Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer

Background: Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown. Methods: To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment. Results: Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression. Conclusion: Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome

Data Descriptor: A global multiproxy database for temperature reconstructions of the Common Era

Reproducible climate reconstructions of the Common Era (1 CE to present) are key to placing industrial-era warming into the context of natural climatic variability. Here we present a community-sourced database of temperature-sensitive proxy records from the PAGES2k initiative. The database gathers 692 records from 648 locations, including all continental regions and major ocean basins. The records are from trees, ice, sediment, corals, speleothems, documentary evidence, and other archives. They range in length from 50 to 2000 years, with a median of 547 years, while temporal resolution ranges from biweekly to centennial. Nearly half of the proxy time series are significantly correlated with HadCRUT4.2 surface temperature over the period 1850-2014. Global temperature composites show a remarkable degree of coherence between high-and low-resolution archives, with broadly similar patterns across archive types, terrestrial versus marine locations, and screening criteria. The database is suited to investigations of global and regional temperature variability over the Common Era, and is shared in the Linked Paleo Data (LiPD) format, including serializations in Matlab, R and Python.(TABLE)Since the pioneering work of D'Arrigo and Jacoby1-3, as well as Mann et al. 4,5, temperature reconstructions of the Common Era have become a key component of climate assessments6-9. Such reconstructions depend strongly on the composition of the underlying network of climate proxies10, and it is therefore critical for the climate community to have access to a community-vetted, quality-controlled database of temperature-sensitive records stored in a self-describing format. The Past Global Changes (PAGES) 2k consortium, a self-organized, international group of experts, recently assembled such a database, and used it to reconstruct surface temperature over continental-scale regions11 (hereafter, ` PAGES2k-2013').This data descriptor presents version 2.0.0 of the PAGES2k proxy temperature database (Data Citation 1). It augments the PAGES2k-2013 collection of terrestrial records with marine records assembled by the Ocean2k working group at centennial12 and annual13 time scales. In addition to these previously published data compilations, this version includes substantially more records, extensive new metadata, and validation. Furthermore, the selection criteria for records included in this version are applied more uniformly and transparently across regions, resulting in a more cohesive data product.This data descriptor describes the contents of the database, the criteria for inclusion, and quantifies the relation of each record with instrumental temperature. In addition, the paleotemperature time series are summarized as composites to highlight the most salient decadal-to centennial-scale behaviour of the dataset and check mutual consistency between paleoclimate archives. We provide extensive Matlab code to probe the database-processing, filtering and aggregating it in various ways to investigate temperature variability over the Common Era. The unique approach to data stewardship and code-sharing employed here is designed to enable an unprecedented scale of investigation of the temperature history of the Common Era, by the scientific community and citizen-scientists alike

Study of direct thermal energy storage technologies for effectiveness of concentrating solar power plants

The paper presents the numerical and technical comparisons between the direct thermal energy storage (TES) technologies with economic considerations in beneficial design and control to lead the process up to the sustainable power production for the concentrating solar power (CSP) plants. The analysis is performed based on the available data in the previous work on 5 MW Archimede plant operating in Sicily (Vitte et al., 2012). Considerations on process control, operability and design improvement in the layout of plant and flexibility related to the selected TES technologies are provided in this work due to making the decisions for optimal control

Quality control of poly(methyl methacrylate) to medical purpose by multiple headspace extraction

The quality of polymers to be used for medical purposes is evaluated by the concentration of residual compounds in the polymeric matrix, especially by the amount of residual monomer. Residual components of the polymerization of monomer can cause allergies and biological complications (stomatitis, dermatitis, cheilitis, and irritability), also collateral effects for the patient which are evident from the first five years after implant placement and could remain for thirty years more. In dentures, for example, these components are dissolved by the saliva and are fixed to adjacent tissue causing allergic reactions, including burning. Multiple headspace extraction gas chromatography (MHS-GC) has been found to be an analytical technique particularly suitable for quantification of residual monomer in process samples with complex matrix, including solids. The major advantage of MHS-GC is that there is no need to pre-treat the sample prior to analysis. In this work, the methodology used to determine the residual monomer of Methyl Methacrylate (MMA) in a polymer of Poly(Methyl Methacrylate) (PMMA) is presented. The PMMA was produced in a controlled pilot plant scale laboratory, with rigorous experimental conditions to be used for medical purposes (artificial bone). The method includes the formulation of a calibration curve which was obtained by injecting different masses (0 - 30 mg) of a standard MMA solution in the Headspace sample vials and treated at ten extraction step in the HS-GC system. The results showed that through the present method it is possible to recover 98% of MMA from a solid matrix of PMMA

Novel two-steps optimal control of batch polymerization reactors and application to PMMA production for the fabrication of artificial bone tissue

It is known that the applications of a material are totally dependent on their characteristics. In the particular case of the manufacture of bone tissues from polymer sources, high molecular weights are necessary to ensure optimum mechanical and optical properties. However, exothermic reactions and strong nonlinearities, which are peculiarities of such reaction systems, require rigorous control in order to achieve to the desired objectives. In this paper, an optimal control policy applied to a batch methyl methacrylate polymerization reactor is presented. The proposed methodology determines the optimal time profile of reactor temperature; if the temperature is maintained along the calculated profiles, a polymer product with desired molecular weight distribution could be obtained at the pre-specified final monomer conversion rate. The good agreement with experimental results reveals that the described control procedure is suitable to ensure that the polymer product satisfies the specifications. © 2013 Elsevier B.V

Pilot-scale synthesis and rheological assessment of poly(methyl methacrylate) polymers: Perspectives for medical application

This work presents the rheological assessment of poly(methyl methacrylate) (PMMA) polymers synthesized in a dedicated pilot-scale plant. This material is to be used for the construction of scaffolds via Rapid Prototyping (RP). The polymers were prepared to match the physical and biological properties required for medical applications. Differential Scanning Calorimetry (DSC) and Size Exclusion Chromatography (SEC) measurements verified that the synthesized polymers were atactic, amorphous and linear in chains. Rheological properties such as viscosity, storage and loss modulus, beyond the loss factor, and creep and recovery were measured in a plate–plate sensor within the viscoelastic linear region. The results showed the relevant influence of the molecular weight on the viscosity and elasticity of the material, and how, as the molecular weight increases, the viscoelastic properties are getting closer to those of human bone. This article demonstrates that by using the implemented methodology it is possible to synthesize a polymer, with properties comparable to commercially-available PMMA

Cytotoxicity assessment of a poly(methyl methacrylate) synthesized for the direct fabrication of bone tissues

A cytotoxicity study is performed on a poly(methyl methacrylate) polymer (PMMA) to be used for the fabrication of bone tissue by Rapid Prototyping (RP). The solution polymerization is conducted in a pilot plant reactor using more appropriated reagents in consideration of the medical application. Moreover, the polymer is efficiently handled to avoid the side effect of the monomer, reducing the concentration of this specie to 287,731 μg MMA/kg PMMA. The cytotoxicity of the polymer is determined through growth monitoring, adherence and morphology of L-929 cells. Additionally, MTT and LIVE/DEAD tests are performed. The results showed continuous and progressive growth of the cells on the surface of the specimens. Moreover, the material did not influence on the viability of mesenchymal cells and inverted fluorescence microscopy images showed a polyanionic dye calcein well retained in the cells in contact with the PMMA as well as the negative control after 72 hours. Thus, the polymer was efficiently synthesized and handled for the expected demands