[Recombinant proteins as therapeutic compounds in clinical oncology]

The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.

Enteroscopia por cápsula e doença de Crohn: Caminhos para a otimização

Tese de Doutoramento em Medicina

Acontecimentos significativos em terapia cognitivo-comportamental: a perspetiva do cliente e do terapeuta

Dissertação de mestrado em Psicologia Aplicada

Una universidad donde confluyen la educación, la investigación y la ciudadanía

El projecte de recerca s'ha basat en el projecte Miquel Martí i Pol, que ha consistit en la creació i manteniment d'un jardí dedicat a la memòria del poeta, amb persones en situació d'exclusió social (per motius de malaltia mental, immigració, pobresa) i estudiants de teràpia ocupacional de la Universitat de Vic, des d'una sinergia única entre la Universitat de Vic i institucions públiques, socials i empresarials. La recerca ve a cobrir la falta de coneixement sobre l'impacte terapèutic de la jardineria, com afirmava Sempik al 2003. Així mateix, genera coneixements sobre l'ocupació humana, la ciutadania, les comunitats inclusives, les aliances estratègiques i sobre noves praxis educatives en el marc del nou Espai Europeu d'Educació Superior (EEES). El marc teòric s'ha basat en una visió transdisciplinària, des de l'educació, la filosofia, la psicologia, la sociologia, la teràpia ocupacional, la política, l'ecologia i l'antropologia. S'ha desenvolupat una recerca inspirada per la investigació acció participativa que ha aprofundit en el significat que ha tingut aquesta experiència per a les persones implicades en el procés de creació del jardí: les persones procedents de col•lectius en situació d'exclusió, els estudiants, així com els representants de les institucions públiques, socials, empresarials i la pròpia Universitat de Vic. Així es van desenvolupar una sèrie d'entrevistes a fons i formularis amb 5 jardiners; 2 estudiants; la Consellera d'Acció Social de l'Ajuntament de Vic; el Conseller d'Acció Social del Consell Comarcal d'Osona; el President de Caritas; la terapeuta ocupacional de la Fundació Centre Mèdic Psicopedagògic d'Osona; la Rectora de la Universitat de Vic; la Directora de l'EUCS i el President del Rotary Club. Els temes que han sorgit en la recerca són: La construcció de l'ocupació significativa; la jardineria com a font de benestar; un espai de bellesa; la dignitat de la ciutadania; la creació de comunitats inclusives; una Universitat al servei de la Humanitat: noves praxis educatives; l'art de les aliances estratègiques i de les sinergies. Els coneixements generats tenen relació amb els estudis de teràpia ocupacional, així com per a educació social, infermeria, psicologia i ciències ambientals. A més a més són una aposta per al desenvolupament de noves praxis educatives en el nou EEES. El treball ha estat qualificat com a excel•lent per unanimitat del tribunal.

Strategies for the development of tdm for targeted anticancer agents

Most of the novel targeted anticancer agents share classical characteristics that define drugs as candidates for blood concentration monitoring: long-term therapy; high interindividual but restricted intraindividual variability; significant drug-drug and drug- food interactions; correlations between concentration and efficacy/ toxicity with rather narrow therapeutic index; reversibility of effects; and absence of early markers of response. Surprisingly though, therapeutic concentration monitoring has received little attention for these drugs despite reiterated suggestions from clinical pharmacologists. Several issues explain the lack of clinical research and development in this field: global tradition of empiricism regarding treatment monitoring, lack of formal conceptual framework, ethical difficulties in the elaboration of controlled clinical trials, disregard from both drug manufacturers and public funders, limited encouragement from regulatory authorities, and practical hurdles making dosage adjustment based on concentration monitoring a difficult task for prescribers. However, new technologies are soon to help us overcome these obstacles, with the advent of miniaturized measurement devices able to quantify circulating drug concentrations at the point-of-care, to evaluate their plausibility given actual dosage and sampling time, to determine their appropriateness with reference to therapeutic targets, and to advise on suitable dosage adjustment. Such evolutions could bring conceptual changes into the clinical development of drugs such as anticancer agents, while increasing the therapeutic impact of population PK-PD studies and systematic reviews. Research efforts in that direction from the clinical pharmacology community will be essential for patients to receive the greatest benefits and the least harm from new anticancer treatments. The example of imatinib, the first commercialized tyrosine kinase inhibitor, will be outlined to illustrate a potential research agenda for the rational development of therapeutic concentration monitoring.

L'influence thérapeutique de la perception de justice informationnelle et interpersonnelle sur les symptômes de stress post-traumatique des victimes d'actes criminels

À la suite d’un crime, les victimes vont ressentir différents besoins et celui d’être informé serait fondamental (Baril, 1984). Les recherches ont permis d’établir que les policiers ont un rôle important à jouer dans la transmission des informations aux victimes puisqu’ils sont les premiers acteurs du système pénal avec lesquels celles-ci sont en contact (Laxminarayan, 2013). De plus, la perception des victimes quant à la façon dont elles ont été traitées par les policiers peut avoir un impact significatif sur leur rétablissement psychologique. Cette étude a pour but de mesurer l’effet thérapeutique des interactions entre les victimes et les policiers ainsi que de la transmission des informations aux victimes à la suite d’un crime sur l’état de stress post-traumatique (ÉSPT). Pour ce faire, l’instrument qui a été administré aux participants (n=188) est l’Échelle modifiée des symptômes du trouble de stress post-traumatique. Cet instrument est une version adaptée et validée en français (Guay, Marchand, Iucci et Martin, 2002) de l’échelle MPSS-SR élaborée par Falsetti, Resnick, Resick et Kilpatrick (1993). Cette échelle permet d’évaluer la présence des symptômes de stress post-traumatique en terme de fréquence et de sévérité. Les résultats de l’étude montrent que l’information est un déterminant important d’un traitement juste et la qualité de ce traitement à un effet thérapeutique sur les symptômes de stress post-traumatique. Une discussion des résultats dans une perspective plus globale concernant les théories en victimologie sur la perception de justice, la problématique de la victimisation secondaire et les implications pour les politiques en matière de droits des victimes sera présentée à la fin de cette recherche.

Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

Tissue engineering strategies for biomaterial-based anticancer drug delivery and enhancement of angiogenesis in tumor-resected bone

Patienten, die an Osteosarkom leiden werden derzeit mit intravenös applizierten krebstherapeutischen Mitteln nach Tumorresektion behandelt, was oftmals mit schweren Nebenwirkungen und einem verzögerten Knochenheilungsprozess einhergeht. Darüber hinaus treten vermehrt Rezidive aufgrund von verbleibenden neoplastischen Zellen an der Tumorresektionsstelle auf. Erfolgreiche Knochenregeneration und die Kontrolle von den im Gewebe verbleibenden Krebszellen stellt eine Herausforderung für das Tissue Engineering nach Knochenverlust durch Tumorentfernung dar. In dieser Hinsicht scheint der Einsatz von Hydroxyapatit als Knochenersatzmaterial in Kombination mit Cyclodextrin als Medikamententräger, vielversprechend. Chemotherapeutika können an Biomaterial gebunden und direkt am Tumorbett über einen längeren Zeitraum freigesetzt werden, um verbliebene neoplastische Zellen zu eliminieren. Lokal applizierte Chemotherapie hat diverse Vorteile, einschließlich der direkten zytotoxischen Auswirkung auf lokale Zellen, sowie die Reduzierung schwerer Nebenwirkungen. Diese Studie wurde durchgeführt, um die Funktionsfähigkeit eines solchen Arzneimittelabgabesystems zu bewerten und um Strategien im Bereich des Tissue Engineerings zu entwickeln, die den Knochenheilungsprozess und im speziellen die Vaskularisierung fördern sollen. Die Ergebnisse zeigen, dass nicht nur Krebszellen von der chemotherapeutischen Behandlung betroffen sind. Primäre Endothelzellen wie zum Beispiel HUVEC zeigten eine hohe Sensibilität Cisplatin und Doxorubicin gegenüber. Beide Medikamente lösten in HUVEC ein tumor-unterdrückendes Signal durch die Hochregulation von p53 und p21 aus. Zudem scheint Hypoxie einen krebstherapeutischen Einfluss zu haben, da die Behandlung sensitiver HUVEC mit Hypoxie die Zellen vor Zytotoxizität schützte. Der chemo-protektive Effekt schien deutlich weniger auf Krebszelllinien zu wirken. Diese Resultate könnten eine mögliche chemotherapeutische Strategie darstellen, um den Effekt eines zielgerichteten Medikamenteneinsatzes auf Krebszellen zu verbessern unter gleichzeitiger Schonung gesunder Zellen. Eine erfolgreiche Integration eines Systems, das Arzneimittel abgibt, kombiniert mit einem Biomaterial zur Stabilisierung und Regeneration, könnte gesunden Endothelzellen die Möglichkeit bieten zu proliferieren und Blutgefäße zu bilden, während verbleibende Krebszellen eliminiert werden. Da der Prozess der Knochengeweberemodellierung mit einer starken Beeinträchtigung der Lebensqualität des Patienten einhergeht, ist die Beschleunigung des postoperativen Heilungsprozesses eines der Ziele des Tissue Engineerings. Die Bildung von Blutgefäßen ist unabdingbar für eine erfolgreiche Integration eines Knochentransplantats in das Gewebe. Daher ist ein umfangreich ausgebildetes Blutgefäßsystem für einen verbesserten Heilungsprozess während der klinischen Anwendung wünschenswert. Frühere Experimente zeigen, dass sich die Anwendung von Ko-Kulturen aus humanen primären Osteoblasten (pOB) und humanen outgrowth endothelial cells (OEC) im Hinblick auf die Bildung stabiler gefäßähnlicher Strukturen in vitro, die auch effizient in das mikrovaskuläre System in vivo integriert werden konnten, als erfolgreich erweisen. Dieser Ansatz könnte genutzt werden, um prä-vaskularisierte Konstrukte herzustellen, die den Knochenheilungsprozess nach der Implantation fördern. Zusätzlich repräsentiert das Ko-Kultursystem ein exzellentes in vitro Model, um Faktoren, welche stark in den Prozess der Knochenheilung und Angiogenese eingebunden sind, zu identifizieren und zu analysieren. Es ist bekannt, dass Makrophagen eine maßgebliche Rolle in der inflammatorisch-induzierten Angiogenese spielen. In diesem Zusammenhang hebt diese Studie den positiven Einfluss THP-1 abgeleiteter Makrophagen in Ko-Kultur mit pOB und OEC hervor. Die Ergebnisse zeigten, dass die Anwendung von Makrophagen als inflammatorischer Stimulus im bereits etablierten Ko-Kultursystem zu einer pro-angiogenen Aktivierung der OEC führte, was in einer signifikant erhöhten Bildung blutgefäßähnlicher Strukturen in vitro resultierte. Außerdem zeigte die Analyse von Faktoren, die in der durch Entzündung hervorgerufenen Angiogenese eine wichtige Rolle spielen, eine deutliche Hochregulation von VEGF, inflammatorischer Zytokine und Adhäsionsmoleküle, die letztlich zu einer verstärkten Vaskularisierung beitragen. Diese Resultate werden dem Einfluss von Makrophagen zugeschrieben und könnten zukünftig im Tissue Engineering eingesetzt werden, um den Heilungsprozess zu beschleunigen und damit die klinische Situation von Patienten zu verbessern. Darüber hinaus könnte die Kombination der auf Ko-Kulturen basierenden Ansätze für das Knochen Tissue Engineering mit einem biomaterial-basierenden Arzneimittelabgabesystem zum klinischen Einsatz kommen, der die Eliminierung verbliebener Krebszellen mit der Förderung der Knochenregeneration verbindet.

ENHANCING COMMUNICATION THROUGH SUCCESSFUL REPAIR: EXAMINING FLUENCY AND MECHANISMS FOR SYNTACTIC PROGRESS IN APHASIC AND NON-APHASIC SPEECH

The fields of Rhetoric and Communication usually assume a competent speaker who is able to speak well with conscious intent; however, what happens when intent and comprehension are intact but communicative facilities are impaired (e.g., by stroke or traumatic brain injury)? What might a focus on communicative success be able to tell us in those instances? This project considers this question in examining communication disorders through identifying and analyzing patterns of (dis) fluent speech between 10 aphasic and 10 non-aphasic adults. The analysis in this report is centered on a collection of data provided by the Aphasia Bank database. The database’s collection protocol guides aphasic and non-aphasic participants through a series of language assessments, and for my re-analysis of the database’s transcripts I consider communicative success is and how it is demonstrated during a re-telling of the Cinderella narrative. I conducted a thorough examination of a set of participant transcripts to understand the contexts in which speech errors occur, and how (dis) fluencies may follow from aphasic and non-aphasic participant’s speech patterns. An inductive mixed-methods approach, informed by grounded theory, qualitative, and linguistic analyses of the transcripts functioned as a means to balance the classification of data, providing a foundation for all sampling decisions. A close examination of the transcripts and the codes of the Aphasia Bank database suggest that while the coding is abundant and detailed, that further levels of coding and analysis may be needed to reveal underlying similarities and differences in aphasic vs. non-aphasic linguistic behavior. Through four successive levels of increasingly detailed analysis, I found that patterns of repair by aphasics and non-aphasics differed primarily in degree rather than kind. This finding may have therapeutic impact, in reassuring aphasics that they are on the right track to achieving communicative fluency.

Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity.

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells.

Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.

Aspirin [acetylsalicylic acid (ASA)], along with its analgesic-antipyretic uses, is now also being considered for cardiovascular protection and treatments in cancer and human immunodeficiency virus infection. Although many of ASA's pharmacological actions are related to its ability to inhibit prostaglandin and thromboxane biosynthesis, some of its beneficial therapeutic effects are not completely understood. Here, ASA triggered transcellular biosynthesis of a previously unrecognized class of eicosanoids during coincubations of human umbilical vein endothelial cells (HUVEC) and neutrophils [polymorphonuclear leukocytes (PMN)]. These eicosanoids were generated with ASA but not by indomethacin, salicylate, or dexamethasone. Formation was enhanced by cytokines (interleukin 1 beta) that induced the appearance of prostaglandin G/H synthase 2 (PGHS-2) but not 15-lipoxygenase, which initiates their biosynthesis from arachidonic acid in HUVEC. Costimulation of HUVEC/PMN by either thrombin plus the chemotactic peptide fMet-Leu-Phe or phorbol 12-myristate 13-acetate or ionophore A23187 leads to the production of these eicosanoids from endogenous sources. Four of these eicosanoids were also produced when PMN were exposed to 15R-HETE [(15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid] and an agonist. Physical methods showed that the class consists of four tetraene-containing products from arachidonic acid that proved to be 15R-epimers of lipoxins. Two of these compounds (III and IV) were potent inhibitors of leukotriene B4-mediated PMN adhesion to HUVEC, with compound IV [(5S,6R,15R)-5,6,15-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoi c acid; 15-epilipoxin A4] active in the nanomolar range. These results demonstrate that ASA evokes a unique class of eicosanoids formed by acetylated PGHS-2 and 5-lipoxygenase interactions, which may contribute to the therapeutic impact of this drug. Moreover, they provide an example of a drug's ability to pirate endogenous biosynthetic mechanisms to trigger new mediators.

Curva de aprendizaje para ecografía cardiaca en residentes de primer y segundo año de medicina crítica de la universidad del rosario en el año 2016

La ecografía básica cardiaca (ECB) es una herramienta útil en la Unidad de Cuidados intensivos al facilitar la realización de ciertas intervenciones. No se ha definido el número de repeticiones necesarias para obtener un nivel de competencia adecuado. La evidencia encontrada indica un número mínimo de cincuenta repeticiones, para alcanzar cierto grado de habilidad.

Multifocal Renal Allograft Biopsy: Impact on Therapeutic Decisions

Objective. There are no data to support the suggestion that samples removed from one segment of the transplanted kidney are representative of the whole graft. The aim of this study was to compare the histological differences between biopsies obtained from different portions of the renal allograft and their impact on treatment recommendations. Patients and Methods. Two hundred percutaneous biopsies were performed on kidney allografts and samples were collected from the upper and lower poles (100 kidneys). All samples were randomized and blindly reviewed. We obtained the discordance rates between the poles for the grading of acute rejection and for the diagnosis of nephrotoxicity due to immunosuppression. We also checked if the differences found were sufficient to call for different clinical recommendations. These values were compared with the intrapathologist variation rates. Results. In 70 kidneys adequate sampling was obtained from both poles. The diagnosis of acute rejection were made in 1.7. The discordance rate between the upper and lower poles was 82.3% (kappa = 0.34), higher than the intrapathologist variation (P =.002). Nephrotoxicity was found in 14 kidneys. The discordance rate between the upper and lower poles was 28.6% (kappa = 0.88), with no difference compared with the intrapathologist variation. In 14 of the 70 kidneys (25.7%), discordances between poles had impact on clinical recommendations, most of these cases due to different gradings of acute rejection (78%). This number was higher than the intrapathologist variation (P =.04). Conclusions. The histopathological changes in the kidney allograft are not always homogeneous. This heterogeneity may affect the therapeutic recommendations.