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Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
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Neoplasias , Procesamiento Postranscripcional del ARN , Humanos , ARN Mensajero/metabolismo , ARN/genética , ARN/metabolismo , Neoplasias/genética , MetilaciónRESUMEN
This work presents a novel approach to estimate brain functional connectivity networks via generative learning. Due to the complexity and variability of rs-fMRI signal, we consider it as a random variable, and utilize variational autoencoder networks to encode it as a confidence distribution in the latent space rather than as a fixed vector, so as to establish the relationship between them. First, the mean time series of each brain region of interest is mapped into a multivariate Gaussian distribution. The correlation between two brain regions is measured by the Jensen-Shannon divergence that describes the statistical similarity between two probability distributions, and then the adjacency matrix is created to indicate the functional connectivity strength of pairwise brain regions. Meanwhile, our findings show that the adjacency matrices obtained at VAE latent spaces of different dimensionalities have good complementarity for MCI identification in precision and recall, and the classification performance can be further boosted by an efficient cascade of classifiers. This proposal constructs brain functional networks from a statistical modeling standpoint, improving the statistical ability of population data and the generalization ability of observation data variability. We evaluate the proposed framework over the task of identifying subjects with MCI from normal controls, and the experimental results on the public dataset show that our method significantly outperforms both the baseline and current state-of-the-art methods.
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Disfunción Cognitiva , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Disfunción Cognitiva/diagnóstico por imagen , AprendizajeRESUMEN
Osteoarthritis occurs when the number of senescent chondrocytes in the joints reaches an intolerable level. The purpose of our study was to explore the therapeutic effect and mechanism of action of A-1331852 in osteoarthritis. Doxorubicin and etoposide were used to induce cell senescence as determined by the cessation of cell proliferation, augmented senescence-associated beta-galactosidase (SA-ß-Gal) staining, and increased p53 expression levels. The CCK-8 cytotoxicity assay and SA-ß-Gal staining demonstrated that Bcl-xL inhibitors could selectively remove senescent chondrocytes without damaging healthy chondrocytes. A-1331852 induced caspase-dependent death of senescent chondrocytes with decreased mitochondrial membrane potential, nuclear concentration, plasma membrane rupture, and PARP cleavage. Most importantly, A-1331852 upregulated BAK expression levels, indicating that BAK plays a key role in the A-1331852-induced apoptosis of senescent chondrocytes. Live-cell fluorescence resonance energy transfer showed that A-1331852 detached the binding of Bcl-xL to BAK and promoted the oligomerization of BAK on the mitochondrial membrane. In conclusion, this study provides the first evidence that A-1331852 selectively promotes apoptosis in senescent chondrocytes by interfering with the interaction between Bcl-xL and BAK.
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Condrocitos , Osteoartritis , Apoptosis , Benzotiazoles/farmacología , Condrocitos/metabolismo , Humanos , Isoquinolinas , Osteoartritis/metabolismo , Proteína bcl-X/metabolismoRESUMEN
Molecular regulatory network among the B cell leukemia-2 (Bcl-2) family proteins is a research hotspot on apoptosis. The inhibitory priority of anti-apoptotic Bcl-2 family proteins (such as Bcl-xL) to pro-apoptotic Bcl-2 family proteins (such as Bad, tBid and Bax) determines the outcome of their interactions. Based on over-expression model system, we here evaluate the inhibitory priority of Bcl-xL to Bad, tBid and Bax by using live-cell imaging assay on cell viability. Fluorescence images of living cells co-expressing CFP-Bcl-xL and YFP-Bad or YFP-tBid or YFP-Bax showed that Bcl-xL markedly inhibited Bad/tBid/Bax-mediated apoptosis, revealing that Bcl-xL inhibits the proapoptotic function of Bad, tBid and Bax. In the case of equimolar co-expression of Bad and CFP-Bcl-xL, the inhibition of Bcl-xL on tBid/Bax mediate-apoptosis was completely relieved. Moreover, co-expression of tBid-P2A-CFP-Bcl-xL significantly relieved the inhibition of Bcl-xL on the pro-apoptotic ability Bax, suggesting that Bcl-xL preferentially inhibits the pro-apoptotic ability of Bad over tBid, subsequently to Bax.
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Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2 , Supervivencia Celular , Proteína X Asociada a bcl-2/genética , Proteína bcl-X/genéticaRESUMEN
Three-cube Förster resonance energy transfer (FRET) method is the most extensively applied approach for live-cell FRET quantification. Reliable measurements of calibration factors are crucial for quantitative FRET measurement. We here proposed a modified TA-G method (termed as mTA-G) to simultaneously obtain the FRET-sensitized quenching transition factor (G) and extinction coefficients ratio (γ) between donor and acceptor. mTA-G method includes four steps: (1) predetermining the ratio ranges of the sensitized emission of acceptor (FC ) to the donor excitation and donor channel image (IDD [(DA])) for all FRET plasmids; (2) culturing the cells which express every FRET plasmid in one dish respectively; (3) distinguishing and marking the cells expressing different FRET plasmids by detecting their FC /IDD (DA) values; (4) linearly fitting FC /IAA (DA) (acceptor excitation and acceptor channel image) to IDD (DA)/IAA (DA) for different kinds of cells. We implemented mTA-G method by imaging tandem constructs cells with different FRET efficiency cultured in one dish on different days, and obtained consistent G and γ values. mTA-G method not only circumvents switchover of different culture dishes but also keep the constant imaging conditions, exhibiting excellent robustness, and thus will expands the biological applications of quantitative FRET analysis in living cells.
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Diagnóstico por Imagen , Transferencia Resonante de Energía de Fluorescencia , Calibración , Plásmidos/genéticaRESUMEN
BACKGROUND: Heterogeneity of metastatic renal cell carcinoma (RCC) constraints accurate prognosis prediction of the tumor. We therefore aimed at developing a novel nomogram for accurate prediction of overall survival (OS) of patients with metastatic RCC. METHODS: We extracted 2010 to 2016 data for metastatic RCC patients in the Surveillance, Epidemiology, and End Results (SEER) database, and randomly stratified them equally into training and validation sets. Prognostic factors for OS were analyzed using Cox regression models, and thereafter integrated into a 1, 3 and 5-year OS predictive nomogram. The nomogram was validated using the training and validation sets. The performance of this model was evaluated by the Harrell's concordance index (C-index), calibration curve, integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), index of prediction accuracy (IPA), and decision curve analysis (DCA). RESULTS: Overall, 2315 metastatic RCC patients in the SEER database who fulfilled our inclusion criteria were utilized in constructing a nomogram for predicting OS of newly diagnosed metastatic RCC patients. The nomogram incorporated eight clinical factors: Fuhrman grade, lymph node status, sarcomatoid feature, cancer-directed surgery and bone, brain, liver, and lung metastases, all significantly associated with OS. The model was superior to the American Joint Committee on Cancer (AJCC) staging system (7th edition) both in training (C-indices, 0.701 vs. 0.612, P < 0.001) and validation sets (C-indices, 0.676 vs. 0.600, P < 0.001). The calibration plots of the nomogram corresponded well between predicted and observed values. NRI, IDI, and IPA further validated the superior predictive capability of the nomogram relative to the AJCC staging system. The DCA plots revealed reliable clinical application of our model in prognosis prediction of metastatic RCC patients. CONCLUSIONS: We developed and validated an accurate nomogram for individual OS prediction of metastatic RCC patients. This nomogram can be applied in design of clinical trials, patient counseling, and rationalizing therapeutic modalities.
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Carcinoma de Células Renales/mortalidad , Neoplasias Renales/mortalidad , Nomogramas , Factores de Edad , Anciano , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Distribución Aleatoria , Estudios Retrospectivos , Factores de Riesgo , Programa de VERF , Tasa de SupervivenciaRESUMEN
ZEITLUPE (ZTL), LOV KELCH PROTEIN 2 (LKP2), and FLAVIN-BINDING KELCH REPEAT F-BOX 1 (FKF1)-blue-light photoreceptors-play important roles in regulating the circadian clock and photoperiodic flowering pathway in plants. In this study, phylogenetic analysis revealed that the LOV (Light, Oxygen, or Voltage) and Kelch repeat-containing F-box (LFK) gene family can be classified into two clades, ZTL/LKP2 and FKF1, with clear differentiation between monocots and dicots within each clade. The LFK family genes underwent strong purifying selection; however, signatures of positive selection to adapt to local conditions still existed in 18 specific codons. In 87 diverse maize inbred lines, significant differences were identified (P ≤ 0.01) for days to female flowering between the haplotypes consisting of eight positive selection sites at ZmFKF1b corresponding to tropical and temperate maize groups of the phylogenetic tree, indicating a key role of ZmFKF1b in maize adaptive evolution. In addition, positive coevolution was detected in the domains of the LFK family for long-term cooperation to targets. The Type-I and Type-II functional divergence analysis revealed subfunctionalization or neofunctionalization of the LFKs, and the ZTL subfamily is most likely to maintain the ancestral function of LFKs. Over 50% of critical amino acid sites involved in the functional divergence were identified in the Kelch repeat domain, resulting in the distinction of substrates for ubiquitination and degradation. These results suggest that evolutionary conservation contributes to the maintenance of critical physiological functions, whereas functional divergence after duplication helps to generate diverse molecular regulation mechanisms.
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Evolución Biológica , Flores/fisiología , Genes de Plantas , Familia de Multigenes , Fotoperiodo , Zea mays/genética , Secuencia de Aminoácidos , Relojes Circadianos , Secuencia Conservada , Haplotipos , Filogenia , Selección Genética , Zea mays/fisiologíaRESUMEN
In this paper, we present a multi-texton representation method for medical image retrieval, which utilizes the locality constraint to encode each filter bank response within its local-coordinate system consisting of the k nearest neighbors in texton dictionary and subsequently employs spatial pyramid matching technique to implement feature vector representation. Comparison with the traditional nearest neighbor assignment followed by texton histogram statistics method, our strategies reduce the quantization errors in mapping process and add information about the spatial layout of texton distributions and, thus, increase the descriptive power of the image representation. We investigate the effects of different parameters on system performance in order to choose the appropriate ones for our datasets and carry out experiments on the IRMA-2009 medical collection and the mammographic patch dataset. The extensive experimental results demonstrate that the proposed method has superior performance.
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Interpretación de Imagen Asistida por Computador/métodos , Almacenamiento y Recuperación de la Información/métodos , Mamografía , Sistemas de Información Radiológica , Femenino , HumanosRESUMEN
In recent years, antitumor and antiviral effect of Caulis spatholobi becomes a hot topic of medical drug research. Experiment shows that the water extract of Caulis spatholobi compound 1802 showed the effect of inhibiting tumor growth, the difference was statistically significant (P<0.05); the rate of tumor inhibition was highest in the high dose group of compound 1802, which could reach 41.99%. Anti tumor drugs generally have high toxicity, therefore, low toxicity is the significant characteristic of Caulis spatholobi. In particular the use of Caulis spatholobi has certain practical significance for development of tumor patients' daily diet products. In summary, the chemical constituents of Caulis spatholobi complex, has extensive pharmacological effects and clinical application.
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Medicamentos Herbarios Chinos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Animales , Línea Celular Tumoral , Fabaceae/química , Humanos , Masculino , Ratones , Extractos Vegetales/farmacologíaRESUMEN
Due to the intra-class diversity of mitotic cells and the morphological overlap with similarly looking imposters, automatic mitosis detection in histopathology slides is still a challenging task. In this paper, we propose a novel mitosis detection model in a weakly supervised way, which consists of a candidate proposal network and a verification network. The candidate proposal network based on patch learning aims to separate both mitotic cells and their mimics from the background as candidate objects, which substantially reduces missed detections in the screening process of candidates. These obtained candidate results are then fed into the verification network for mitosis refinement. The verification network adopts an RBF-based subcategorization scheme to deal with the problems of high intra-class variability of mitosis and the mimics with similar appearance. We utilize the RBF centers to define subcategories containing mitotic cells with similar properties and capture representative RBF center locations through joint training of classification and clustering. Due to the lower intra-class variation within a subcategory, the localized feature space at subcategory level can better characterize a certain type of mitotic figures and can provide a better similarity measurement for distinguishing mitotic cells from nonmitotic cells. Our experiments manifest that this subcategorization scheme helps improve the performance of mitosis detection and achieves state-of-the-art results on the publicly available mitosis datasets using only weak labels.
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Neoplasias de la Mama , Mitosis , Mitosis/fisiología , Humanos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Femenino , Interpretación de Imagen Asistida por Computador/métodos , Algoritmos , Aprendizaje ProfundoRESUMEN
This work presents a deep network architecture to improve nuclei detection performance and achieve the high localization accuracy of nuclei in breast cancer histopathology images. The proposed model consists of two parts, generating nuclear candidate module and refining nuclear localization module. We first design a novel patch learning method to obtain high-quality nuclear candidates, where in addition to categories, location representations are also added to the patch information to implement the multi-task learning process of nuclear classification and localization; meanwhile, the deep supervision mechanism is introduced to obtain the coherent contributions from each scale layer. In order to refine nuclear localization, we propose an iterative correction strategy to make the prediction progressively closer to the ground truth, which significantly improves the accuracy of nuclear localization and facilitates neighbor size selection in the nonmaximum suppression step. Experimental results demonstrate the superior performance of our method for nuclei detection on the H&E stained histopathological image dataset as compared to previous state-of-the-art methods, especially in multiple cluttered nuclei detection, can achieve better results than existing techniques.
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Algoritmos , Neoplasias de la Mama , Humanos , Femenino , Mama/diagnóstico por imagen , Mama/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Núcleo Celular/patología , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
As a highly contagious opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa) is one of the main causes of healthcare-associated infections. The drug-resistant nature of P. aeruginosa can render antibiotic treatments ineffective, leading to a high morbidity and mortality. Higher specificity and reduced toxicity are features of immunotherapy, which can generate robust immune responses and preserve long-term immunological memory to completely eradicate infections. In this study, we developed a type of P. aeruginosa vaccine based on a metal-organic framework. Specifically, MIL-101-Al nanoparticles were synthesized to encapsulate antigens derived from the bacterial lysate (BL) of PAO1, a drug-resistant P. aeruginosa, and the adjuvant unmethylated cytosine-phosphate-guanine oligonucleotide (CpG), which were then modified with palmitic acid (PAA) to obtain MIL-BC@PAA. The stability and biocompatibility were significantly increased by capping with PAA. Moreover, MIL-BC@PAA showed significantly enhanced uptake by antigen presenting cells (APCs), and promoted their maturation. Importantly, immunity studies revealed the greatly elicited antigen-specific humoral and cellular responses, and a protection rate of about 70% was observed in P. aeruginosa-challenged mice. Overall, these results demonstrate the promising potential of MIL-BC@PAA as an ideal nanovaccine for P. aeruginosa vaccination.
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Adyuvantes Inmunológicos , Estructuras Metalorgánicas , Ácido Palmítico , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/efectos de los fármacos , Animales , Ratones , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/prevención & control , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Ácido Palmítico/química , Femenino , Nanopartículas/química , Ratones Endogámicos BALB C , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/farmacologíaRESUMEN
RNA modification has garnered increasing attention in recent years due to its pivotal role in tumorigenesis and immune surveillance. N6-methyladenosine (m6A) modification is the most prevalent RNA modification, which can affect the expression of RNA by methylating adenylate at the sixth N position to regulate the occurrence and development of tumors. Dysregulation of m6A affects the activation of cancer-promoting pathways, destroys immune cell function, maintains immunosuppressive microenvironment, and promotes tumor cell growth. In this review, we delve into the latest insights into how abnormalities in m6A modification in both tumor and immune cells orchestrate immune evasion through the activation of signaling pathways. Furthermore, we explore how dysregulated m6A modification in tumor cells influences immune cells, thereby regulating tumor immune evasion via interactions within the tumor microenvironment (TME). Lastly, we highlight recent discoveries regarding specific inhibitors of m6A modulators and the encapsulation of m6A-targeting nanomaterials for cancer therapy, discussing their potential applications in immunotherapy.
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Adenosina , Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Escape del Tumor/inmunología , Animales , Evasión Inmune/inmunología , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: N6-methyladenosine (m6A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. METHODS: RNA m6A levels were analysed in NPC using m6A dot blot assay. The expression level of methyltransferase-like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT-qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m6A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half-life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP-qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes. RESULTS: We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m6A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism-related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl-CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22-mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC. CONCLUSIONS: The identified METTL14-ANKRD22-SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers.
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Metabolismo de los Lípidos , Metiltransferasas , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Metiltransferasas/metabolismo , Metiltransferasas/genética , Metabolismo de los Lípidos/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , ARN Mensajero/metabolismo , ARN Mensajero/genética , Progresión de la Enfermedad , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Ratones , Animales , Regulación Neoplásica de la Expresión Génica/genética , Reprogramación MetabólicaRESUMEN
Abivertinib (AC) is a novel epidermal growth factor receptor tyrosine kinase inhibitor with highly efficient antitumor activity. Here, we report the capacity of AC to induce both reactive oxygen species (ROS)-dependent apoptosis and ferroptosis in tumor cells. Our data showed that AC induced iron- and ROS-dependent cytotoxicity in MCF7, HeLa, and A549 cell lines. Flow cytometry analyses showed that AC increased ferrous ions and ROS and induced ferroptosis in MCF-7 cells. This was confirmed by the findings that AC not only decreased solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression but also induced iron- and ROS-dependent aggrandized lipid ROS accumulation and plasma membrane damage. Meanwhile, AC induced nuclear condensation and increased ROS-dependent phosphatidylserine (PS) eversion, caspase-3 activation, and cleaved-PARP expression, suggesting that AC also induced ROS-dependent apoptosis. In addition, mitochondrial depletion significantly inhibited AC-induced cytotoxicity, including ferroptosis and apoptosis, indicating the key role of mitochondria in AC-induced ferroptosis and apoptosis. Moreover, knockout of Bim or Bax not only remarkably inhibited AC-induced apoptosis, but also markedly inhibited AC-triggered downregulation of SLC711 and GPX4, accumulation of lipid ROS, and damage to the plasma membrane. This suggests that Bim and Bax act upstream of SLC7A11 and GPX4 to mediate AC-induced ferroptosis. Collectively, AC induces ferroptosis and apoptosis, in which the Bim- and Bax-mediated mitochondrial pathways play a dominant role.
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Ferroptosis , Apoptosis , Línea Celular Tumoral , Mitocondrias/metabolismo , Pirimidinas , Especies Reactivas de Oxígeno/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Metformin (Met) exhibits anticancer ability in various cancer cell lines. This report aims to explore the exact molecular mechanism of Met-induced apoptosis in HCT116 cells, a human colorectal cancer cell line. Met-induced reactive oxygen species (ROS) increase and ROS-dependent cell death accompanied by plasma membrane blistering, mitochondrial swelling, loss of mitochondrial membrane potential, and release of cytochrome c. Western blotting analysis showed that Met upregulated Bak expression but downregulated Bax expression. Most importantly, silencing Bak instead of Bax inhibited Met-induced loss of mitochondrial membrane potential, indicating the key role of Bak in Met-induced apoptosis. Live-cell fluorescence resonance energy transfer (FRET) analysis showed that Met unlocked the binding of Mcl-1 to Bak, and enhanced the binding of Bim to Bak and subsequent Bak homo-oligomerization. Western blotting analysis showed that Met enhanced AMPK phosphorylation and Bim expression, and compound C, an inhibitor of AMPK, inhibited Met-induced Bim upregulation. Although Met increased the expression of Bcl-xL, overexpression of Bcl-xL did not prevent Met-induced apoptosis. In summary, our data demonstrate for the first time that Met promotes ROS-dependent apoptosis by regulating the Mcl-1-Bim-Bak axis.
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PURPOSE: This study aimed to establish a nomogram to predict the long-term overall survival (OS) for patients with penile squamous cell carcinoma (PSCC). METHOD: The PSCC patients receiving regional lymph node dissection (RLND) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The dataset of all eligible patients were used to develop the predictive model. The significant independent predictors were identified through Cox regression modeling based on the Bayesian information criterion and then incorporated into a nomogram to predicted 1-, 3-, and 5-year OS. Internal validation was performed using the bootstrap resampling method. The model performance was evaluated using Harrell's concordance index (C-index), calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). RESULTS: Totally, 384 eligible PSCC patients were enrolled from the SEER database. A nomogram for OS prediction was developed, in which three clinical variables significantly associated with OS were integrated, including age, N classification, and log odds of positive lymph nodes (LODDS). The C-index of the nomogram (0.746, 95% CI: 0.702-0.790) was significantly higher than that of the American Joint Committee on Cancer (AJCC) staging system (0.692, 95% CI: 0.646-0.738, P = .020). The bootstrap optimism-corrected C-index for the nomogram was 0.739 (95% CI: 0.690-0.784). The bias-corrected calibration plots showed the predicted risks were in good accordance with the actual risks. The results of NRI, IDI, and DCA exhibited superior predictive capability and higher clinical use of the nomogram compared with the AJCC staging system. CONCLUSION: We successfully constructed a simple and reliable nomogram for OS prediction among PSCC patients receiving RLND, which would be beneficial to clinical trial design, patient counseling, and therapeutic modality selection.
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Carcinoma de Células Escamosas/complicaciones , Ganglios Linfáticos/patología , Nomogramas , Neoplasias del Pene/complicaciones , Carcinoma de Células Escamosas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias del Pene/mortalidadRESUMEN
This work develops a biologically inspired neural network for contour detection in natural images by combining the nonclassical receptive field modulation mechanism with a deep learning framework. The input image is first convolved with the local feature detectors to produce the classical receptive field responses, and then a corresponding modulatory kernel is constructed for each feature map to model the nonclassical receptive field modulation behaviors. The modulatory effects can activate a larger cortical area and thus allow cortical neurons to integrate a broader range of visual information to recognize complex cases. Additionally, to characterize spatial structures at various scales, a multiresolution technique is used to represent visual field information from fine to coarse. Different scale responses are combined to estimate the contour probability. Our method achieves state-of-the-art results among all biologically inspired contour detection models. This study provides a method for improving visual modeling of contour detection and inspires new ideas for integrating more brain cognitive mechanisms into deep neural networks.
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The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid ß protein alloform 140 (Aß140) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aß140 coinjection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by coinjection of APOE4 + Aß140. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcriptionquantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubuleassociated protein tau and glycogen synthase kinase 3ß (GSK3ß). APOE4 and Aß140 coaggregation decreased the shortterm spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aß140 coaggregationinduced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aß140 coaggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3ß protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3ß phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aß140 coaggregation in model rats.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Lesiones Encefálicas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Histona Desacetilasa 6/biosíntesis , Inhibidores de Histona Desacetilasas/farmacología , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/metabolismo , Animales , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Colina O-Acetiltransferasa/biosíntesis , Hipocampo/patología , Hipocampo/fisiopatología , Histona Desacetilasa 6/antagonistas & inhibidores , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/fisiopatología , Ratas , Ratas Sprague-Dawley , Memoria Espacial/efectos de los fármacos , Proteínas tau/metabolismoRESUMEN
BACKGROUND: The suicide risk was higher in kidney cancer patients than in the general population. The purpose of this study was to characterize the suicide rates among kidney cancer patients and to identify the potential risk factors associated with suicide from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Kidney cancer patients were identified from the SEER database during 1973-2015. Suicide rates and standardized mortality ratios (SMRs) of this population were calculated, and the US general population during 1981-2015 was chosen as a reference. Univariable and multivariable Cox regression were performed to find out potential risk factors of suicide. RESULTS: There were 207 suicides identified among 171 819 individuals with kidney cancer observed for 948 272 person-years. The suicide rate was 21.83 per 100 000 person-years, and SMR was 1.83 (95% CI: 1.59-2.10). On Cox regression, diagnosis in early years (1973-1982 vs 2003-2015, HR: 2.03, 95% CI: 1.01-4.11, P = 0.048; 1983-1992 vs 2003-2015, HR: 1.99, 95% CI: 1.18-3.35, P = 0.010), male sex (vs female sex, HR: 4.43, 95% CI: 2.95-6.65, P < 0.001), unmarried status (vs married status, HR: 2.54, 95% CI: 1.91-3.38, P < 0.001), non-black race (white race vs black race, HR: 4.47, 95% CI: 2.09-9.58, P < 0.001; other races vs black race, HR: 3.01, 95% CI: 1.08-8.37, P = 0.035), higher histologic grade (grade IV vs grade I, HR: 3.27, 95% CI: 1.50-7.13, P = 0.003; grade III vs grade I, HR: 2.13, 95% CI: 1.19-3.81, P = 0.011) and cancer-directed surgery not performed (vs performed, HR: 2.78, 95% CI: 1.52-5.11, P < 0.001) were independent risk factors of suicide among kidney cancer patients. CONCLUSIONS: Diagnosis in early years, male sex, unmarried status, non-black race, higher histologic grade, and cancer-directed surgery not performed were significantly associated with suicide among kidney cancer patients. In order to prevent suicidal death, clinicians should pay more attention to patients with high-risk factors of suicide.