Background Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an ...opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail. Identification of new metabolic biomarkers of inflammation may improve diagnosis of patients with aggressive PCa. Methods Plasma samples were profiled from 41 South African men with PCa using nuclear magnetic resonance (NMR) spectroscopy. A total of 41 features, including metabolites, lipid classes, total protein, and the inflammatory NMR markers, GlycA, and GlycB, were quantified from each NMR spectrum. The Bruker's B.I.-LISA protocols were used to characterize 114 parameters related to the lipoproteins. The unsupervised KODAMA method was used to stratify the patients of our cohort based on their metabolic profile. Results We found that the plasma of patients with very high risk, aggressive PCa and high level of C-reactive protein have a peculiar metabolic phenotype (metabotype) characterized by extremely high levels of GlycA and GlycB. The inflammatory processes linked to the higher level of GlycA and GlycB are characterized by a deep change of the plasma metabolome that may be used to improve the stratification of patients with PCa. We also identified a not previously known relationship between high values of VLDL and low level of GlycB in a different metabotype of patients characterized by lower-risk PCa. Conclusions For the first time, a portrait of the metabolic changes in African men with PCa has been delineated indicating a strong association between inflammation and metabolic profiles. Our findings indicate how the metabolic profile could be used to identify those patients with high level of inflammation, characterized by aggressive PCa and short life expectancy. Integrating a metabolomic analysis as a tool for patient stratification could be important for opening the door to the development of new therapies. Further investigations are needed to understand the prevalence of an inflammatory metabotype in patients with aggressive PCa. Keywords: Metabolomics, NMR spectroscopy, GlycA, GlycB, Histidine, Prostate cancer, Africa
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response ...pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses, respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose and lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used to predict patient survival and inform treatment intervention.
With the ever-growing data traffic in computer networks nowadays, the management of large-scale networks is a challenge for guaranteeing the quality of the provided services. This is due to the ...increasingly usage of connected applications, such as Internet of Things and cloud computing environments. Software-defined networking (SDN) is a new paradigm that aims to make this management process easier by centralizing the configuration of all network devices into a single programmable central controller. However, as any centralized service, this architecture is susceptible to security vulnerabilities, such as distributed denial of service (DDoS) and port scan attacks. Thus, security methods are necessary to guarantee the normal operation of SDN's central controller. Furthermore, networks are transporting an increasingly amount of information day by day, which could mean data loss in case of long network unavailability. For this reason, security mechanisms must operate online, with fast-responding countermeasures to mitigate the impact of the detected attacks over the SDN. In this paper, we present a fast SDN defense system against DDoS and port scan attacks, which runs directly into the central controller and uses a game theoretical approach for attack mitigation. For the detection, we compare three different approaches, particle swarm optimization, multi-layer perceptron neural network, and discrete wavelet transform. We test our approach over IP flow data generated over Mininet network emulator, along with floodlight controller, and the presented defense system achieved good outcomes for both detection and mitigation processes.
Characterization of Human Respiratory Syncytial Virus (HRSV) protein interactions with host cell components is crucial to devise antiviral strategies. Viral nucleoprotein, phosphoprotein and matrix ...protein genes were optimized for human codon usage and cloned into expression vectors. HEK-293T cells were transfected with these vectors, viral proteins were immunoprecipitated, and co-immunoprecipitated cellular proteins were identified through mass spectrometry. Cell proteins identified with higher confidence scores were probed in the immunoprecipitation using specific antibodies. The results indicate that nucleoprotein interacts with arginine methyl-transferase, methylosome protein and Hsp70. Phosphoprotein interacts with Hsp70 and tropomysin, and matrix with tropomysin and nucleophosmin. Additionally, we performed immunoprecipitation of these cellular proteins in cells infected with HRSV, followed by detection of co-immunoprecipitated viral proteins. The results indicate that these interactions also occur in the context of viral infection, and their potential contribution for a HRSV replication model is discussed.
Abstract
Summary
Computational analysis and interpretation of metabolomic profiling data remains a major challenge in translational research. Exploring metabolic biomarkers and dysregulated metabolic ...pathways associated with a patient phenotype could offer new opportunities for targeted therapeutic intervention. Metabolite clustering based on structural similarity has the potential to uncover common underpinnings of biological processes. To address this need, we have developed the MetChem package. MetChem is a quick and simple tool that allows to classify metabolites in structurally related modules, thus revealing their functional information.
Availabilityand implementation
MetChem is freely available from the R archive CRAN (http://cran.r-project.org). The software is distributed under the GNU General Public License (version 3 or later).
The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. In prostate cancer, PDEF is involved in ...regulating prostate-specific antigen expression via interaction with the androgen receptor and NKX3.1, and down-regulation of PDEF by antiproliferative agents has been associated with reduced PDEF expression. We now report that reduced expression of PDEF leads to a morphologic change, increased migration and invasiveness in prostate cancer cells, reminiscent of transforming growth factor beta (TGFbeta) function and epithelial-to-mesenchymal transition. Indeed, inhibition of PDEF expression triggers a transcriptional program of genes involved in the TGFbeta pathway, migration, invasion, adhesion, and epithelial dedifferentiation. Our results establish PDEF as a critical regulator of genes involved in cell motility, invasion, and adhesion of prostate cancer cells.
Purpose
Polymorphisms in
MSH3
gene confer risk of esophageal cancer when in combination with tobacco smoke exposure. The purpose of this study was to investigate the methylation status of
MSH3
gene ...in esophageal cancer patients in order to further elucidate possible role of
MSH3
in esophageal tumorigenesis.
Methods
We applied nested methylation-specific polymerase chain reaction to investigate the methylation status of the
MSH3
promoter in tumors and matching adjacent normal-looking tissues of 84 esophageal cancer patients from a high-risk South African population. The Cancer Genome Atlas data were used to examine DNA methylation profiles at 17 CpG sites located in the
MSH3
locus.
Results
Overall, promoter methylation was detected in 91.9 % of tumors, which was significantly higher compared to 76.0 % in adjacent normal-looking esophageal tissues (
P
= 0.008). When samples were grouped according to different demographics (including age, gender and ethnicity) and smoking status of patients, methylation frequencies were found to be significantly higher in tumor tissues of Black subjects (
P
= 0.024), patients of 55–65 years of age (
P
= 0.032), males (
P
= 0.037) and tobacco smokers (
P
= 0.015). Furthermore, methylation of the
MSH3
promoter was significantly more frequent in tumor samples from smokers compared to tumor samples from non-smokers odds ratio (OR) = 31.9,
P
= 0.031. The TCGA data confirmed significantly higher DNA methylation level at the
MSH3
promoter region in tumors (
P
= 0.0024). In addition, we found evidence of an aberrantly methylated putative
MSH3
-associated distal enhancer element.
Conclusion
Our results suggest that methylation of
MSH3
together with exposure to tobacco smoke is involved in esophageal carcinogenesis. Due to the active role of the MSH3 protein in modulating chemosensitivity of cells, methylation of
MSH3
should further be examined in association with the outcome of esophageal cancer treatment using anticancer drugs.
The neddylation conjugation pathway has a pivotal role in mediating ubiquitination of proteins and regulation of numerous biological processes. Dysregulation in the ubiquitination and neddylation ...pathways is associated with many cancers. Ubiquitination involves covalent attachment of ubiquitin to target proteins, leading to protein degradation by the proteasome system. The activity of the E3-ubiquitin ligase family, cullin-RING ligases, is essential for promoting ubiquitin transfer to the appropriate substrates. Neddylation, a process mediated by the protein NEDD8, is required for conformational changes of cullins, a scaffolding protein situated in the core of cullin-RING ligases, and regulation of E3 ligase activity. In this review, we present a comprehensive discussion of the recent findings on the neddylation pathway and its importance during tumorigenesis. The ramifications regarding the potential therapeutic use of ubiquination and neddylation inhibition are also discussed.
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