Criminal but Beautiful: A Study on Graffiti and the Role of Value Judgments and Context in Perceiving Disorder

Criminal Justice: Legitimacy, accountability, and effectivit

De digitale schandpaal: opsporingsberichtgeving in een gedigitaliseerde samenleving

Criminal Justice: Legitimacy, accountability, and effectivit

Effectiveness and Preclinical Safety Profile of Doxycycline to Be Used “Off-Label” to Induce Therapeutic Transgene Expression in a Phase I Clinical Trial for Glioma

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults; it carries a dismal prognosis despite improvements in standard of care. We developed a combined gene therapy strategy using (1) herpes simplex type 1-thymidine kinase in conjunction with the cytotoxic prodrug ganciclovir to kill actively proliferating tumor cells and (2) doxycycline (DOX)-inducible Fms-like tyrosine kinase 3 ligand (Flt3L), an immune stimulatory molecule that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we examined the efficacy and safety of this approach (Muhammad et al., 2010, 2012). In the present article, we investigated the efficacy and safety of the ?off-label? use of the antibiotic DOX to turn on the high-capacity adenoviral vector (HC-Ad) encoding therapeutic Flt3L expression. DOX-inducible Flt3L expression in male Lewis rats was assessed using DOX doses of 30.8?mg/kg/day (low-DOX) or 46.2?mg/kg/day (high-DOX), which are allometrically equivalent (Voisin et al., 1990) to the human doses that are recommended for the treatment of infections: 200 or 300?mg/day. Naïve rats were intracranially injected with 1?109 viral particles of HC-Ad-TetOn-Flt3L, and expression of the therapeutic transgene, that is, Flt3L, was assessed using immunohistochemistry in brain sections after 2 weeks of DOX administration via oral gavage. The results show robust expression of Flt3L in the rat brain parenchyma in areas near the injection site in both the low-DOX and the high-DOX groups, suggesting that Flt3L will be expressed in human glioma patients at a DOX dose of 200 or 300?mg/day. These doses have been approved by the U.S. Food and Drug Administration to treat infections in humans and would thus be considered safe for an off-label use to treat GBM patients undergoing HC-Ad-mediated gene therapy in a phase I clinical trial.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140104/1/humc.2013.139.pd

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

Glioblastoma multiforme (GBM) is the most commonly occurring primary brain cancer in adults, in whom its highly infiltrative cells prevent total surgical resection, often leading to tumor recurrence and patient death. Our group has discovered a gene therapy approach for GBM that utilizes high-capacity ?gutless? adenoviral vectors encoding regulatable therapeutic transgenes. The herpes simplex type 1-thymidine kinase (TK) actively kills dividing tumor cells in the brain when in the presence of the prodrug, ganciclovir (GCV), whereas the FMS-like tyrosine kinase 3 ligand (Flt3L) is an immune-stimulatory molecule under tight regulation by a tetracycline-inducible ?Tet-On? activation system that induces anti-GBM immunity. As a prelude to a phase I clinical trial, we evaluated the safety and efficacy of Food and Drug Administration (FDA)?approved doses of the tetracycline doxycycline (DOX) allometrically scaled for rats. DOX initiates the expression of Flt3L, which has been shown to recruit dendritic cells to the brain tumor microenvironment?an integral first step in the development of antitumor immunity. The data revealed a highly safe profile surrounding these human-equivalent doses of DOX under an identical therapeutic window as proposed in the clinical trial. This was confirmed through a neuropathological analysis, liver and kidney histopathology, detection of neutralizing antibodies, and systemic toxicities in the blood. Interestingly, we observed a significant survival advantage in rats with GBM receiving the 300?mg/day equivalent dosage of DOX versus the 200?mg/day equivalent. Additionally, rats rejected ?recurrent? brain tumor threats implanted 90 days after their primary brain tumors. We also show that DOX detection within the plasma can be an indicator of optimal dosing of DOX to attain therapeutic levels. This work has significant clinical relevance for an ongoing phase I clinical trial in humans with primary GBM and for other therapeutic approaches using Tet-On transactivation system in humans.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140103/1/hgtb.2015.168.pd

Social security or insecurity? The experience of welfare participation by financially vulnerable households in the Netherlands

Social welfare aims to support financially vulnerable households by protecting them from financial shocks and providing them with a basic standard of living. Many eligible households, however, do not take up social welfare. We present the results of in-depth interviews with 31 members of financially vulnerable households in two large Dutch cities about their experiences with welfare. We examined the role of money in their lives, what inhibited them from taking up social welfare, and how they sought support. For many interviewed households, money was a source of stress. The fear of reclaims and mistrust of government institutions were the main inhibitors to participating in welfare programs. Whereas the experience of shame and stigma were substantial inhibitors for claiming local welfare benefits, they were not for participating in national welfare programs. Formal and informal help promoted welfare participation, but many participants lacked access to both. We discuss policies that could decrease the perceived uncertainty of benefits receipt and give directions for future research.Social decision makin

Report of the 2011-2012 Standing Committee on Advocacy: The Relevance of Excellent Research: Strategies for Impacting Public Policy

According to the Bylaws of the American Association of Colleges of Pharmacy (AACP), the Advocacy Committee

A Preparative Method for the Isolation and Fractionation of Dissolved Organic Acids from Bitumen-influenced Waters

The surface mining of oil sands north of Fort McMurray, Alberta produces considerable tailings waste that is stored in large tailings ponds on industrial lease sites. Viable strategies for the detoxification of oil sands process affected water (OSPW) are under investigation. In order to assess the toxic potential of the suite of dissolved organics in OSPW, a method for their extraction and fractionation was developed using solid phase extraction. The method successfully isolated organic compounds from 180 L of an aged OSPW source. Using acidic- or alkaline-conditioned non-polar ENV+ resin and soxhlet extraction with ethyl acetate and methanol, three fractions (F1–F3) were generated. Chemical characterization of the generated fractions included infusion to electrospray ionization ultrahigh-resolution mass spectrometry (ESI-UHRMS), liquid chromatography quadrupole time-of-flight mass spectrometry, gas chromatography triple quadrupole time-of-flight mass spectrometry, and synchronous fluorescence spectroscopy (SFS). Additionally, ESI-UHRMS class distribution data and SFS identified an increased degree of oxygenation and aromaticity, associated with increased polarity. Method validation, which included method and matrix spikes with surrogate and labelled organic mono carboxylic acid standards, confirmed separation according to acidity and polarity with generally good recoveries (average 76%). Because this method is capable of extracting large sample volumes, it is amenable to thorough chemical characterization and toxicological assessments with a suite of bioassays. As such, this protocol will facilitate effects-directed analysis of toxic components within bitumen-influenced waters from a variety of sources

The diagnostic MRCP examination: overcoming technical challenges to ensure clinical success

The magnetic resonance cholangiopancreatography (MRCP) examination has all but replaced the diagnostic endoscopic retrograde cholangiopancreatography (ERCP) examination for imaging the biliary tree and pancreatic ducts in many practical aspects of the clinical setting. Despite this increase in popularity, many magnetic resonance imaging (MRI) radiographers still find aspects of the MRCP examination quite challenging. The aim of this tutorial paper is to provide useful technical advice on how to overcome such perceived challenges and thus produce a successful diagnostic MRCP examination. This paper will be of interest to novice MRI radiographers who are at the beginning of their learning curve in MRCP examination. Other MRI radiographers who are interested in practical tips for protocol variations may also find the paper useful

Een klacht is een gratis advies

Klachtbehandeling wordt door de politie gezien als een mogelijkheid om samen met de burger de kwaliteit van het politieoptreden te verbeteren. In dit onderzoek is gekeken welke andere kanalen, naast de klachtenregeling, de politie zou kunnen gebruiken om ‘oog en oor’ te hebben voor de samenleving en een realistisch beeld te krijgen van uitingen van ongenoegen van burgers. Ook is onderzocht hoe de politie op meerdere niveaus in de organisatie kan leren van klachten. Een belangrijke bevinding is dat de klachtenregeling zich richt op een specifieke categorie klachten en bij voorbaat diverse andere categorieën van klachten uitsluit. Verder blijkt dat via de klachtenregeling van de politie op individueel niveau vrij systematisch van klachten geleerd wordt, maar het is belangrijk dat lessen ook op andere niveaus (groep, organisatie) hun weerslag gaan vinden. Burgers hebben meer en ook andere klachten dan die voorzien zijn in de klachtenregeling en zij uiten die klachten via andere kanalen. De sociale media zijn een rijke bron voor het vinden van klachten over de politie en ook het directe contact tussen burgers en agenten is een belangrijk kanaal om het ongenoegen van burgers te peilen. Daarnaast beschikken intermediërende organisaties over een rijke schat aan informatie over wat leeft onder burgers. Een conclusie van dit onderzoek is dat de politie deze drie kanalen systematisch kan gebruiken als zij meer vormen van ongenoegen van burgers wil waarnemen en tot leermomenten wil omzetten. Betekent dit dat de politie op iedere tweet moet reageren en ieder ongenoegen in actie moet omzetten? Dit zou volstrekt onmogelijk zijn. Het einddoel zou moeten zijn dat klachten systematisch gebruikt worden als ‘gratis advies’ van de burger om de politiezorg constant te verbeteren. Dit boek kan hier een bijdrage aan leveren door inzicht te bieden in de mogelijkheden