41 research outputs found
The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells
No full textThe RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP-AST487, a N,N'-diphenyl urea with an IC(50) of 0.88 mumol/L on RET kinase, inhibited RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP-AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. MTCs secrete calcitonin, a useful indicator of tumor burden. Human plasma calcitonin levels derived from the TT cell xenografts were inhibited shortly after treatment, when tumor volume was still unchanged, indicating that the effects of RET kinase inhibition on calcitonin secretion were temporally dissociated from its tumor-inhibitory properties. Accordingly, NVP-AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription. These data point to a previously unknown physiologic role of RET signaling on calcitonin gene expression. Indeed, the RET ligands persephin and GDNF robustly stimulated calcitonin mRNA, which was blocked by pretreatment with NVP-AST487. Antagonists of RET kinase activity in patients with MTC may result in effects on plasma calcitonin that are either disproportionate or dissociated from the effects on tumor burden, because RET kinase mediates a physiologic pathway controlling calcitonin secretion. The role of traditional tumor biomarkers may need to be reassessed as targeted therapies designed against oncoproteins with key roles in pathogenesis are implemented
Software Design and Implementation of a UNIX Based Graphics System
No full textiv, 206 p.The author describes his internship as a Programmer/Analyst at u.s. Windpower Inc., the nation’s largest windmill producer and his work on the design, implementation, and testing of a UNIX-based graphics system named AUTOGRAPH.Power Plant Systems Development. U.S. Windpower, Inc. Burlington, Massachusetts.Analytic Studies. U.S. Windpower, Inc. Burlington, Massachusetts
The role of illness representations in the process of coping and psychosocial adjustment among adults with epilepsy
No full textThe self-regulation model (Leventhal, Nerenz and Steele, 1984) emphasises the role of cognitive representations of illness and coping efforts on patients responses to
health threats. In this thesis the relationships between illness representations, coping and psychosocial adjustment were investigated among 94 epilepsy patients. The sample comprised three groups; recently diagnosed, chronic (clinic) and chronic (GP) patients.
An instrument was developed to assess patients cognitive representations of epilepsy. The protocol used yielded both qualitative and quantitative data.
Both chronic (clinic) and recently diagnosed patients exhibited significant adjustment problems. In contrast, among chronic (GP) patients psychosocial adjustment was
good. Differences in coping and illness representations were found between groups. Chronic (clinic) patients were distinguished by greater reliance on wishful thinking
and avoidance coping. Avoidance coping strategies were least prevalent among chronic (GP) patients. In terms of illness representations, recent onset patients were
characterised by, weaker illness identity, acute timeline and perceptions of less severe consequences. Chronic (clinic) patients were characterised by; a strong illness
identity, chronic timeline, perception of serious consequences and high contamination beliefs. Chronic (GP) patients also possessed a strong illness identity and chronic time perception, but on the consequences and self-illness components more closely resembled recent onset patients.
A series of multiple regression analyses indicated that illness representations explained a greater proportion of variance in; mental health, psychological distress,
self-esteem and social anxiety than did the coping strategies after controlling for neuroepileptic factors. The illness representation component self-illness relationship had the strongest overall association with adjustment. Additional components making a significant contribution were; illness identity, timeline and control. There were several distinct relationships between illness representations and coping. Illness identity, blaming others, perception of serious consequences and negative self-illness appraisals were positively related to wishful thinking and avoidance coping. Among the four coping strategies assessed; avoidance,problem-focused and wishful thinking were related to adjustment. Seeking social support did not emerge as a significant predictor of adjustment. Patients with a strong illness identity, who perceived
themselves as unable to contain the effects of epilepsy, utilised wishful thinking and avoidance coping emerged as having the poorest mental health and self-esteem.
This thesis demonstrates the value of the self-regulation paradigm in understanding psychosocial adjustment to epilepsy. Results are discussed with respect to
operationalizing the model to investigate epilepsy, the presence of both direct effects of illness representations on adjustment and indirect effects via coping. The implications for clinical intervention work are considered
Knowing your audience: How graphic designers perceive their audience
No full textThis thesis work began with the observation of an apparent disparity between what graphic designers say and what they demonstrate through practice and education with regard to "knowing the audience." Through investigation of literature in design and related disciplines such as marketing, demographics, psychographics, visual literacy, information processing, cognitive thought processing, schema theory, and ethnic/cultural diversity issues, this study sought to form a basis for understanding what information is available about audience, how it might be collected and how information can be effected by personal experience, biases, and attitudes (schema theory) within the cognitive mechanisms of perception. To form an understanding of how graphic designers gather information about the audiences, a survey was designed and distributed.
To follow up the survey a short series of three case studies were conducted to follow the actual design process with three design practitioners. The picture of graphic designers offered by the survey results is one of intelligent, educated, experienced visual communicators who operate on the assumption that they understand their audience. They use some statistical information when it is convenient, or if they are paid to gather it, but they somehow distrust it. They insist that they have to know their audience in order to communicate. And, they insist that they do know their audience. However, they fail to explain how it is that they have gained this understanding. The study concludes that designers and design educators alike feel knowing the audience is extremely important. But, when it comes to actually gathering information about the audience, designers depend more often on their client's to form the basis for audience understanding.
And, more often on their intuitive, artistic sense to create designs. The study speculates that perhaps designers are missing out on something by so often taking the audience factor for granted. We believe that the artistic element of design is the bringer of innovation and breakthrough, and the author agrees. But, asks, isn't it possible that careful understanding of particular audience factors can teach us better communication and offer just as much potential for breakthrough as our pursuit of the artistic
Protocol for stage 2 of the GaP study (genetic testing acceptability for Paget's disease of the bone) : a questionnaire study to investigate whether relatives of people with Paget's disease would accept genetic testing and preventative treatment if they were available
No full textBackground: Paget's disease of bone (PDB) disrupts normal bone architecture and causes pain, deformity, deafness, osteoarthritis, and fractures. Genetic factors play a role in PDB and genetic tests are now conducted for research purposes. It is thus timely to investigate the potential for a clinical programme of genetic testing and preventative treatment for people who have a family history of PDB. This study examines the beliefs of relatives of people with PDB. It focuses particularly on illness and treatment representations as predictors of the acceptability and uptake of potential clinical programmes. Illness representations are examined using Leventhal's Common Sense Self-Regulation Model while cognitions about treatment behaviours (acceptance of testing and treatment uptake) are conceptualised within the Theory of Planned Behaviour. Methods/Design: A postal questionnaire of non-affected relatives of people with Paget's disease. The sample will include relatives of Paget's patients with a family history of Paget's disease and relatives of Paget's patients without a family history of Paget's disease. The questionnaire will explore whether a range of factors relate to acceptability of a programme of genetic testing and preventive treatment in relatives of Paget's disease sufferers. The questionnaire will include several measures: illness representations (as measured by the Brief Illness Perceptions Questionnaire); treatment representations (as measured by Theory of Planned Behaviour-based question items, informed by a prior interview elicitation study); descriptive and demographic details; and questions exploring family environment and beliefs of other important people. Data will also be collected from family members who have been diagnosed with Paget's disease to describe the disease presentation and its distribution within a family. Discussion: The answers to these measures will inform the feasibility of a programme of genetic testing and preventive treatment for individuals who are at a high risk of developing Paget's disease because they carry an appropriate genetic mutation. They will also contribute to theoretical and empirical approaches to predicting diagnostic and treatment behaviours from the combined theoretical models.We wish to acknowledge the Medical Research Council for financial support of this study. [...] The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorates.Publisher PD
Short communication: Describing mortality and euthanasia practices on Canadian dairy farms
No full textThe objective of this study was to describe mortality rates and euthanasia practices used for cows, heifer calves, and male dairy calves on Canadian dairy farms. An internet survey was administered to Canadian dairy producers between March and April 2015 to collect information on current management practices. Approximately 81% (867/1,076) and 63% (673/1,065) of respondents reported that at least one animal died unassisted and at least one animal was euthanized on the farm in the preceding 12-mo period, respectively. Overall, mean mortality was 8% for cows, and 6 and 2% for preweaning and weaned heifers, respectively. On average, 48, 76, and 89% of all reported mortality events in cows, weaned heifers, and preweaning heifers were recorded as unassisted deaths. Cows that died without assistance were necropsied more often than preweaning heifers dying without assistance; these cows were also necropsied more than cows that were euthanized. Conversely, preweaning heifers that were euthanized were necropsied more frequently than those that died without assistance. Choosing not to perform necropsies on animals that die of unknown causes could represent a missed opportunity to identify cause of death and inform changes to prevent future deaths. The use of a firearm was the most common method for euthanizing cows and heifers (54%) and male dairy calves (51%). Approximately 7% of respondents reported using blunt force to euthanize animals. The use of this method was much higher for euthanasia of male dairy calves (34%) than for heifer calves (7%). Quebec respondents euthanized their animals using blunt force more often than farmers from other regions. Further, 53% of respondents using blunt force indicated it was their primary method of calf euthanasia; these results are extremely concerning. Approximately 31% of respondents who reported that they do not use blunt force to euthanize heifers and cows did report using blunt force to euthanize male dairy calves. These results can be used to inform veterinarian--client communication, broader extension tools and programs, and industry policies to improve dairy cattle health and welfare, a goal that is becoming of increasing importance from a consumer assurance perspective.Dairy Farmers of CanadaAgriculture and Agri-Food Canad
Canadian National Dairy Study: Describing Canadian dairy producer practices and perceptions surrounding cull cow management
No full textFarmer decisions surrounding culling have an important effect on the health and welfare of cull cows. The objectives of this study were to describe the self-reported shipment behaviors of Canadian dairy producers and understand farmer perspectives on the factors that were most influential in their decision to cull a cow. A nationwide survey was administered between March and April 2015 that included 192 questions covering producer background information, farm characteristics, biosecurity practices, disease prevalence, calf health, cow welfare, lameness, milking hygiene, reproduction, and Internet and social media use. The survey yielded a 12% response rate; a total of 1,076 respondents (78% of all survey respondents completed the culling section of the survey) were included in this study for analysis. Approximately 80, 51, and 38% of respondents reported shipping at least 1 cow to auction, direct to slaughter, and to another dairy farm in the past 12 mo, respectively. Ability of the cow to remain standing (93% of respondents) and drug withdrawal times (92% of respondents) were identified as the most important factors for consideration when culling cows. The time between culling decision and when the cow was actually transported was longer for lame cows than sick cows; almost 70% of respondents reported that cows culled for illness were typically shipped within 1 wk of culling decision, whereas only 51% of respondents indicated the same was true for lame cows. Last, Canadian dairy producers generally exhibited strong confidence that their culled cows would arrive at slaughter in the same condition as they left, but felt very unsure about knowing the location of their final destination. These results highlight several gaps between producer perceptions and the true situation, and can be used to develop tailored programs and inform policy and regulatory decisions aimed at improving cull cow decisions and cow welfare.Dairy Farmers of CanadaAgriculture and Agri-Food Canad
Immunological boosting and personalization of oncolytic virotherapies for cancer treatment
No full textCancer is the leading cause of death worldwide creating a need for novel cancer treatments that are more efficient but also safer and more specific. Oncolytic viruses (OVs) have shown a solid safety profile in clinical trials. OVs are nowadays considered immunotherapies because of to their ability to stimulate the host immune system to fight against cancer. Promising efficacy has been seen in some trials, however, efficacy is often seen only in a small group of patients.
The purpose of the thesis was to improve the efficacy of OV therapies by boosting the immunogenicity of the viruses, and to optimize the therapeutic efficacy by selecting favorable patient populations and by developing a method to tailor the drug individually for each patient.
In the first study, an oncolytic adenovirus (OAd) was modified to express human tumor necrosis factor alpha (hTNFα), a potent immunomodulatory cytokine. The TNFα-virus showed effective tumor cell killing associated with signs of immunogenic cell death and enhanced recruitment of immune cells to the infection site. We also saw potential for combining the TNFα-virus therapy with radiation. In another study the immunogenicity of an oncolytic vaccinia virus was enhanced by modifying it to express DNA-dependent activator of interferon-regulatory factors (DAI), a potent inducer of innate immune responses during virus infection. We showed that the DAI-virus induces expression of genes involved in immune responses, and treatments with the virus showed improved cancer-killing efficacy and immunogenicity in murine and human melanoma models, suggesting applicability also in vaccine design.
Response rates after virotherapies vary between patients, and there is a lack of markers that would help predict the patient cohorts who would benefit from the therapy. We screened over 200 cancer patients treated with OAds for two Fc gamma receptor (FcγR) polymorphisms to determine if these polymorphisms would affect the responsiveness to the treatments. We observed a certain FcγR genotype combination (FcγRIIIa-VV + FcγRIIa-HR) to be predictive of poor overall survival after OAd treatments.
To tailor the OV therapy for enhanced specificity, we developed a novel platform (PeptiCRAd) to coat a virus with tumor-specific antigens (peptides) for improved induction of cancer-specific immunity. Efficacy and immunogenic potency of the PeptiCRAd were shown in several in vivo models. Our results suggest that administration of tumor-specific peptides on the surface of OVs increases the anti-tumor efficacy compared to treatments with viruses or peptides alone. This platform has potential to be used as a carrier and adjuvant for patient-specific peptides to trigger anti-tumor immunity in a personalized manner.Syöpä on maailman yleisin kuolinsyy. Tarve uusille, tehokkaammille, turvallisemmille ja kohdistetummille syöpähoidoille on suuri. Onkolyyttisten (syöpäsoluja tappavien) virusten turvallisuus on osoitettu useissa kliinisissä tutkimuksissa. Onkolyyttisia virushoitoja pidetään nykyään yhtenä immunoterapian muotona, sillä niillä on kyky herättää immuunijärjestelmä taistelemaan syöpää vastaan. Nämä virushoidot ovat osoittaneet lupaavia tuloksia joissakin tutkimuksissa, mutta ne tehoavat usein vain pieneen joukkoon potilaita.
Väitöskirjan tutkimusten tarkoituksena oli parantaa virushoitojen tehokkuutta lisäämällä virusten immunogeenisyyttä eli kykyä aktivoida kehon immuunipuolustus syöpäkasvainta vastaan. Lisäksi tavoitteena oli optimoida hoitojen tehokkuutta etsimällä hoidolle suotuisia potilasryhmiä sekä kehittää menetelmä, jolla virushoito voidaan räätälöidä yksilöllisesti kullekin potilaalle.
Muunsimme geneettisesti onkolyyttisen adenoviruksen ja vaccinia-viruksen (lehmärokkoviruksen) tuottamaan immunomodulatorisia proteiineja kasvaimissa. Adenoviruksen muunsimme tuottamaan tuumorinekroositekijä alfa (TNFα) -sytokiinia, ja vaccinia-viruksen muunsimme tuottamaan DNA:ta tunnistavaa reseptoria, DAI:ta. Kumpikin uusi virus osoittautui tutkimuksissa tehokkaaksi syöpäsolujen tappajaksi ja sai aikaan tehostetun immuunipuolustuksen syöpää vastaan koe-eläimissä.
Virushoitojen hoitovasteen on huomattu vaihtelevan suuresti potilaiden kesken. Toistaiseksi ei myöskään ole olemassa biomarkkereita, joiden avulla voitaisiin valikoida virushoidoista parhaiten hyötyvät potilaat. Määritimme yli 200:n onkolyyttisilla adenoviruksilla hoidetun syöpäpotilaan genotyypit kahden Fc gamma reseptoripolymorfian (FcyR) suhteen, ja tutkimme vaikuttavatko nämä polymorfismit potilaiden hoitovasteeseen. Havaitsimme tietyn FcyR genotyyppiyhdistelmän (FcγRIIIa-VV + FcyRIIa-HR) indikoivan huonoa elinajanodotetta, eli kyseisen genotyypin omaavat potilaat eivät näyttäisi hyötyvän virushoidoista.
Syöpien monimuotoisuudesta ja potilaiden eroista johtuen yksi syöpähoito ei tehoa kaikkiin kasvaimiin. Siksi kehitimme uuden viruspohjaisen alustan (PeptiCRAd:n), jolla voidaan saada aikaan tarkennetumpi immuunivaste kasvainta vastaan. PeptiCRAd on kasvainspesifisillä peptideillä päällystetty onkolyyttinen virus, ikään kuin virus kasvaimen vaatteissa , jossa virusvektorin tehokkuus ja kyky herättää immuunivaste yhdistyy peptidihoitojen spesifiyteen. Osoitimme PeptiCRAd:n tehon ja immunogeenisyyden useissa kasvainmalleissa. Tuloksemme viittaavat siihen, että tällainen viruksen ja kasvainpeptidien yhdistelmä voisi toimia tehokkaana alustana personoidulle syöpähoidolle.ei saavutettav
Repeatability of Whole-Building Airtightness Testing in a Residential Wood-Framed Building Under Varying Weather Conditions
No full textThis study investigates the repeatability of whole-building airtightness testing under varying weather conditions in a two-story, wood-framed residential building with an enclosure volume of 818 m³ and an area of 532 m², located in Victoria, Canada, situated in Climatic Zone 4C (Marine), characterized by mild, wet winters and cool summers. Air leakage tests, performed in accordance with ASTM E779, were conducted using blower door pressurization and depressurization methods. Weather variables recorded during testing included wind speed (2–14 km/h), indoor (17–23°C) and outdoor (5–16°C) temperatures, and relative humidity (indoor: 34–59%; outdoor: 46–96%). Regression analysis revealed no significant correlation between weather variability and airtightness metrics. Depressurization tests consistently demonstrated more airtight results compared to pressurization. These findings reinforce that blower door testing results are repeatable and reliable despite weather fluctuations, validating the applicability of single-event airtightness tests for evaluating building envelopes.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
