Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer

The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis.

Inhibition of protease-ENaC signaling improves mucociliary function in cystic fibrosis airways

Rationale: In cystic fibrosis (CF) a reduction in airway surface liquid (ASL) height<br/>compromises mucociliary clearance, favoring mucus plugging and chronic bacterial infection. Inhibitors of ENaC have therapeutic potential in CF airways to reduce the hyperstimulated sodium and fluid absorption to levels which can restore airways hydration.<br/><br/>Objectives: To determine whether a novel compound (QUB-TL1) designed to inhibit protease/ENaC signaling in CF airways restores ASL volume and mucociliary function.<br/><br/>Methods: Protease activity was measured using fluorogenic activity assays. Differentiated primary airway epithelial cell cultures (F508del homozygotes) were used to determined ENaC activity (Ussing chamber recordings), ASL height (confocal microscopy) and mucociliary function (by tracking the surface flow of apically applied microbeads). Cell toxicity was measured by LDH assay.<br/><br/>Measurements and Results: QUB-TL1 inhibits extracellularly-located CAPs, including prostasin, matriptase and furin, the activities of which are observed at excessive levels at the apical surface of CF airway epithelial cells (AECs). QUB-TL1-mediated CAPs inhibition results in diminished ENaC-mediated Na+ absorption in CF AECs due to internalization of a prominent pool of cleaved (active) ENaCγ from the cell surface. Importantly, diminished ENaC activity correlates with improved airway hydration status and mucociliary clearance. We further demonstrate QUB-TL1-mediated furin inhibition, which is in contrast to other serine protease inhibitors (camostat mesylate and aprotinin), affords protection against neutrophil elastase-mediated ENaC activation and Pseudomonas aeruginosa exotoxin A induced cell death.<br/><br/>Conclusions: QUB-TL1 corrects aberrant CAP activities providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CFTR mutation.<br/>

Melt processing and properties of linear low density polyethylene-graphene nanoplatelet composites

Composites of Linear Low Density Polyethylene (LLDPE) and Graphene Nanoplatelets (GNPs) were processed using a twin screw extruder under different extrusion conditions. The effects of screw speed, feeder speed and GNP content on the electrical, thermal and mechanical properties of composites were investigated. The inclusion of GNPs in the matrix improved the thermal stability and conductivity by 2.7% and 43%, respectively. The electrical conductivity improved from 10−11 to 10−5 S/m at 150 rpm due to the high thermal stability of the GNPs and the formation of phonon and charge carrier networks in the polymer matrix. Higher extruder speeds result in a better distribution of the GNPs in the matrix and a significant increase in thermal stability and thermal conductivity. However, this effect is not significant for the electrical conductivity and tensile strength. The addition of GNPs increased the viscosity of the polymer, which will lead to higher processing power requirements. Increasing the extruder speed led to a reduction in viscosity, which is due to thermal degradation and/or chain scission. Thus, while high speeds result in better dispersions, the speed needs to be optimized to prevent detrimental impacts on the properties.

Sistemas de gestión ambiental

analizar el concepto de un Sistema de Gestión Ambiental (S.G.A), sus elementos y características, además de sus beneficios y aplicabilidad en empresas nacionales e internacionales.

Estructura organizacional del área de responsabilidad social de Pacific E&P

Este artículo tiene como objetivo describir la estructura del área de Responsabilidad Social de Pacific E&P, mediante un proceso que explique el funcionamiento y desarrollo de la estructura de RSE. Este trabajo se desarrolla bajo una matriz estratégica la cual incluye variables como: evolución del área (historia), plataforma estratégica (plan de acción que desarrolla una ventaja competitiva de la empresa), división del trabajo (Fragmentación de trabajo y especialización entre sus fuerzas laborales) y por último la coordinación del trabajo (sincronización de fuerzas laborales). Los resultados que se obtienen de este estudio mostrarán las distintas unidades de trabajo de la organización y la forma de trabajar de la misma, bajo el marco de la Responsabilidad Social Corporativa.

Geology of the Lost Creek-Modesty Creek Area Deerlodge County, Montana

In 1915 the United States Geological Survey published a folio by Calkins and Emmons on the geology of the Philipsburg Quadrangle, which ad­joins the area now under study to the west. Geology of this portion of Montana had not been mapped previously; consequently the purpose of this thesis is to make a geological reconnais­sance of the stratigraphy and structure of the area.

Analysis of masked mutations in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease characterized by the development of hundreds of adenomatous polyps of the colorectum. Approximately 80% of FAP patients can be shown to have truncating mutations of the APC gene. To determine the cause of FAP in the other 20% of patients, MAMA (monoallelic mutation analysis) was used to independently examine the status of each of the two APC alleles. Seven of nine patients analyzed were found to have significantly reduced expression from one of their two alleles whereas two patients were found to have full-length expression from both alleles. We conclude that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FAP patients argues strongly against the requirement for dominant negative effects of APC mutations. The results also suggest that there may be at least one additional gene, besides APC, that can give rise to FAP.

The manufacture of concrete blocks and their use in building construction /

Includes index.

Principles of woollen spinning,

Mode of access: Internet.

The Motor vehicle act and the Highway travel act /

Mode of access: Internet.

An evaluation of the significance and use of the K factor of yarn strength and its relation to raw-cotton quality.

Mode of access: Internet.

1921 annotations to Corpus juris : 1-22 C.J. ; and Workmen's compensation acts third volume permanent cyc annotations : contains annotations from all cases decided since the original treatises were written ; also errata corrected, new principles announced, etc. /

On cover: Annotations, Corpus juris-Cyc service. Permanent volume. 1921. C.J., A-Ev ; Cyc, Ex-Z.

Journal of John James Audubon made while obtaining subscriptions to his "Birds of America" 1840-1843,

An exact copy, except for a few corrections, of the original manuscript which is in the Museum of Comparative Zoology of Harvard University; now published for the first time.

Journal of John James Audubon made while obtaining subscriptions to his "Birds of America" 1840-1843,

An exact copy, except for a few corrections, of the original manuscript which is in the Museum of comparative zoology of Harvard university; now published for the first time.