Selecting highly affine and well-expressed TCRs for gene therapy of melanoma.

A recent phase 1 trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T-cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared with results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition. We therefore sought to develop standardized procedures for the selection of well-expressed, high-affinity, and safe human TCRs. Here we show that TCR surface expression can be improved by modification of TCR alpha and beta sequences and that such improvement has a marked effect on the in vivo function of TCR gene-modified T cells. From a panel of human, melanoma-reactive TCRs we subsequently selected the TCR with the highest affinity. Furthermore, a generally applicable assay was used to assess the lack of alloreactivity of this TCR against a large series of common human leukocyte antigen alleles. The procedures described in this study should be of general value for the selection of well- and stably expressed, high-affinity, and safe human TCRs for subsequent clinical testing.

Development of Non-Petroleum-Based Binders for Use in Flexible Pavements – Phase II, TR-650, 2015

Bio-binders can be utilized as asphalt modifiers, extenders, and replacements for conventional asphalt in bituminous binders. From the rheology results of Phase I of this project, it was found that the bio-binders tested had good performance, similar to conventional asphalt, except at low temperatures. Phase II of this project addresses this shortcoming and evaluates the Superpave performance of laboratory mixes produced with the enhanced bio-binders. The main objective of this research was to develop a bio-binder capable of replacing conventional asphalt in flexible pavements by incorporating ground tire rubber (GTR) into bio-oil derived from fast pyrolysis of agriculture and forestry residues. The chemical compatibility of the new bio-binder with GTR was assessed, and the low-temperature performance of the bio-binders was enhanced by the use of GTR. The newly developed binder, which consisted of 80 percent conventional binder and 20 percent rubber-modified bio-oil (85 percent bio-oil with 15 percent GTR), was used to produce mixes at two different air void contents, 4 and 7 percent. The laboratory performance test results showed that the performance of the newly developed bio-binder mixes is as good as or better than conventional asphalt mixes for fatigue cracking, rutting resistance, moisture sensitivity, and low-temperature cracking. These results need to be validated in field projects in order to demonstrate adequate performance for this innovative and sustainable technology for flexible pavements.

Improved three-dimensional free-breathing coronary magnetic resonance angiography using gadocoletic acid (B-22956) for intravascular contrast enhancement.

PURPOSE: To evaluate gadocoletic acid (B-22956), a gadolinium-based paramagnetic blood pool agent, for contrast-enhanced coronary magnetic resonance angiography (MRA) in a Phase I clinical trial, and to compare the findings with those obtained using a standard noncontrast T2 preparation sequence. MATERIALS AND METHODS: The left coronary system was imaged in 12 healthy volunteers before B-22956 application and 5 (N = 11) and 45 (N = 7) minutes after application of 0.075 mmol/kg of body weight (BW) of B-22956. Additionally, imaging of the right coronary system was performed 23 minutes after B-22956 application (N = 6). A three-dimensional gradient echo sequence with T2 preparation (precontrast) or inversion recovery (IR) pulse (postcontrast) with real-time navigator correction was used. Assessment of the left and right coronary systems was performed qualitatively (a 4-point visual score for image quality) and quantitatively in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel sharpness, visible vessel length, maximal luminal diameter, and the number of visible side branches. RESULTS: Significant (P < 0.01) increases in SNR (+42%) and CNR (+86%) were noted five minutes after B-22956 application, compared to precontrast T2 preparation values. A significant increase in CNR (+40%, P < 0.05) was also noted 45 minutes postcontrast. Vessels (left anterior descending artery (LAD), left coronary circumflex (LCx), and right coronary artery (RCA)) were also significantly (P < 0.05) sharper on postcontrast images. Significant increases in vessel length were noted for the LAD (P < 0.05) and LCx and RCA (both P < 0.01), while significantly more side branches were noted for the LAD and RCA (both P < 0.05) when compared to precontrast T2 preparation values. CONCLUSION: The use of the intravascular contrast agent B-22956 substantially improves both objective and subjective parameters of image quality on high-resolution three-dimensional coronary MRA. The increase in SNR, CNR, and vessel sharpness minimizes current limitations of coronary artery visualization with high-resolution coronary MRA.

Planning, Developing, and Implementing the Iowa Pavement Marking Management System (IPMMS): Phases I and II, 2006

With an annual pavement marking program of approximately $2 million and another $750 thousand invested in maintenance of durable markings each year, the Iowa DOT is seeking every opportunity to provide all-year markings staying in acceptable condition under all weather conditions. The goal of this study is to analyze existing pavement marking practices and to develop a prototype Pavement Marking Management System (PMMS). This report documents the first two phases of a three-phase research project. Phase I includes an overview of the Iowa DOT’s existing practices and a literature review regarding pavement marking practices in other states. Based on this information, a work plan was developed for Phases II and III of this study. Phase II organized the key components necessary to develop a prototype PMMS for the Iowa DOT. The two primary components are (1) performance/life cycle curves for pavement marking products, and (2) an application matrix tailored to the pavement marking products and roadway and environmental conditions faced by the Iowa DOT. Both components will continue to be refined and tailored to Iowa materials and conditions as more performance data becomes available.

Material and Construction Optimization for Prevention of Premature Pavement Distress in PCC Pavements, Phase III Final Report, 2008

Mixture materials, mix design, and pavement construction are not isolated steps in the concrete paving process. Each affects the other in ways that determine overall pavement quality and long-term performance. However, equipment and procedures commonly used to test concrete materials and concrete pavements have not changed in decades, leaving gaps in our ability to understand and control the factors that determine concrete durability. The concrete paving community needs tests that will adequately characterize the materials, predict interactions, and monitor the properties of the concrete. The overall objectives of this study are (1) to evaluate conventional and new methods for testing concrete and concrete materials to prevent material and construction problems that could lead to premature concrete pavement distress and (2) to examine and refine a suite of tests that can accurately evaluate concrete pavement properties. The project included three phases. In Phase I, the research team contacted each of 16 participating states to gather information about concrete and concrete material tests. A preliminary suite of tests to ensure long-term pavement performance was developed. The tests were selected to provide useful and easy-to-interpret results that can be performed reasonably and routinely in terms of time, expertise, training, and cost. The tests examine concrete pavement properties in five focal areas critical to the long life and durability of concrete pavements: (1) workability, (2) strength development, (3) air system, (4) permeability, and (5) shrinkage. The tests were relevant at three stages in the concrete paving process: mix design, preconstruction verification, and construction quality control. In Phase II, the research team conducted field testing in each participating state to evaluate the preliminary suite of tests and demonstrate the testing technologies and procedures using local materials. A Mobile Concrete Research Lab was designed and equipped to facilitate the demonstrations. This report documents the results of the 16 state projects. Phase III refined and finalized lab and field tests based on state project test data. The results of the overall project are detailed herein. The final suite of tests is detailed in the accompanying testing guide.

Highway Maintenance Concept Vehicle Final Report: Phase Three, 2001

This report documents Phase III of a four-phase project. The goals of the project are to study the feasibility of using advanced technology from other industries to improve he efficiency and safety of winter highway maintenance vehicle operations, and to provide travelers with the level of service defined by policy during the winter season at the least cost to the taxpayers. The results of the first phase of the research were documented in the Concept Highway Maintenance Vehicle Final Report: Phase One dated April 1997, which describes the desirable functions of a concept maintenance vehicle and evaluates its feasibility. Phase I concluded by establishing the technologies that would be assembled and tested on the prototype vehicles in Phase II. The primary goals of phase II were to install the selected technologies on the prototype winter maintenance vehicles and to conduct proof of concept in advance of field evaluations planned for Phase III. This Phase III final report documents the work completed since the end of Phase II. During this time period, the Phase III work plan was completed and the redesigned friction meter was field tested. A vendor meeting was held to discuss future private sector participation and the new design for the Iowa vehicle. In addition, weather and roadway condition data were collected from the roadway weather information systems at selected sites in Iowa and Minnesota, for comparison to the vehicles' onboard temperature sensors. Furthermore, the team received new technology, such as the mobile Frensor unit, for bench testing and later installation.

Clinical studies of experimental vaccines.

PURPOSE OF REVIEW: The scope of this review is to provide the current status of HIV vaccine clinical development. A series of issues regarding the type of immune response stimulated by the candidate vaccines in the pipeline, the advances in the immune correlates of protection, the need for an effective decision-making process for selection of candidate vaccines into further clinical development and the rationale for clinical trials will also be discussed. RECENT FINDINGS: Efforts in the development of HIV vaccines inducing broad neutralizing antibodies have failed so far. The current pipeline is predominantly composed of candidate vaccines designed to induce cellular immunity and particularly T-cell response. For these reasons, these candidate vaccines have been termed 'T-cell vaccines'. A large number of candidate vaccines or vaccine combinations have entered phase I-II clinical trials in 2005. Furthermore, an adenovirus vector-based vaccine has entered proof-of-concept efficacy trial and a canarypox vector in combination with a protein-based vaccine is currently being evaluated in phase III clinical trials. T-cell vaccines have been shown to be safe and the most recent generation of these vaccines also has substantial immunogenicity. SUMMARY: Only clinical trials can provide the definitive answer to immune correlates of protection and vaccine efficacy.

On-line desorption of dried blood spots coupled to hydrophilic interaction/reversed-phase LC/MS/MS system for the simultaneous analysis of drugs and their polar metabolites.

An assay for the simultaneous analysis of pharmaceutical compounds and their metabolites from micro-whole blood samples (i.e. 5 microL) was developed using an on-line dried blood spot (on-line DBS) device coupled with hydrophilic interaction/reversed-phase (HILIC/RP) LC/MS/MS. Filter paper is directly integrated to the LC device using a homemade inox desorption cell. Without any sample pretreatment, analytes are desorbed from the paper towards an automated system of valves linking a zwitterionic-HILIC column to an RP C18 column. In the same run, the polar fraction is separated by the zwitterionic-HILIC column while the non-polar fraction is eluted on the RP C18. Both fractions are detected by IT-MS operating in full scan mode for the survey scan and in product ion mode for the dependant scan using an ESI source. The procedure was evaluated by the simultaneous qualitative analysis of four probes and their relative phase I and II metabolites spiked in whole blood. In addition, the method was successfully applied to the in vivo monitoring of buprenorphine metabolism after the administration of an intraperitoneal injection of 30 mg/kg on adult female Wistar rat.

Concept Highway Maintenance Vehicle, Final Report, Phase One, 1997

The state Departments of Transportation (DOTs) of Iowa, Michigan, and Minnesota formed a consortium to define and develop the next generation highway maintenance vehicle. The Center for Transportation Research and Education of Iowa State University provided staff support to the concept highway maintenance vehicle project, which focused on winter maintenance activities. Phase I of the three-phase project focused on describing the desirable functions of a concept maintenance vehicle. Phase II will include the development, operation, and evaluation of prototype winter maintenance vehicles. Phase III is envisioned to be a comprehensive fleet evaluation of prototype winter maintenance vehicles. This report covers the activities of Phase I. Phase I included conducting a literature review of materials related to winter highway maintenance activities, identifying ideal capabilities of a winter maintenance vehicle, inviting private sector equipment and technology providers to join the project and commit equipment and expertise for Phase II, and determining the specific equipment and technology to be included on the three prototype vehicles for the winter of 1996-1997. Phase I concluded by establishing that assembling the three prototype vehicles would be beneficial to the project and to the three state DOTs.

Access Management Research and Awareness Program : Phase IV, 1999

Access management involves balancing the dual roles that roadways must play - through travel and access to property and economic activity. When these roles are not in proper balance, the result is a roadway system that functions sub-optimally. Arterial routes that have a too high driveway density and provide overly extensive access to property have high crash rates and begin to suffer in terms of traffic operations. Such routes become congested, delays increase, and mean travel speeds decline. The Iowa access management research and awareness project has had four distinct phases. Phase I involved a detailed review of the extensive national access management literature so lessons learned elsewhere could be applied in Iowa. In Phase II original case study research was conducted in Iowa. Phase III of the project concentrated on outreach and education about access management. Phase IV of the Iowa access management project extended the work conducted during Phases II and III. The main work products for Phase IV were as follows: 1) three additional before and after case studies, illustrating the impacts of various access management treatments on traffic safety, traffic operations, and business vitality; 2) an access management handbook aimed primarily at local governments in Iowa; 3) a modular access management toolkit with brief descriptions of various access management treatments and considerations; and 4) an extensive outreach plan aimed at getting the results of Phases I through IV of the project out to diverse audiences in Iowa and elsewhere.

Comprehensive Statewide Transportation Model: Multimodal Investment Analysis Methodology Phase II, CTRE Project 02-126, 2001

The purposes of this report (Phase II of the project) are to specify in mathematical form the individual modules of the conceptual model developed in Phase I, to identify and evaluate sources of data for the model set, and to develop the transport networks necessary to support the models.

Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia.

Abstract Background: Tigecycline, an expanded broad-spectrum glycylcycline, exhibits in vitro activity against many common pathogens associated with community-acqui red pneumonia (CAP), as well as penetration into lung tissues that suggests effectiveness in ho spitalized CAP patients. The aim of the present study was to compare the efficacy and safety of intravenous (IV) tigecycline with IV levofloxacin in hospitalized adults with CAP. Methods: In this prospective, double-blin d, non-inferiority phase 3 trial, eligible patients with a clinical diagnosis of CAP supported by radiographic evidence were stratified by Fine Pneumonia Severity Index and randomized to tigecycline or levofloxacin for 7-14 days of therapy. Co-primary efficacy endpoints were clinical response in the clinically evaluable (CE) and clinical modified intent- to-treat (c-mITT) populations at te st-of-cure (Day 10-21 post-therapy). Results: Of the 428 patients who received at least on e dose of study drug, 79% had CAP of mild-moderate severity according to their Fine score. Clinical cure rates for the CE population were 88.9% for tigecycline and 85.3% for levofloxac in. Corresponding c-mITT population rates were 83.7% and 81.5%, respectively. Eradication rates for Streptococcus pneumoniae were 92% for tigecycline and 89% for levofloxac in. Nausea, vomiting, and diarrhoea were the most frequently reported adverse events. Rates of premature disc continuation of study drug or study withdrawal because of any adverse event were similar for both study drugs. Conclusion: These findings suggest that IV tigecycline is non-inferior to IV levofloxacin and is generally well-tolerated in the treatment of hospitalized adults with CAP.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Cognitively Empowering Internet-Based Patient Education for Ambulatory Orthopaedic Surgery Patients

Tiedollista voimavaraistumista tukeva internet-perustainen ohjaus päiväkirurgisille ortopedisille potilaille Tutkimuksen tarkoituksena oli kehittää tiedollista voimavaraistumista tukeva Internetperustainen potilasohjausohjelma sekä arvioida sitä. Tutkimusprosessi jaettiin kahteen vaiheeseen. Ensimmäisessä vaiheessa luotiin sisältö tiedollista voimavaraistumista tukevalle Internet-perustaiselle ohjaukselle päiväkirurgisia ortopedisia potilaita varten. Toisessa vaiheessa arvioitiin Internet-perustaisen ohjauksen (koeryhmä) hyväksyttävyyttä käyttäjien arvioimana ja ohjauksen tuloksia sekä verrattiin Internet-perustaisen ohjauksen (koeryhmä) tuloksia tiedollisesti voimavaraistumista tukevan sairaanhoitajan välittämään ohjauksen (kontrolliryhmä) tuloksiin. Tutkimuksen tavoitteena oli luoda uusi potilasohjausmuoto joka tarjoaa yksilöllisen, osallistavan ja aikaan ja paikkaan sitomattoman ohjauksen päiväkirurgiseen ortopediseen leikkaukseen tulevalle potilaalle. Tutkimuksen ensimmäisessä vaiheessa käytettiin kuvailevaa ja vertailevaa tutkimusmenetelmää (ennen ja jälkeen testaus). Tutkimukseen osallistui 120 päiväkirurgista ortopedista potilasta joiden tiedon odotuksia ja heille välitettyä tietoa tarkasteltiin. Tutkimuksen ensimmäisen vaiheen tuloksien ja aikaisemman voimavaraistumista käsittävän tiedon perusteella luotiin sisältö tiedollista voimavaraistumista tukevalle Internet-perustaiselle ohjaukselle. Sisältö rakentui voimavaraistavan tiedon kuudesta eri osa-alueesta. Tutkimuksen toisessa vaiheessa käytettiin randomoitua kokeellista tutkimusasetelmaa. Päiväkirurgiseen ortopediseen leikkaukseen tulevat potilaat randomoitiin koeryhmään (n=72) Internetperustaiseen ohjaukseen ja kontrolliryhmään (n=75) sairaanhoitajan välittämään ohjaukseen. Aineisto kerättiin strukturoitujen mittareiden avulla ja tulokset analysoitiin tilastollisesti. Tutkimuksen tulokset osoittavat, että kehitettyä tiedollisesti voimavaraistumista tukevaa Internet-perustaista potilasohjausmenetelmää voidaan suositella käytettäväksi ortopedisten päiväkirurgisten potilaiden ohjauksessa ja potilailla on hyvät mahdollisuudet voimavaraistua tiedollisesti sen avulla. Monipuolista tietoa sisältävä Internet-perustainen ohjaus osoittautui käyttäjien näkökulmasta hyväksyttäväksi. Vaikka Internet ohjauksen hyväksyttävyys koettiin osittain heikommaksi kuin sairaanhoitajan välittämän ohjauksen, potilaat käyttivät nettisivustoa ongelmitta ja arvioivat sen helppokäyttöiseksi. Ohjausmuodolla ei ollut vaikutusta hoidosta aiheutuneisiin kustannuksiin. Sen sijaan kustannuksista organisaatiolle voitiin puolittaa sairaanhoitajan ohjaukseen käyttämä aika Internet-perustaisen ohjauksen avulla. Internet-perustaiseen ohjaukseen osallistuneiden potilaiden tiedon taso ja kokemus tiedon riittävyydestä lisääntyivät ohjauksen jälkeen enemmän kuin sairaanhoitajan välittämään potilasohjaukseen osallistuneiden potilaiden tiedot. Ohjausmuodolla ei ollut vaikutusta potilaiden kokemien tunteiden ja oireiden voimakkuuteen. Yhteenvetona voidaan todeta, että tiedollisesti voimavaraistava Internet-perustaista ohjausta voidaan suositella vaihtoehtoiseksi menetelmäksi sairaanhoitajan välittämälle ohjaukselle päiväkirurgiseen ortopediseen leikkaukseen tuleville potilaille.

I must walk through the gate : an ontological necessity

This research is a self-study into my life as an athlete, elementary school teacher, leamer, and as a teacher educator/academic. Throughout the inquiry, I explore how my beliefs and values infused my lived experiences and ultimately influenced my constructivist, humanist, and ultimately my holistic teaching and learning practice which at times disrupted the status quo. I have written a collection of narratives (data generation) which embodied my identity as an unintelligent student/leamer, a teacher/learner, an experiential learner, a tenacious participant, and a change agent to name a few. As I unpack my stories and hermeneutically reconstruct their intent, I question their meaning as I explore how I can improve my teaching and learning practice and potentially effect positive change when instructing beginning teacher candidates at a Faculty of Education. At the outset I situate my story and provide the necessary political, social, and cultural background information to ground my research. I follow this with an in depth look at the elements that interconnect the theoretical framework of this self-study by presenting the notion of writing at the boundaries through auto ethnography (Ellis, 2000; Ellis & Bochner, 2004) and writing as a method of inquiry (Richardson, 2000). The emergent themes of experiential learning, identity, and embodied knowing surfaced during the data generation phase. I use the Probyn' s (1990) .. metaphor of locatedness to unpack these themes and ponder the question, Where is experience located? I deepen the exploration by layering Drake's (2007) KnowlDo/Be framework alongside locatedness and offer descriptions of learning moments grounded in pedagogical theories. In the final phase, I introduce thirdspace theory (Bhabha, 1994; Soja, 1996) as a space that allowed me to puzzle educational dilemmas and begin to reconcile the binaries that existed in my life both personally, and professionally. I end where I began by revisiting the questions that drove this study. In addition, Ireflect upon the writing process and the challenges that I encountered while immersed in this approach and contemplate the relevance of conducting a self-study. I leave the reader with what is waiting for me on the other side of the gate, for as Henry James suggested, "Experience is never limited, and it is never complete."