RESUMO
The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1-SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot mutations. Experiments confirmed that all the cancer-associated mutations in these regions, as well as mutations affecting other residues in the SF3B1-SUGP1 interface, not only weaken or disrupt the interaction but also alter splicing similarly to SF3B1 cancer mutations. Finally, structural modeling of a trimeric protein complex reveals that the SF3B1-SUGP1 interaction "loops out" the G-patch for interaction with the helicase DHX15. Our study thus provides an unprecedented molecular view of a protein complex essential for accurate splicing and also reveals that numerous cancer-associated mutations disrupt the critical SF3B1-SUGP1 interaction.
Assuntos
Neoplasias , Spliceossomos , Humanos , RNA Mensageiro/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Fatores de Processamento de RNA/química , Splicing de RNA/genética , Neoplasias/genética , Neoplasias/metabolismo , Mutação , Fosfoproteínas/metabolismoRESUMO
SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1 and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggest plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is a common defect of spliceosomes with disease-causing SF3B1 mutations and, because this defect can be rescued, suggests possibilities for therapeutic intervention.
Assuntos
Leucemia Eritroblástica Aguda/metabolismo , Mutação , Síndromes Mielodisplásicas/metabolismo , Fosfoproteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , Splicing de RNA , Spliceossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Humanos , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fenótipo , Fosfoproteínas/genética , Ligação Proteica , Fatores de Processamento de RNA/genética , Spliceossomos/genética , Spliceossomos/patologiaRESUMO
Alternative splicing (AS) is a fundamental process that governs almost all aspects of cellular functions, and dysregulation in this process has been implicated in tumor initiation, progression and treatment resistance. With accumulating studies of carcinogenic mis-splicing in cancers, there is an urgent demand to integrate cancer-associated splicing changes to better understand their internal cross-talks and functional consequences from a global view. However, a resource of key functional AS events in human cancers is still lacking. To fill the gap, we developed ASCancer Atlas (https://ngdc.cncb.ac.cn/ascancer), a comprehensive knowledgebase of aberrant splicing in human cancers. Compared to extant databases, ASCancer Atlas features a high-confidence collection of 2006 cancer-associated splicing events experimentally proved to promote tumorigenesis, a systematic splicing regulatory network, and a suit of multi-scale online analysis tools. For each event, we manually curated the functional axis including upstream splicing regulators, splicing event annotations, downstream oncogenic effects, and possible therapeutic strategies. ASCancer Atlas also houses about 2 million computationally putative splicing events. Additionally, a user-friendly web interface was built to enable users to easily browse, search, visualize, analyze, and download all splicing events. Overall, ASCancer Atlas provides a unique resource to study the functional roles of splicing dysregulation in human cancers.
Assuntos
Processamento Alternativo , Bases de Dados Genéticas , Neoplasias , Humanos , Processamento Alternativo/genética , Bases de Dados Factuais , Neoplasias/genética , Splicing de RNA , Atlas como AssuntoRESUMO
SF3B1 is the most frequently mutated spliceosomal gene in cancer. Several hotspot mutations are known to disrupt the interaction of SF3B1 with another splicing factor, SUGP1, resulting in the RNA missplicing that characterizes mutant SF3B1 cancers. Properties of SUGP1, especially the presence of a G-patch motif, a structure known to function by activating DEAH-box RNA helicases, suggest the requirement of such an enzyme in SUGP1 function in splicing. However, the identity of this putative helicase has remained an important unanswered question. Here, using a variety of protein-protein interaction assays, we identify DHX15 as the critical helicase. We further show that depletion of DHX15 or expression of any of several DHX15 mutants, including one implicated in acute myeloid leukemia, partially recapitulates the splicing defects of mutant SF3B1. Moreover, a DHX15-SUGP1 G-patch fusion protein is able to incorporate into the spliceosome to rescue the splicing defects of mutant SF3B1. We also present the crystal structure of the human DHX15-SUGP1 G-patch complex, which reveals the molecular basis of their direct interaction. Our data thus demonstrate that DHX15 is the RNA helicase that functions with SUGP1 and additionally provide important insight into how mutant SF3B1 disrupts splicing in cancer.
Assuntos
Neoplasias , RNA Helicases , Fatores de Processamento de RNA , Splicing de RNA , Humanos , DNA Helicases , Genes Reguladores , Fosfoproteínas , RNA Helicases/genética , Splicing de RNA/genética , Fatores de Processamento de RNA/genética , Spliceossomos/genéticaRESUMO
SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in â¼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.
Assuntos
Anemia/metabolismo , Eritropoese , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Mutação , Síndromes Mielodisplásicas/metabolismo , Fosfoproteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , Anemia/genética , Anemia/patologia , Diferenciação Celular/genética , Células Eritroides/metabolismo , Células Eritroides/patologia , Humanos , Células K562 , MAP Quinase Quinase Quinases/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Ocean energy harvesting based on a triboelectric nanogenerator (TENG) has great application potential, while the encapsulation of triboelectric devices in water poses a critical issue. Herein, a triboelectric-electromagnetic hybrid nanogenerator (TE-HNG) consisting of TENGs and electromagnetic generators (EMGs) is proposed to harvest water flow energy. A magnetic coupling transmission component is applied to replace traditional bearing structures, which can realize the fully enclosed packaging of the TENG devices and achieve long-lasting energy harvesting from water flow. Under the intense water impact, magnetic coupling reduces the possibility of internal gear damage due to excessive torque, indicating superior stability and robustness compared to conventional TENG. At the waterwheel rotates speed of 75 rpm, the TE-HNG can generate an output peak power of 114.83 mW, corresponding to a peak power density of 37.105 W m-3. After 5 h of continuous operation, the electrical output attenuation of TENG is less than 3%, demonstrating excellent device durability. Moreover, a self-powered temperature sensing system and a self-powered cathodic protection system based on the TE-HNG are developed and illustrated. This work provides a prospective strategy for improving the output stability of TENGs, which benefits the practical applications of the TENGs in large-scale blue energy harvesting.
RESUMO
RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.
Assuntos
Leucemia , RNA Helicases , Humanos , Animais , Camundongos , RNA Helicases/genética , RNA Helicases/metabolismo , Splicing de RNA , Spliceossomos/genética , Leucemia/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Básicos/metabolismoRESUMO
BACKGROUND: This study was conducted to assess the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cardiovascular disease (CVD) mortality in older people with chronic kidney disease (CKD) in the United States. METHODS: We identified 3230 CKD participants aged ≥ 60 years from the National Health and Nutrition Examination Survey (2001-2018). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Mortality outcomes were determined by linkage to National Death Index (NDI) records through December 31, 2019. Restricted cubic spline based on Cox regression models were utilized to elucidate the nonlinear relationship between serum 25(OH)D concentrations and mortality in patients with CKD. RESULTS: During median 74 months of follow-up, 1615 all-cause death and 580 CVD death were recorded. We found an L-shaped association between serum 25(OH)D concentrations and all-cause and CVD mortality, reaching a plateau at 90 nmol/L. Accordingly, per one-unit increment in natural log-transformed 25(OH)D was associated with a 32% and 33% reduced risk of all-cause mortality (hazard ratio [HR] 0.68; 95%CI, 0.56 to 0.83) and CV mortality (HR 0.69; 95%CI, 0.49 to 0.97) in participants with serum 25(OH)D < 90 nmol/L, but no considerable difference was observed in participants with serum 25(OH)D ≥ 90 nmol/L. Compared with those in the deficiency group (< 50 nmol/L), insufficient (50 to < 75 nmol/L) and sufficient group (≥ 75 nmol/L) were significantly associated with lower all-cause mortality (HR,0.83; 95%CI, 0.71 to 0.97 and HR, 0.75; 95%CI, 0.64 to 0.89) and CV mortality (HR,0.87; 95%CI, 0.68 to 1.10 and HR, 0.77; 95%CI, 0.59 to < 1.0), respectively. CONCLUSION: An L-shaped relationship between serum 25(OH)D levels with all-cause and CVD mortality was observed in elderly CKD patients in the United States. A 25(OH)D concentration of 90 nmol/L may be the target to reduce the risk of premature death.
Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Idoso , Humanos , Inquéritos Nutricionais , Estudos ProspectivosRESUMO
The gene encoding the core spliceosomal protein SF3B1 is the most frequently mutated gene encoding a splicing factor in a variety of hematologic malignancies and solid tumors. SF3B1 mutations induce use of cryptic 3' splice sites (3'ss), and these splicing errors contribute to tumorigenesis. However, it is unclear how widespread this type of cryptic 3'ss usage is in cancers and what is the full spectrum of genetic mutations that cause such missplicing. To address this issue, we performed an unbiased pan-cancer analysis to identify genetic alterations that lead to the same aberrant splicing as observed with SF3B1 mutations. This analysis identified multiple mutations in another spliceosomal gene, SUGP1, that correlated with significant usage of cryptic 3'ss known to be utilized in mutant SF3B1 expressing cells. Remarkably, this is consistent with recent biochemical studies that identified a defective interaction between mutant SF3B1 and SUGP1 as the molecular defect responsible for cryptic 3'ss usage. Experimental validation revealed that five different SUGP1 mutations completely or partially recapitulated the 3'ss defects. Our analysis suggests that SUGP1 mutations in cancers can induce missplicing identical or similar to that observed in mutant SF3B1 cancers.
Assuntos
Biologia Computacional/métodos , Mutação , Neoplasias/genética , Fosfoproteínas/genética , Sítios de Splice de RNA , Fatores de Processamento de RNA/genética , Splicing de RNA , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/patologia , SpliceossomosRESUMO
A stretchable triboelectric nanogenerator (TENG) can be a promising solution for the power supply of various flexible electronics. However, the detailed electrification mechanism of elastic triboelectric materials still needs to be clarified. In this work, we found crystallization behavior induced by strain and low temperature can lead to a shift in a triboelectric series for commonly used triboelectric elastomers and even reverse the triboelectric polarity. This effect is attributed to the notable rearrangement of surface electron cloud density happening along with the crystallization process of the molecular chain. This effect is significant with natural rubber, and silicone rubber can experience this effect at low temperature, which also leads to a shift in a triboelectric series, and an applied strain at low temperature can further enhance this shift. This study demonstrated that the electrification polarity of triboelectric materials should be re-evaluated under different strains and different temperatures, which provides a mechanism distinct from the general understanding of elastic triboelectric materials.
RESUMO
Conventional approaches to studying fish kinematics pose a great challenge for the real-time monitoring of fish motion kinematics. Here, a multifunctional fish-wearable data snooping platform (FDSP) for studying fish kinematics is demonstrated based on an air sac triboelectric nanogenerator (AS-TENG) with antibacterial coating. The AS-TENG not only can harvest energy from fish swimming but also serves as the self-powered sensory module to monitor the swimming behavior of the fish. The peak output power generated from each swing of the fishtail can reach 0.74 mW, while its output voltage can reflect the real-time behavior of the fishtail. The antibacterial coating on the FDSP can improve its biocompatibility and the elastic texture of the FDSP allows it to be tightly attached to fish. The wireless communication system is designed to transmit the sensory data to a cell phone, where the detailed parameters of fish motion can be obtained, including swing angle, swing frequency, and even the typical swing gestures. This FDSP has broad application prospects in underwater self-powered sensors, wearable tracking devices, and soft robots.
Assuntos
Nanotecnologia , Dispositivos Eletrônicos Vestíveis , Fenômenos Biomecânicos , Monitorização Fisiológica , Movimento (Física)RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.
Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/fisiologia , Células Estromais/patologia , Animais , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína Amiloide A Sérica/genética , Células Estromais/metabolismo , Microambiente TumoralRESUMO
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome. DESIGN: We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA. RESULTS: We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673 and FAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines. CONCLUSIONS: Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.
Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos/genética , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Estimativa de Kaplan-Meier , Polimorfismo de Nucleotídeo Único , Prognóstico , RNA Neoplásico/genética , TranscriptomaRESUMO
It has been demonstrated that excessively activated endoplasmic reticulum stress (ERS) is closely associated with ageing-related diseases and male reproductive dysfunction. Wuzi Yanzong recipe (WZ) is a classical Traditional Chinese Medicine prescription for treatment of male reproductive system diseases. However, it remains unknown whether WZ improves testicular dysfunction with ageing via ERS. In this study, we investigated the protective effects and its mechanism of WZ on testicular dysfunction in ageing rats. The results showed that treatment with WZ for 4 months significantly increased the testicular weight and index, sperm count and viability, and the levels of testosterone and decreased the levels of estradiol. In addition, WZ significantly activated the onset of ERS and prevented germ cell apoptosis by upregulating the expression levels of ERS-responsive proteins GRP78, phospho-PERK, phospho-eIF2α, ATF4, phospho-IRE-1α, XBP1 and ATF6α, and downregulating the expression levels of pro-apoptotic proteins p-JNK, Caspase12 and CHOP in testicular germ cell of ageing rats. Besides, WZ significantly decreased the numbers of TUNEL-positive cells. Taken together, WZ effectively improves ageing-related testicular dysfunction through inhibition of germ cell apoptosis via ERS.
Assuntos
Envelhecimento/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Espermatozoides/metabolismo , Testículo/metabolismoRESUMO
This study aimed to investigate the molecular mechanism and protective effect of total saponins of Panax japonicas (TSPJ) on HepG2 cells apoptosis induced by palmitic acid (PA).The HepG2 cells were cultured in vitro, and divided into five groups: the control group, the model group, the high-dose group (50 mg·L⻹), the middle-dose group (25 mg·L⻹) and the low-dose group (12.5 mg·L⻹).The cells of the five groups were cultured continuously for 24 hours. The cell viability was measured with MTT. HepG2 cells apoptosis was detected by Hoechest staining and Annexin V-FITC/PI staining. The protein expressions of BCL-2, CHOP and TLR4 were measured with western blotting and flow cytometry analysis. The mRNA expressions of TNF-α, IL-1ß, BCL-2, CHOP and GAPDH were measured with RT-PCR. The results suggested that compared with the control group, the number of HepG2 cells of the model group were reduced significantly (P<0.01), while the number of apoptotic HepG2 cells were increased. Compared with the model group, the number of HepG2 cells of the high-dose group and the middle-dose group were increased significantly (P<0.01), whereas the number of apoptotic HepG2 cells were reduced. Compared with the control group, TNF-α, IL-1ß and CHOP mRNA expressions and CHOP and TLR4 protein expressions in the model group were significantly up-regulated (P<0.01), while BCL-2 protein and mRNA expressions in the model group were significantly decreased (P<0.01). Compared with the model group, TNF-α, IL-1ß and CHOP mRNA expressions and CHOP and TLR4 protein expressions in the high-dose group were significantly decreased (P<0.01), while BCL-2 protein and mRNA expressions in the high-dose group were significantly up-regulated (P<0.01).In conclusion, TSPJ can reduce inflammation and apoptosis induced by palmitic acid, with a certain protective effect on liver cells.
Assuntos
Apoptose , Panax/química , Saponinas/farmacologia , Células Hep G2 , Humanos , Ácidos Palmíticos , Compostos Fitoquímicos/farmacologiaRESUMO
MOTIVATION: In prognosis and survival studies, an important goal is to identify multi-biomarker panels with predictive power using molecular characteristics or clinical observations. Such analysis is often challenged by censored, small-sample-size, but high-dimensional genomic profiles or clinical data. Therefore, sophisticated models and algorithms are in pressing need. RESULTS: In this study, we propose a novel Area Under Curve (AUC) optimization method for multi-biomarker panel identification named Nearest Centroid Classifier for AUC optimization (NCC-AUC). Our method is motived by the connection between AUC score for classification accuracy evaluation and Harrell's concordance index in survival analysis. This connection allows us to convert the survival time regression problem to a binary classification problem. Then an optimization model is formulated to directly maximize AUC and meanwhile minimize the number of selected features to construct a predictor in the nearest centroid classifier framework. NCC-AUC shows its great performance by validating both in genomic data of breast cancer and clinical data of stage IB Non-Small-Cell Lung Cancer (NSCLC). For the genomic data, NCC-AUC outperforms Support Vector Machine (SVM) and Support Vector Machine-based Recursive Feature Elimination (SVM-RFE) in classification accuracy. It tends to select a multi-biomarker panel with low average redundancy and enriched biological meanings. Also NCC-AUC is more significant in separation of low and high risk cohorts than widely used Cox model (Cox proportional-hazards regression model) and L1-Cox model (L1 penalized in Cox model). These performance gains of NCC-AUC are quite robust across 5 subtypes of breast cancer. Further in an independent clinical data, NCC-AUC outperforms SVM and SVM-RFE in predictive accuracy and is consistently better than Cox model and L1-Cox model in grouping patients into high and low risk categories. CONCLUSION: In summary, NCC-AUC provides a rigorous optimization framework to systematically reveal multi-biomarker panel from genomic and clinical data. It can serve as a useful tool to identify prognostic biomarkers for survival analysis. AVAILABILITY AND IMPLEMENTATION: NCC-AUC is available at http://doc.aporc.org/wiki/NCC-AUC. CONTACT: ywang@amss.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Algoritmos , Área Sob a Curva , Biomarcadores/análise , Neoplasias da Mama/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Interpretação Estatística de Dados , Genômica/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Modelos Biológicos , Reconhecimento Automatizado de Padrão , Prognóstico , Modelos de Riscos Proporcionais , Máquina de Vetores de Suporte , Taxa de Sobrevida , Biologia de Sistemas , Integração de SistemasRESUMO
BACKGROUND: Identification of tumor heterogeneity and genomic similarities across different cancer types is essential to the design of effective stratified treatments and for the discovery of treatments that can be extended to different types of tumors. However, systematic investigations on comprehensive molecular profiles have not been fully explored to achieve this goal. RESULTS: Here, we performed a network-based integrative pan-cancer genomic analysis on >3000 samples from 12 cancer types to uncover novel stratifications among tumors. Our study not only revealed recurrently reported cross-cancer similarities, but also identified novel ones. The macro-scale stratification demonstrates strong clinical relevance and reveals consistent risk tendency among cancer types. The micro-scale stratification shows essential pan-cancer heterogeneity with subgroup-specific gene network characteristics and biological functions. CONCLUSIONS: In summary, our comprehensive network-based pan-cancer stratification provides valuable information about inter- and intra- cancer stratification for patient clinical assessments and therapeutic strategies.
Assuntos
Redes Reguladoras de Genes/genética , Neoplasias/genética , Bases de Dados Genéticas , Genômica/métodos , HumanosRESUMO
OBJECTIVE: To investigate the protective effect of Panax notoginseng Total Saponins (PNTS) on D-galactose-induced H9c2 cell senescence and the underlying mechanism. METHODS: D-galactose was used to cause H9c2 cells senescence. Different concentrations of PNTS (5,25 and 50 µg/mL) were added into medium to protect H9c2 cells. Cell senescence was identified by senescence associated ß-galactosidase. Level of reactive oxgen species (ROS) was observed according to the effect of DCFH-DA detection. The activity of superoxide dicmutase (SOD) and the content of malondialdehyde (MDA) in cells were measured by biochemical assay kits. The apoptosis of cells was tested by Hochest. RESULTS: Compared with the control group, the number of ß-galactosidase positive cells and the fluorescence intensity of ROS in the model group were markedly increased. Meanwhile, the activity of SOD was decreased whereas the content of MDA was increased. The apoptosis level assessed by the Hochest dyeing was significantly increased with chromatin concentration and condensation. Compared with the model group, the quantity of ß-galactosidase in different PNTS treatment group was obviously decreased, the activity of SOD was increased and the content of MDA was reduced. The apoptosis rate in the cells treated with PNTS was improved. CONCLUSION: PNTS improved D-galactose-induced H9c2 cell senescence through upregulation of antioxidative ability and attenuation of cell apoptosis.
Assuntos
Senescência Celular/efeitos dos fármacos , Galactose/farmacologia , Panax notoginseng/química , Substâncias Protetoras/farmacologia , Saponinas/farmacologia , Apoptose , Linhagem Celular , Fluoresceínas , MalondialdeídoRESUMO
Triboelectric nanogenerators (TENGs) play a crucial role in attaining sustainable energy for various wearable devices. Polymer materials are essential components of TENGs. Biopolymers are suitable materials for TENGs because of their degradability, natural sourcing, and cost-effectiveness. Herein, the latest progress in commonly used biopolymers and well-designed biomimetic techniques for TENG is summarized. The applications of natural rubber, polysaccharides, protein-based biopolymers, and other common synthetic biopolymers in TENG technology are summarized in detail. Each biopolymer is discussed based on its electrification capability, polarity variations, and specific functionalities as active and functional layers of TENGs. Important biomimetic strategies and related applications of specific biopolymers are also summarized to guide the structural and functional design of TENG. In the future, the study of triboelectric biopolymers may focus on exploring alternative candidates, enhancing charge density, and expanding functionality. Various possible applications of biopolymer-based TENGs are proposed in this review. By applying biopolymers and related biomimetic methods to TENG devices, the applications of TENG in the fields of healthcare, environmental monitoring, and wearable/implantable electronics can be further promoted.
RESUMO
Sodium (Na) metal batteries such as Na-ion batteries and Na-CO2 batteries are considered to be excellent alternatives to lithium batteries in terms of their potential applications because of their high specific capacity and low cost. However, the sodium anode showed low efficiency and poor cycling in Na-metal battery performance due to the formation of sodium dendrites and serious corrosion. In this work, nitrogen (N), phosphorus (P) co-doped carbon paper (NP-CP) modified with cobalt tetroxide (Co3O4) nanoparticles was prepared as the Na anode carrier (Co3O4@NP-CP), and a sodium-based composite anode (Na-Co@NP-CP) was further prepared by electrodepositing sodium. The experimental results indicate that the N, P and Co3O4 multi-doped carbon paper has good sodiophilicity, which can induce the uniform plating/stripping of Na+ ions and inhibit the growth of Na dendrites. The N, P doped carbon paper provides a high surface area and tremendous three-dimensional (3D) framework to effectively reduce the areal current density, facilitate the transfer of electrons, and enhance battery life. Therefore, Na-Co@NP-CP based symmetric cells exhibit stable cycling of over 1100 hours at current densities of 1 mA cm-2 and fixed capacity of 1 mA h cm-2. When the Na-Co@NP-CP anode couples with CO2, the assembled batteries can deliver a stable cycling of 165 cycles at current densities of 500 mA g-1 and limited capacity of 500 mA h g-1. When Na-Co@NP-CP anode couples with Na3V2(PO4)3 (NVP) cathode, the assembled cells exhibit lower hysteresis and batter cycling performance.