REGγ is associated with multiple oncogenic pathways in human cancers

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest a role of the proteasome activator, REGγ, in cancer progression. Since there are limited numbers of known REGγ targets, it is not known which cancers and pathways are associated with REGγ.</p> <p>Methods</p> <p>REGγ protein expressions in four different cancers were investigated by immunohistochemistry (IHC) analysis. Following NCBI Gene Expression Omnibus (GEO) database search, microarray platform validation, differential expressions of REGγ in corresponding cancers were statistically analyzed. Genes highly correlated with REGγ were defined based on Pearson's correlation coefficient. Functional links were estimated by Ingenuity Core analysis. Finally, validation was performed by RT-PCR analysis in established cancer cell lines and IHC in human colon cancer tissues</p> <p>Results</p> <p>Here, we demonstrate overexpression of REGγ in four different cancer types by micro-tissue array analysis. Using meta-analysis of publicly available microarray databases and biological studies, we verified elevated REGγ gene expression in the four types of cancers and identified genes significantly correlated with REGγ expression, including genes in p53, Myc pathways, and multiple other cancer-related pathways. The predicted correlations were largely consistent with quantitative RT-PCR analysis.</p> <p>Conclusions</p> <p>This study provides us novel insights in REGγ gene expression profiles and its link to multiple cancer-related pathways in cancers. Our results indicate potentially important pathogenic roles of REGγ in multiple cancer types and implicate REGγ as a putative cancer marker.</p

A Resource Aware MapReduce Based Parallel SVM for Large Scale Image Classifications

Machine learning techniques have facilitated image retrieval by automatically classifying and annotating images with keywords. Among them support vector machines (SVMs) are used extensively due to their generalization properties. However, SVM training is notably a computationally intensive process especially when the training dataset is large. This paper presents RASMO, a resource aware MapReduce based parallel SVM algorithm for large scale image classifications which partitions the training data set into smaller subsets and optimizes SVM training in parallel using a cluster of computers. A genetic algorithm based load balancing scheme is designed to optimize the performance of RASMO in heterogeneous computing environments. RASMO is evaluated in both experimental and simulation environments. The results show that the parallel SVM algorithm reduces the training time significantly compared with the sequential SMO algorithm while maintaining a high level of accuracy in classifications.National Basic Research Program (973) of China under Grant 2014CB34040

Involvement of VDAC, Bax and Ceramides in the Efflux of AIF from Mitochondria during Curcumin-Induced Apoptosis

Contains fulltext : 80085.pdf (publisher's version ) (Open Access)BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process. PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion. CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought

Physicochemical Characterization of Passive Films and Corrosion Layers by Differential Admittance and Photocurrent Spectroscopy

Two different electrochemical techniques, differential admittance and photocurrent spectroscopy, for the characterization of electronic and solid state properties of passive films and corrosion layers are described and critically evaluated. In order to get information on the electronic properties of passive film and corrosion layers as well as the necessary information to locate the characteristic energy levels of the passive film/electrolyte junction like: flat band potential (Ufb), conduction band edge (EC) or valence band edge (EV), a wide use of Mott-Schottky plots is usually reported in corrosion science and passivity studies. It has been shown, in several papers, that the use of simple M-S theory to get information on the electronic properties and energy levels location at the film/electrolyte interface can be seriously misleading and/or conflicting with the physical basis underlying the M-S theory. A critical appraisal of this approach to the study of very thin and thick anodic passive film grown on base-metals (Cr, Ni, Fe, SS etc..) or on valve metals (Ta, Nb, W etc..) is reported in this work, together with possible alternative approach to overcome some of the mentioned inconsistencies. At this aim the theory of amorphous semiconductor Schottky barrier, introduced several years ago in the study of passive film/electrolyte junction, is reviewed by taking into account some of the more recent results obtained by the present authors. Future developments of the theory appears necessary to get more exact quantitative information on the electronic properties of passive films, specially in the case of very thin film like those formed on base metals and their alloys. The second technique described in this chapter, devoted to the physico-chemical characterization of passive film and corrosion layers, is a more recent technique based on the analysis of the photo-electrochemical answer of passive film/electrolyte junction under illumination with photons having suitable energy. Such a technique usually referred to as Photocurrent Spectroscopy (PCS) has been developed on the basis of the large research effort carried out by several groups in the 1970’s and aimed to investigate the possible conversion of solar energy by means of electrochemical cells. In this work the fundamentals of semiconductor/electrolyte junctions under illumination will be highlighted both for crystalline and amorphous materials. The role of amorphous nature and film thickness on the photo-electrochemical answer of passive film/solution interface is reviewed as well the use of PCS for quantitative analysis of the film composition based on a semi-empirical correlation between optical band gap and difference of electronegativity of film constituents previously suggested by the present authors. In this frame the results of PCS studies on valve metal oxides and valve metal mixed oxides will be discussed in order to show the validity of the proposed method. The results of PCS studies aimed to get information on passive film composition and carried out by different authors on base metals (Fe, Cr, Ni) and their alloys, including stainless steel, will be also compared with compositional analysis carried out by well-established surface analysis techniques

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe