The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this ...cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.
Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 ...(F3-T3) in 3% of human glioblastoma cases. Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.
The production of a plasma by a pulsed laser beam in solids, liquids or gas is often associated with the generation of a strong shock wave, which can be studied and interpreted in the framework of ...the theory of strong explosion. In this review, we will briefly present a theoretical interpretation of the physical mechanisms of laser-generated shock waves. After that, we will discuss how the study of the dynamics of the laser-induced shock wave can be used for obtaining useful information about the laser–target interaction (for example, the energy delivered by the laser on the target material) or on the physical properties of the target itself (hardness). Finally, we will focus the discussion on how the laser-induced shock wave can be exploited in analytical applications of Laser-Induced Plasmas as, for example, in Double-Pulse Laser-Induced Breakdown Spectroscopy experiments.
The genomic landscape of schwannoma Agnihotri, Sameer; Jalali, Shahrzad; Wilson, Mark R ...
Nature genetics,
11/2016, Letnik:
48, Številka:
11
Journal Article
Recenzirano
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. ...Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.
A ‘hybrid’ method is proposed for the quantitative analysis of materials by LIBS, combining the precision of the calibration-free LIBS (CF-LIBS) algorithm with the quickness of artificial neural ...networks. The method allows the precise determination of the samples’ composition even in the presence of relatively large laser fluctuations and matrix effects. To show the strength and robustness of this approach, a number of synthetic LIBS spectra of Cu–Ni binary alloys with different composition were computer-simulated, in correspondence of different plasma temperatures, electron number densities and ablated mass. The CF-LIBS/ANN approach here proposed demonstrated to be capable, after appropriate training, of ‘learning’ the basic physical relations between the experimentally measured line intensities and the plasma parameters. Because of that the composition of the sample can be correctly determined, as in CF-LIBS measurements, but in a much shorter time.
The Tomb of the Diver has been subject for many decades of fierce debate among archaeologists and classicists. Since its discovery in 1968, some scholars have considered it a unique example of the ...lost tradition of Greek painting, others have emphasized Etruscan or Italic parallels. More recently, a possible local production has been suggested. With the aim of trying to solve the archaeological question, an archaeometric comparison among this well-known artwork and several frescoed tombs coming from Hellenistic and Lucan necropolis was carried out. The multi-analytical study was focused on the identification of peculiar features of executive techniques and raw materials since the first period of the archaeological site. The analytical investigation has been preliminary based on a non-destructive approach, performed in-situ by portable equipment including imaging diagnostics and compositional spectroscopic techniques for identifying pigments and the conservation state of original painted surface; subsequently, a further deepening by using destructive techniques was performed in-lab for the mortar-based supports characterization. Archaeometric study suggested that technological choices slightly changed in a time span of about two centuries, highlighting important markers that allow clustering the contemporary artistic productions. Moreover, a comparison with mortars from temples decorations was provided to better understand the whole artistic context. The archaeometric data showed that the Tomb of the Diver could be traced back to a local artisanal tradition and therefore is neither Etruscan nor Greek, but the first and foremost an expression of the local elite culture of Paestum.
This paper investigates the durability of geopolymers and geopolymeric mortars made with metakaolin and alkaline activators, with and without a coconut fiber addition, after immersion for seven days ...into solutions of citric acid (1%, 2.5%, 5%, and 10%); hydrochloric acid (1%, 2.5%, 5%, and 10%); and sulfuric acid (1%, 2.5%, 5%, and 10%). The study focuses on mass changes, uniaxial compressive strength, flexural strength, and ultrasound pulse velocity measurements. X-ray diffraction and scanning electron microscopy are used to analyze the degradation products and microstructural changes. The aim is to assess the effect of acid exposure on the strength and stability of geopolymer materials and identify any protective effects of coconut fiber reinforcement. The samples are immersed in acid solutions of varying concentrations, and their mechanical properties are measured. The presence of coconut fibers slightly modifies the physical properties and the compressive strength, improving the mechanical flexural strength. Geopolymer and geopolymeric mortar materials experienced a weak decrease in strength when exposed to solutions of citric acid and a significant one when exposed to solutions of hydrochloric and sulfuric acids, attributed to depolymerization of the aluminosilicate binders. Brick waste geopolymeric mortars reinforced with coconut fibers showed the best performance in acid solutions with respect to geopolymers and quartz-rich sand geopolymeric mortars, suggesting a more stable cross-linked aluminosilicate geopolymer structure in this material.
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes ...associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Display omitted
•Comprehensive molecular profiling of 1,122 adult diffuse grade II, III, and IV gliomas•Telomere length and telomere maintenance defined by somatic alterations•DNA methylation profiling reveals subtypes of IDH mutant and IDH-wild-type glioma•Integrated molecular analysis of progression from low-grade to high-grade disease
Integration of a large sample size of glioma tumors with multidimensional ‘omic characterization and clinical annotation provides insights into molecular classification, telomere maintenance mechanisms, progression from low to high grade disease, driver mutations, and therapeutic options.
The quarrying of marble and its processing to produce building materials often generates a negative impact on the environment. In the Apuan Alps marble district, a renowned quarrying area in Italy ...since ancient times, the aquatic pollution of water bodies, caused by the presence of marble waste in the form of powder or sludge, represents a significant and current environmental problem. Depending on the different national and international regulations on waste management, the marble waste can be classified as a special non-hazardous industrial waste. If marble waste has been managed according to environmental international and national laws, it can be reused as a by-product. For this, the present work aims to evaluate the reuse of marble waste as a material in replacement for cement for producing mortars. Subsequently, the mechanical and physical tests were carried out to evaluate the specific properties of the obtained materials during and after the curing time. The results showed that replacement of cement into mortars by marble waste always causes a decrease of mechanical properties, with still acceptable values for many applications up to a substitution of less than 25%. From the collected data, the use of marble waste in the production of cement mortars represents an adequate and sustainable destination of this by-product.
The usual approach to laser-induced breakdown spectroscopy (LIBS) quantitative analysis is based on the use of calibration curves, suitably built using appropriate reference standards. More recently, ...statistical methods relying on the principles of artificial neural networks (ANN) are increasingly used. However, ANN analysis is often used as a ‘black box’ system and the peculiarities of the LIBS spectra are not exploited fully. An a priori exploration of the raw data contained in the LIBS spectra, carried out by a neural network to learn what are the significant areas of the spectrum to be used for a subsequent neural network delegated to the calibration, is able to throw light upon important information initially unknown, although already contained within the spectrum. This communication will demonstrate that an approach based on neural networks specially taylored for dealing with LIBS spectra would provide a viable, fast and robust method for LIBS quantitative analysis. This would allow the use of a relatively limited number of reference samples for the training of the network, with respect to the current approaches, and provide a fully automatizable approach for the analysis of a large number of samples.
•A methodological approach to neural network analysis of LIBS spectra is proposed.•The architecture of the network and the number of inputs are optimized.•The method is tested on bronze samples already analyzed using a calibration-free LIBS approach.•The results are validated, compared and discussed.
PDF
