds. Linkage disequilibrium analysis showed that the selection intensity of Xichuan black-bone chickens is higher than for other chicken breeds. The estimated time of divergence between the Xichuan black-bone chickens and other breeds is 2.89 ka years ago. Fst analysis identified a selective sweep that contains genes related to melanogenesis. This region is probably associated with the black skin of the Xichuan black-bone chickens and may be the product of long-term artificial selection. A combined analysis of genomic and transcriptomic data suggests that the candidate gene related to the black-bone trait, EDN3, might interact with the upstream ncRNA LOC101747896 to generate black skin color during melanogenesis. CONCLUSIONS: These findings help explain the unique genetic and phenotypic characteristics of Xichuan black-bone chickens, and provide basic research data for studying melanin deposition in animals.


Assuntos
Galinhas , Animais , Galinhas/genética , Desequilíbrio de Ligação , Carne , Polimorfismo de Nucleotídeo Único
6.
Invest New Drugs ; 38(5): 1601-1604, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31907737

RESUMO

Introduction Given the high level of uncertainty surrounding the outcomes of early phase clinical trials, whole genome and transcriptome analysis (WGTA) can be used to optimize patient selection and study assignment. In this retrospective analysis, we reviewed the impact of this approach on one such program. Methods Patients with advanced malignancies underwent fresh tumor biopsies as part of our personalized medicine program (NCT02155621). Tumour molecular data were reviewed for potentially clinically actionable findings and patients were referred to the developmental therapeutics program. Outcomes were reviewed in all patients, including those where trial selection was driven by molecular data (matched) and those where there was no clear molecular rationale (unmatched). Results From January 2014 to January 2018, 28 patients underwent WGTA and enrolled in clinical trials, including 2 patients enrolled in two trials. Fifteen patients were matched to a treatment based on a molecular target. Five patients were matched to a trial based upon single-gene DNA changes, all supported by RNA data. Ten cases were matched on the basis of genome-wide data (n = 4) or RNA gene expression only (n = 6). With a median follow-up of 6.7 months, the median time on treatment was 8.2 weeks. Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA.


Assuntos
Perfilação da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Sequenciamento Completo do Genoma , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Seleção de Pacientes , Medicina de Precisão , Estudos Retrospectivos , Falha de Tratamento
7.
Poult Sci ; 103(2): 103292, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38100950

RESUMO

The cluster homolog of immunoglobulin-like receptors (CHIRs), previously known as the "chicken homolog of immunogloublin-like receptors," represents is a large group of transmembrane glycoproteins that direct the immune response. However, the full repertoire of putatively activating, inhibitory, or dual function CHIRA, CHIRB, and CHIRAB on chickens' immune responses is poorly understood. Herein, the study objective was to determine the genes encoding CHIR proteins and predict their function by searching canonical protein structure. A bioinformatics pipeline based on previous work was employed to search for the CHIRs from the newly updated broiler and layer genomes. The categorization into CHIRA, CHIRB, and CHIRAB types was assigned through motif searches, multiple sequence alignment, and phylogeny. In total, 150 protein-encoding genes on Chromosome 31 were identified as CHIRs. Gene members of each functional group (CHIRA, CHIRB, CHIRAB) were classified in accordance with previously recognized proteins. The genes were renamed to "cluster homolog of immunoglobulin-like receptors" (CHIRs) to allow for the naming of orthologous genes in other avian species. Additionally, expression analysis of the classified CHIRs across various reinforces their importance as immune regulators and activation in inflammatory tissues. Furthermore, over 1,000 diverse and rare CHIRs variants associated with differential Marek's disease response (P < 0.05) emphasize the impact of CHIRs on shaping avian immune responses in diverse contexts. The practical applications of these findings encompass advancing immunology, improving poultry health management, optimizing breeding programs for disease resistance, and enhancing overall animal health through a deeper understanding of the roles and functions of CHIRA, CHIRB, and CHIRAB types in avian immune responses.


Assuntos
Galinhas , Doença de Marek , Animais , Galinhas/genética , Genoma , Filogenia , Imunoglobulinas/genética
8.
Front Cell Neurosci ; 17: 1155405, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37252192

RESUMO

Sensory processes have often been argued to play a central role in the selection of ecological niches and in the formation of new species. Butterflies are among the best studied animal groups with regards to their evolutionary and behavioral ecology and thereby offer an attractive system to investigate the role of chemosensory genes in sympatric speciation. We focus on two Pieris butterflies with overlapping host-plant ranges: P. brassicae and P. rapae. Host-plant choice in lepidopterans is largely based on their olfactory and gustatory senses. Although the chemosensory responses of the two species have been well characterized at the behavioral and physiological levels, little is known about their chemoreceptor genes. Here, we compared the chemosensory genes of P. brassicae and P. rapae to investigate whether differences in these genes might have contributed to their evolutionary separation. We identified a total of 130 and 122 chemoreceptor genes in the P. brassicae genome and antennal transcriptome, respectively. Similarly, 133 and 124 chemoreceptors were identified in the P. rapae genome and antennal transcriptome. We found some chemoreceptors being differentially expressed in the antennal transcriptomes of the two species. The motifs and gene structures of chemoreceptors were compared between the two species. We show that paralogs share conserved motifs and orthologs have similar gene structures. Our study therefore found surprisingly few differences in the numbers, sequence identities and gene structures between the two species, indicating that the ecological differences between these two butterflies might be more related to a quantitative shift in the expression of orthologous genes than to the evolution of novel receptors as has been found in other insects. Our molecular data supplement the wealth of behavioral and ecological studies on these two species and will thereby help to better understand the role of chemoreceptor genes in the evolution of lepidopterans.

9.
BMC Med Genomics ; 15(1): 190, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071521

RESUMO

BACKGROUND: Tumor mutation burden (TMB) is a key characteristic used in a tumor-type agnostic context to inform the use of immune checkpoint inhibitors (ICI). Accurate and consistent measurement of TMB is crucial as it can significantly impact patient selection for therapy and clinical trials, with a threshold of 10 mutations/Mb commonly used as an inclusion criterion. Studies have shown that the most significant contributor to variability in mutation counts in whole genome sequence (WGS) data is differences in analysis methods, even more than differences in extraction or library construction methods. Therefore, tools for improving consistency in whole genome TMB estimation are of clinical importance. METHODS: We developed a distributable TMB analysis suite, TMBur, to address the need for genomic TMB estimate consistency in projects that span jurisdictions. TMBur is implemented in Nextflow and performs all analysis steps to generate TMB estimates directly from fastq files, incorporating somatic variant calling with Manta, Strelka2, and Mutect2, and microsatellite instability profiling with MSISensor. These tools are provided in a Singularity container downloaded by the workflow at runtime, allowing the entire workflow to be run identically on most computing platforms. To test the reproducibility of TMBur TMB estimates, we performed replicate runs on WGS data derived from the COLO829 and COLO829BL cell lines at multiple research centres. The clinical value of derived TMB estimates was then evaluated using a cohort of 90 patients with advanced, metastatic cancer that received ICIs following WGS analysis. Patients were split into groups based on a threshold of 10/Mb, and time to progression from initiation of ICIs was examined using Kaplan-Meier and cox-proportional hazards analyses. RESULTS: TMBur produced identical TMB estimates across replicates and at multiple analysis centres. The clinical utility of TMBur-derived TMB estimates were validated, with a genomic TMB ≥ 10/Mb demonstrating improved time to progression, even after correcting for differences in tumor type (HR = 0.39, p = 0.012). CONCLUSIONS: TMBur, a shareable workflow, generates consistent whole genome derived TMB estimates predictive of response to ICIs across multiple analysis centres. Reproducible TMB estimates from this approach can improve collaboration and ensure equitable treatment and clinical trial access spanning jurisdictions.


Assuntos
Biomarcadores Tumorais/genética , Mutação , Neoplasias/genética , Sequenciamento Completo do Genoma/métodos , Humanos , Estimativa de Kaplan-Meier , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Neoplasias/metabolismo , Neoplasias/terapia , Seleção de Pacientes , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes
10.
Front Oncol ; 12: 941868, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439494

RESUMO

Objectives: Adenocarcinoma at the gastroesophageal junction (ACGEJ) refers to a malignant tumor that occurs at the esophagogastric junction. Despite some progress in targeted therapies for HER2, FGFR2, EGFR, MET, Claudin 18.2 and immune checkpoints in ACGEJ tumors, the 5-year survival rate of patients remains poor. Thus, it is urgent to explore genomic alterations and neoantigen characteristics of tumors and identify CD8+ T-cell infiltration-associated genes to find potential therapeutic targets and develop a risk model to predict ACGEJ patients' overall survival (OS). Methods: Whole-exome sequencing (WES) was performed on 55 paired samples from Chinese ACGEJ patients. Somatic mutations and copy number variations were detected by Strelka2 and FACETS, respectively. SigProfiler and SciClone were employed to decipher the mutation signature and clonal structure of each sample, respectively. Neoantigens were predicted using the MuPeXI pipeline. RNA sequencing (RNA-seq) data of ACGEJ samples from our previous studies and The Cancer Genome Atlas (TCGA) were used to identify genes significantly associated with CD8+ T-cell infiltration by weighted gene coexpression network analysis (WGCNA). To construct a risk model, we conducted LASSO and univariate and multivariate Cox regression analyses. Results: Recurrent MAP2K7, RNF43 and RHOA mutations were found in ACGEJ tumors. The COSMIC signature SBS17 was associated with ACGEJ progression. CCNE1 and VEGFA were identified as putative CNV driver genes. PI3KCA and TP53 mutations conferred selective advantages to cancer cells. The Chinese ACGEJ patient neoantigen landscape was revealed for the first time, and 58 potential neoantigens common to TSNAdb and IEDB were identified. Compared with Siewert type II samples, Siewert type III samples had significant enrichment of the SBS17 signature, a lower TNFRSF14 copy number, a higher proportion of samples with complex clonal architecture and a higher neoantigen load. We identified 10 important CD8+ T-cell infiltration-related Hub genes (CCL5, CD2, CST7, GVINP1, GZMK, IL2RB, IKZF3, PLA2G2D, P2RY10 and ZAP70) as potential therapeutic targets from the RNA-seq data. Seven CD8+ T-cell infiltration-related genes (ADAM28, ASPH, CAMK2N1, F2R, STAP1, TP53INP2, ZC3H3) were selected to construct a prognostic model. Patients classified as high risk based on this model had significantly worse OS than low-risk patients, which was replicated in the TCGA-ACGEJ cohort. Conclusions: This study provides new neoantigen-based immunotherapeutic targets for ACGEJ treatment and effective disease prognosis biomarkers.

11.
3 Biotech ; 11(1): 20, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33442518

RESUMO

Colle totrichum falcatum, an intriguing pathogen causing red rot in sugarcane, exhibits enormous variation for pathogenicity under field conditions. A species-specific marker is very much needed to classify the virulence among the varying population and to identify the potential of a pathotype by mining the microsatellites, which are considered to be the largest genetic source to develop molecular markers for an organism. In this study, we have mined the C. falcatum genome using MISA database which yielded 12,121 SSRs from 48.1 Mb and 2745 SSRs containing sequences. The most frequent SSR types from the genome of C. falcatum was di-nucleotide which constitutes 50.89% followed by tri-nucleotide 39.60%, hepta-nucleotide 6.7%, hexa-nucleotide 1.38% and penta-nucleotide 1.3%. Over 90 SSR containing sequences from the genome were predicted using BlastX which are found to be non-homologs. Most of the annotated SSR containing sequences fell in CAZy superfamilies, proteases, peptidases, plant cell wall degrading enzymes (PCDWE) and membrane transporters which are considered to be pathogenicity gene clusters. Among them, glycosyl hydrolases (GH) were found to be abundant in SSR containing sequences which again proved our previous transcriptome results. Our in-silico results suggested that the mined microsatellites from C. falcatum genome show absence of homolog sequences which suggests that these markers could be used as an ideal species-specific molecular marker. Two virulence specific markers were characterized using conventional PCR assays from C. falcatum along with virulent species-specific (VSS) marker developed for C. gloeosporioides. The study lays the foundation for the development of C. falcatum specific molecular marker to phenotype the pathotypes based on virulence.

12.
Plants (Basel) ; 10(12)2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34961087

RESUMO

As a result of the breeding process, there are two main types of flax (Linum usitatissimum L.) plants. Linseed is used for obtaining seeds, while fiber flax is used for fiber production. We aimed to identify the genes associated with the flax plant type, which could be important for the formation of agronomically valuable traits. A search for polymorphisms was performed in genes involved in the biosynthesis of cell wall components, lignans, fatty acids, and ion transport based on genome sequencing data for 191 flax varieties. For 143 of the 424 studied genes (4CL, C3'H, C4H, CAD, CCR, CCoAOMT, COMT, F5H, HCT, PAL, CTL, BGAL, ABC, HMA, DIR, PLR, UGT, TUB, CESA, RGL, FAD, SAD, and ACT families), one or more polymorphisms had a strong correlation with the flax type. Based on the transcriptome sequencing data, we evaluated the expression levels for each flax type-associated gene in a wide range of tissues and suggested genes that are important for the formation of linseed or fiber flax traits. Such genes were probably subjected to the selection press and can determine not only the traits of seeds and stems but also the characteristics of the root system or resistance to stresses at a particular stage of development, which indirectly affects the ability of flax plants to produce seeds or fiber.

13.
Plant Direct ; 4(6): e00232, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32537559

RESUMO

Oryza rufipogon and O. longistaminata are important wild relatives of cultivated rice, harboring a promising source of novel genes for rice breeding programs. Here, we present de novo assembled draft genomes and annotation of O. rufipogon and O. longistaminata. Our analysis reveals a considerable number of lineage-specific gene families associated with the self-incompatibility (SI) and formation of reproductive separation. We show how lineage-specific expansion or contraction of gene families with functional enrichment of the recognition of pollen, thus enlightening their reproductive diversification. We documented a large number of lineage-specific gene families enriched in salt stress, antifungal response, and disease resistance. Our comparative analysis further shows a genome-wide expansion of genes encoding NBS-LRR proteins in these two outcrossing wild species in contrast to six other selfing rice species. Conserved noncoding sequences (CNSs) in the two wild rice genomes rapidly evolve relative to selfing rice species, resulting in the reduction of genomic variation owing to shifts of mating systems. We find that numerous genes related to these rapidly evolving CNSs are enriched in reproductive structure development, flower development, and postembryonic development, which may associate with SI in O. rufipogon and O. longistaminata.

14.
Cancer Lett ; 357(2): 510-9, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25499081

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, although the treatment of this disease has changed little in recent decades because most of the genetic events that initiate this disease remain unknown. To better understand HCC pathogenesis at the molecular level and to uncover novel tumor-initiating events, we integrated RNA-seq and DNA-seq data derived from two pairs of HCC tissues. We found that BLCAP is novel editing gene in HCC and has over-editing expression in 40.1% HCCs compared to adjacent liver tissues. We then used RNA interference and gene transfection to assess the roles of BLCAP RNA editing in tumor proliferation. Our results showed that compared to the wild-type BLCAP gene, the RNA-edited BLCAP gene may stably promote cell proliferation (including cell growth, colony formation in vitro, and tumorigenicity in vivo) by enhancing the phosphorylation of AKT, mTOR, and MDM2 and inhibiting the phosphorylation of TP53. Our current results suggest that the RNA over-editing of BLCAP gene may serve as a novel potential driver in advanced HCC through activating AKT/mTOR signal pathway.


Assuntos
Carcinoma Hepatocelular/genética , Genoma Humano/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Edição de RNA , Transcriptoma/genética , Adulto , Idoso , Animais , Western Blotting , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Análise de Sequência/métodos , Serina-Treonina Quinases TOR/metabolismo , Transplante Heterólogo , Proteína Supressora de Tumor p53/metabolismo
15.
Oncotarget ; 6(34): 36652-74, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26474389

RESUMO

Invasive ductal carcinoma (IDC) is a major histo-morphologic type of breast cancer. Histological grading (HG) of IDC is widely adopted by oncologists as a prognostic factor. However, HG evaluation is highly subjective with only 50%-85% inter-observer agreements. Specifically, the subjectivity in the assignment of the intermediate grade (histologic grade 2, HG2) breast cancers (comprising ~50% of IDC cases) results in uncertain disease outcome prediction and sub-optimal systemic therapy. Despite several attempts to identify the mechanisms underlying the HG classification, their molecular bases are poorly understood.We performed integrative bioinformatics analysis of TCGA and several other cohorts (total 1246 patients). We identified a 22-gene tumor aggressiveness grading classifier (22g-TAG) that reflects global bifurcation in the IDC transcriptomes and reclassified patients with HG2 tumors into two genetically and clinically distinct subclasses: histological grade 1-like (HG1-like) and histological grade 3-like (HG3-like). The expression profiles and clinical outcomes of these subclasses were similar to the HG1 and HG3 tumors, respectively. We further reclassified IDC into low genetic grade (LGG = HG1+HG1-like) and high genetic grade (HGG = HG3-like+HG3) subclasses. For the HG1-like and HG3-like IDCs we found subclass-specific DNA alterations, somatic mutations, oncogenic pathways, cell cycle/mitosis and stem cell-like expression signatures that discriminate between these tumors. We found similar molecular patterns in the LGG and HGG tumor classes respectively.Our results suggest the existence of two genetically-predefined IDC classes, LGG and HGG, driven by distinct oncogenic pathways. They provide novel prognostic and therapeutic biomarkers and could open unique opportunities for personalized systemic therapies of IDC patients.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinoma Ductal de Mama/patologia , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Pessoa de Meia-Idade , Prognóstico , Transcriptoma
16.
Genome Biol Evol ; 6(12): 3182-98, 2014 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-25381665

RESUMO

Members of Myxozoa, a parasitic metazoan taxon, have considerable detrimental effects on fish hosts and also have been associated with human food-borne illness. Little is known about their biology and metabolism. Analysis of the genome of Thelohanellus kitauei and comparative analysis with genomes of its two free-living cnidarian relatives revealed that T. kitauei has adapted to parasitism, as indicated by the streamlined metabolic repertoire and the tendency toward anabolism rather than catabolism. Thelohanellus kitauei mainly secretes proteases and protease inhibitors for nutrient digestion (parasite invasion), and depends on endocytosis (mainly low-density lipoprotein receptors-mediated type) and secondary carriers for nutrient absorption. Absence of both classic and complementary anaerobic pathways and gluconeogenesis, the lack of de novo synthesis and reduced activity in hydrolysis of fatty acids, amino acids, and nucleotides indicated that T. kitauei in this vertebrate host-parasite system has adapted to inhabit a physiological environment extremely rich in both oxygen and nutrients (especially glucose), which is consistent with its preferred parasitic site, that is, the host gut submucosa. Taking advantage of the genomic and transcriptomic information, 23 potential nutrition-related T. kitauei-specific chemotherapeutic targets were identified. This first genome sequence of a myxozoan will facilitate development of potential therapeutics for efficient control of myxozoan parasites and ultimately prevent myxozoan-induced fish-borne illnesses in humans.


Assuntos
Absorção Fisiológica , Adaptação Fisiológica , Genoma Fúngico , Thelohania/genética , Aminoácidos/metabolismo , Animais , Carpas/microbiologia , Ácidos Graxos/metabolismo , Gluconeogênese , Ácidos Nucleicos/metabolismo , Oxigênio/metabolismo , Proteólise , Thelohania/metabolismo , Thelohania/patogenicidade , Transcriptoma
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