A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.

RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.

CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

« Good night, sleep tight, don’t let the bed bugs bite» : exploring the mental health fallout of urban bed bug infestation in Montréal, Québec

Problématique : La littérature scientifique ne contient actuellement aucune étude épidémiologique portant sur la relation entre l’exposition à une infestation de punaises de lit (Cimex lectularis) et la santé mentale. L’objectif de cette étude est d’explorer la relation entre le statut d’exposition aux punaises de lit et des mesures de dépression, anxiété et perturbation du sommeil. Méthodes : Cette recherche est une étude transversale basée sur une analyse secondaire des données provenant de N=91 adultes locataires de logements insalubres qui ont répondu à un questionnaire de santé au moment d’interventions médico-environnementales menées par la direction de santé publique de Montréal entre janvier et juin 2010. Le questionnaire de santé inclut le « Questionnaire de santé du patient (QSP-9) », qui est un outil mesurant les symptômes associés à la dépression, l’outil de dépistage d’anxiété généralisée (GAD-7) et les items 1-18 de l’indice de la qualité du sommeil de Pittsburgh (PSQI). L’association entre une exposition autorapportée à une infestation de punaises de lit et le niveau de perturbation du sommeil selon la sous-échelle correspondante du PSQI, les symptômes dépressifs selon le QSP-9 et les symptômes anxieux selon le GAD-7, a été évaluée en utilisant une analyse de régression linéaire multivariée. Des données descriptives relatives aux troubles de sommeil autodéclarés et à des comportements reliés à un isolement social, dus à une exposition aux punaises de lit, sont aussi présentées. Résultats : L’échantillon comprenait 38 hommes et 53 femmes. Parmi les 91 participants, 49 adultes ont signalé une exposition aux punaises de lit et de ce nombre, 53,06% (26/49) ont déclaré des troubles de sommeil et 46,94% (23/49) des comportements d’isolement social, en raison de l’exposition. Les adultes exposés à des punaises de lit ont obtenu des résultats significativement plus élevés sur le QSP-9 (p=0,025), le GAD-7 (p=0,026) et sur la sous-échelle mesurant la perturbation du sommeil (p=0,003) comparativement à ceux qui n’étaient pas exposés. Conclusions : Cette première étude exploratoire met en évidence une association significative entre l’état d’exposition aux punaises de lit et des troubles de sommeil, ainsi que des symptômes anxieux et dépressifs, indiquant que ceux qui sont exposés aux punaises de lit représentent un groupe possiblement à risque de développer des problèmes de santé mentale. Ces résultats viennent en appui aux initiatives des décideurs pour organiser des efforts coordonnés d’éradication au niveau des villes et des provinces.

Let's talk about sex(ism): cross-national perspectives on women partners’ narratives on equality and sexism at work in Germany and the UK

While the accounting academy has contributed in important ways to furthering our understanding of the relative absence of women in top positions in Professional Service Firms, in-depth empirical research that focuses specifically on sexism is rare, especially so from a cross-national perspective. Drawing on sixty interviews with women partners in public accountancy firms in Germany and the United Kingdom, this article examines how women partners talk about sexism and equal opportunities in the accountancy profession and considers how these narratives are patterned cross-nationally. Employing cultural theory, this study explores how elite women discursively relate to sexism and equal opportunities through their career histories and demonstrates the complex interrelation between the context in which these narratives are produced and the past and present positions of the respondents. Interestingly, it was the German respondents who drew on problematic notions of ‘choice’ and responsibility, where it was upon women to make a choice between their careers and home lives, while this decision-making process was not expected from men. This was in contrast to the accounts of the UK participants who, although also unveiling tensions in their talk, were more inclined to acknowledge continuing structural constraints.

Let's kill the 'C' word: notions of authentic and synthetic in the teaching of journalism

One of the less desirable aftermaths of the so-called "Media Wars" - the intellectual debate over the role of cultural studies in the study of journalism - was reinforcement for some of the notion of fortress journalism: a Windschuttlian purist version of the Empire. This paper uses the alleged confrontation between the forces of that Empire (that is, proponents of pure journalism) and the forces of the Dark (that is, critics from a cultural studies tradition) as a means of examining the teaching of journalism in universities. The paper questions how the discipline of journalism should interface with others within the academy and asks what notion of journalism underpins our pedagogy and our epistemology. It is argued that it is time to discard an outdated craft model with its associations of authenticity and replace it with a model of synthetic professionalism.

Status of tailings dumps : let D5s go working in the past?

It was decided in the De Beers v Ataqua Mining (Pty) Ltd that ''tailings dumps'' created by mining companies before the Mineral and Petroleum Resources Development Act, 28 of 2002 ("the MPRDA") came into operation are not governed by its provisions because such dumps are not "residue stockpiles" or "residue deposits" for purposes of the MPRDA. Ownership of tailings dumps is determined by the common law principles of accession. Ownership of a movable dump has to be transferred by one of the recognised forms of delivery of movables. Processing of these dumps will, however, still be subject to compliance with South African environmental, health and safety laws in general. It is submitted that mine dumps or tailings dumps created upon the exercise of "old order mining rights" before the commencement of the MPRDA and even after commencement of the MPRDA until eventual termination of the "old order mining rights" are not subject to the extensive, mining, environmental, empowerment provisions of the MPRDA. Termination of "old order mining rights" takes place upon: (i) refusal of an application for conversion of a mining right during (or even after) the period of transition, (ii) conversion into and registration of new order mining rights during (or even after) the period of transition or (iii) termination of unconverted "old order mining rights" on 30 April 2009. To the extent that this decision has made it possible to embark on a shorter and less cumbersome route in the reprocessing and eventual disappearance of most tailings dumps, it is to be welcomed from an economical, environmental, job creation and aesthetic perspective. Proposed amendments to the MPRDA to undo the impact of the De Beers decision should be carefully considered against these mentioned benefits and a possible finding that it may amount to an expropriation without compensation.

Lo sviluppo dell'allevamento in Emilia-Romagna Aspetti economici e implicazioni sociali nella gestione della risorsa animale durante l’età del Bronzo

Il dibattito sullo sviluppo delle culture dell’età del Bronzo nel territorio dell’Emilia-Romagna sta portando una rinnovata attenzione sull’area romagnola. Le indagini si sono concentrate sull’area compresa tra il fiume Panaro e il Mare Adriatico, riconoscibile nell’odierna Romagna ed in parte della bassa pianura emiliana. Si trattava un territorio strategico, un vero e proprio crocevia socio-economico fra la cultura terramaricola e quelle centro italiche di Grotta Nuova. La presente ricerca di dottorato ha portato alla ricostruzione dei sistemi di gestione e di sfruttamento delle risorse animali in Emilia-Romagna durante l’Età del Bronzo, con particolare attenzione alla definizione della capacità portante ambientale dei diversi territori indagati e delle loro modalità di sfruttamento in relazione alla razionalizzazione della pratiche di allevamento. Sono state studiate in dettaglio le filiere di trasformazione dei prodotti animali primari e secondari definendo, quindi, i caratteri delle paleoeconomie locali nel processo di evoluzione della Romagna durante l’età del Bronzo. La ricerca si è basata sullo studio archeozoologico completo su 13 siti recentemente indagati, distribuiti nelle provincie di: Bologna, Ferrara, Ravenna, Forlì/Cesena e Rimini, e su una revisione completa delle evidenze archeozoologiche prodotte da studi pregressi. Le analisi non si sono limitate al riconoscimento delle specie, ma hanno teso all’individuazione ed alla valutazione di parametri complessi per ricostruire le strategie di abbattimento e le tecniche di sfruttamento e macellazione dei diversi gruppi animali. E’ stato possibile, quindi, valutare il peso ecologico di mandrie e greggi sul territorio e l’impatto economico ed ecologico di un allevamento sempre più sistematico e razionale, sia dal punto di vista dell’organizzazione territoriale degli insediamenti, sia per quanto riguarda le ripercussioni sulla gestione delle risorse agricole ed ambientali in generale.

Let the Sun Shine In: Open Government and the Public's Right-to-Know in Montana's 1972 Constitution - Mike Meloy "In the Crucible of Change"

Abstract to be posted.

Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer

Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.

The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells

The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.

Evaluation of Polymer Gel Dosimeters for Measurements of Dose and LET in Proton Beams

This project assessed the effectiveness of polymer gel dosimeters as tools for measuring the dose deposited by and LET of a proton beam. A total of three BANG® dosimeter formulations were evaluated: BANG®-3-Pro-2 BANGkits™ for dose measurement and two BANG®-3 variants, the LET-Baseline and LET-Meter dosimeters, for LET measurement. All dosimeters were read out using an OCT scanner. The basic characteristics of the BANGkits™ were assessed in a series of photon and electron irradiations. The dose-response relationship was found to be sigmoidal with a threshold for response of approximately 15 cGy. The active region of the dosimeter, the volume in which dosimeter response is not inhibited by oxygen, was found to make up roughly one fourth of the total dosimeter volume. Delivering a dose across multiple fractions was found to yield a greater response than delivering the same dose in a single irradiation. The dosimeter was found to accurately measure a dose distribution produced by overlapping photon fields, yielding gamma pass rates of 95.4% and 93.1% from two planar gamma analyses. Proton irradiations were performed for measurements of proton dose and LET. Initial irradiations performed through the side of a dosimeter led to OCT artifacts. Gamma pass rates of 85.7% and 89.9% were observed in two planar gamma analyses. In irradiations performed through the base of a dosimeter, gel response was found to increase with height in the dosimeter, even in areas of constant dose. After a correction was applied, gamma pass rates of 94.6% and 99.3% were observed in two planar gamma analyses. Absolute dose measurements were substantially higher (33%-100%) than the delivered doses for proton irradiations. Issues encountered while calibrating the LET-Meter gel restricted analysis of the LET measurement data to the SOBP of a proton beam. LET-Meter overresponse was found to increase linearly with track-average LET across the LET range that could be investigated (1.5 keV/micron – 3.5 keV/micron).

Let's Gain More Confidence Of Clinicians With Our Colorful Contours: Blood Flow Simulation In Arteries Using Abaqus & STAR-CCM+

The objective of the current work is to present the results of several numerical simulations of pulsatile blood flow in healthy and diseased arteries and compare with clinical expectations. Different realistic and physiological aspects such as blood flow interaction with arterial walls, effect of heart movement, cardiovascular autoregulation, arterial walls' hyperelasticity and cardiovascular disorders have been incorporated in the models thanks to a direct coupling of Abaqus and STAR-CCM+. Comparisons of implicit and explicit coupling methods in cardiovascular simulations have been discussed. An in-house methodology combined with explicit FSI coupling has reduced considerably calculation time while the simulations stay realistic and reliable for clinicians

Corporate Taxation in Europe: Let's get it together! CEPS Commentary, 16 February 2015

More comprehensive cooperation in corporate taxation at European level could significantly advance the region’s socio-economic prosperity, but its potential contribution is unfortunately overlooked in the current search for growth and job creation. Lucrative tax niches established in some member states and the fear of losing fiscal autonomy prevent several countries from accepting the move towards an EU single market for taxation. If ‘Lux leaks’ and other revelations of tax avoidance and evasion can succeed in changing the dominant attitudes in the European tax debate, this commentary outlines the steps that need to be taken to allow tax policy to play a positive role in promoting economic prosperity.