Zugl.: Siegen, Univ., Diss., 2009

Gastric cancer is one of the worldwide leading cancers which is highly prevalent in Eastern Asia. In Hong Kong, there were 1101 new cases and 687 cancer death in year 2011. So far gastric cancer is known to have poor prognosis and high relapse rate, for which a more effective therapy is sorely needed. With increasing knowledge in the role of HER2 in gastric cancer, a novel targeting agent, Trastuzumab, in combination with chemotherapy has become a promising personalized therapy for advanced gastric cancer and gastro-oesophageal junction cancer patients, particularly effective in HER2 positive patient subgroup. The clinical efficacy and safety of Trastuzumab therapy were ascertained by a recent worldwide phrase III randomized controlled trial called ToGA study in 2010. The assessment of the HER2 status has become crucial in selecting the right patient that will benefit most for the trastuzumab therapy. The aim of our study is to evaluate the local HER2 amplification rate in a group of gastric cancer patients and the associated tumour characteristics as well as sharing our technical experience in optimizing/standardizing the Silver ISH protocol including problem shooting in some difficult cases. From Oct 2012 to Apr 2014, we have accessed 68 requests of gastric cancer for HER2 status determination using Ventana Silver ISH assay, 61 were from stomach or gastro-oesophageal junction, 40 of them were endoscopic biopsy and 21 were resection specimens. Among them the majority were poorly differentiated (65.8%) and of intestinal sub-type (59.1%) according to Lauren classification. Thirteen out of 61 (21.3%) samples were found to be HER2 amplified. Majority of the HER2 positive cases were found in intestinal type and moderately differentiated adenocarcinoma. Eighty percent of the IHC 3+ cases and 29.6% of the IHC 2+ equivocal cases that required reflex tested with SISH were found to be HER2 amplified. There exists a great variation in the reported HER2 amplification rates in previous studies, which are apparently due to the difference in methodology and scoring algorithm apart from the different population groups. Recently, the introduction of the Hofmann’s modification on the scoring algorithm of HER2 assay dedicated for gastric cancer, and the increasing popularity in using DISH/SISH as a reliable alternative to FISH in detecting the HER2 status, have standardized the test and hence narrowed the variation. In order to achieve a more reliable staining result and accurate interpretation, optimization/ standardization of the analytical procedures, as well as the pre-analytical procedures become necessary. The standardization of the formalin fixation time seems to be a crucial factor in this regard. Therefore, the establishment of gastric cancer specimen handling guideline hospital-wide, and specific guideline recommendations for gastric cancer from ASCO/CAP are warranted. / published_or_final_version / Pathology / Master / Master of Medical Sciences

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Els motius que m’han mogut a fer aquest treball han estat dos. Primerament, he observat que no hi havia un estudi exhaustiu i unitari en el temps, sobre l’evolució del baptisme. És cert però, que hi ha moltes monografies sobre qüestions puntuals, estudis parcials, llibres sagramentals d’èpoques diverses, que evidencien que els rituals són els mateixos, o poc han canviat, etc. Per tant, el meu interès ha estat estudiar a fons i amb el màxim rigor històric possible per treure conclusions, els períodes històrics, sobretot els que van des dels inicis del cristianisme fins el segle XVI. He observat que a partir d’aquest segle els estudis eclesiàstics sobre el baptisme han patit una davallada en profunditat i en quantitat. Els Concilis de l’Església, generals i locals, aporten molta informació sobre qüestions doctrinals i de disciplina, força interessant per conèixer el que en pensaven a cada època, i quins eren els seus problemes, moltes vegades lligats a l’entorn social i polític del moment. Pensem que, durant segles, la societat vivia en una època de cristiandat que ho amarava tot. He intentat donar unes pinzellades sobre cada moment històric. L’Església, en el transcurs dels segles, ha sofert desavinences que han desembocat en separacions de grups cristians. Per tant, he estudiat les diferents confessions cristianes segons la seva incidència en la història i en el nostre entorn de la Província Eclesiàstica de Barcelona, sobre el fet concret de la celebració del baptisme: el per què el celebren i com el celebren. El segon motiu que m’ha empès a completar aquest treball, han estat les piles baptismals: l’objecte material concret on històricament s’hi ha desenvolupat el ritu del baptisme. Comencem pensant que antigament el baptisme s’havia de celebrar en aigua viva. La pràctica va desembocar a celebrar-lo en piscines d’immersió. Aquestes, amb el temps, van esdevenir més petites, on només hi cabia el nou batejat i no el celebrant, com era norma fer-ho en les piscines grans. Obligats per qüestions d’higiene, es va passar del bateig d’immersió al bateig d’infusió; i les piscines o piles, que ja eren de mida reduïda, encara es van reduir més, i només servien per col•locar-hi l’aigua i al mateix temps recollir-hi la que queia del cap del batejat. Tot i que el Concili Vaticà II ha dictat normes per a la celebració digne del sagrament del baptisme, avui en dia en moltes esglésies es bateja amb un gibrell o palangana. És interessant aquesta evolució històrica, ja que és paral•lela a l’evolució de les tendències artístiques de cada moment. Partint del principi que només els bisbats i les parròquies tenen encomanada la celebració del baptisme, s’han estudiat totes les piles baptismals que hi ha o hi ha hagut en aquests centres de culte, per tal de confeccionar una catalogació històrica i actual de les piles existents o que han existit. La informació necessària per desenvolupar aquest treball s’ha obtingut de documents existents en arxius, entrevistes personals i treball de camp, recollint informació in situ i creant un complet arxiu fotogràfic. S’hi ha incorporat tota la informació que s’ha pogut recollir de piles situades en ermites, monestirs, o oratoris particulars. I s’ha fet un paral•lelisme amb piles artístiques característiques fora de l’àmbit d’aquest estudi, a títol comparatiu. / Los motivos que me han llevado a desarrollar este trabajo han sido dos. En primer lugar, he observado que no existia un estudio exhaustivo y unitario en el tiempo, sobre la evolución del bautismo. Es cierto que existen muchas monografias sobre cuestiones puntuales, estudios parciales, libros sacramentales de distintas épocas, que ponen en evidencia que los rituales son los mismos, o poco han variado, etc. Por tanto, mi interés ha sido estudiar a fondo y con el máximo rigor histórico posible para extraer conclusiones, los períodos históricos, en especial los que van desde el inicio del cristianismo hasta el siglo XVI. A partir de este siglo los estudios eclesiásticos sobre el bautismo han sufrido un menoscabo, tanto en profundidad como en cualidad. Los Concilios de la Iglesia, generales y locales, aportan mucha información sobre cuestiones doctrinales y disciplinares, muy interesante para conocer lo que pensaban en cada época, y cuales eran sus problemas, muchas veces unidos al entorno social y político del momento. Durante siglos la sociedad vivia en una época de cristiandad que lo condicionaba todo. He intentado dar unas pautas sobre cada momento histórico. La Iglesia, en el devenir de los siglos, ha sufrido separaciones de grupos cristianos. Por tanto he estudiado las distintas confesiones cristianas según su incidencia en la historia y en el entorno de la Provincia Eclesiástica de Barcelona, sobre la cuestión concreta de la celebración del bautismo: el por que lo celebran y como lo celebran. El segundo motivo que me ha llevado a completar este trabajo, han sido las pilas bautismales: el objeto material donde históricamente se ha desarrollado el rito del bautismo. Antiguamente el bautismo tenia que celebrarse en agua viva. La práctica hizo que terminara por celebrarse en piscinas de immersión. Éstas, con el tiempo, se redujeron, y en ellas solamente podia entrar el bautizado y no el celebrante, como era norma hacerto en las piscinas grandes. Obligados por cuestiones de higiene, se pasó del bautismo de immersión al de infusión; y las piscinas o pilas, se redujeron aún más; solamente servian para colocar el agua, y al propio tiempo recoger la que caia de la cabeza del bautizado. El Concilio Vaticano II dictó normas para una digna celebración del bautismo. Pero, hoy en día en muchas iglesias se bautiza en una jofaina. Es intersante esta evolución histórica, paralela a la evolución de las tendencias artísticas de cada momento. Ya que solamente los obispados y las parroquias pueden bautizar, se han estudiado todas las pilas bautismales que tienen o han tenido estos centros de culto, confeccionando una catalogación histórica y actual de Las pilas existentes, o que han existido. La información necesaria para desarrollar este trabajo se ha obtenido de documentos existentes en archivos, entrevistas personales i trabajo de campo, recogiendo información in situ y creando un completo archivo fotográfico. Se ha incorporado la información que se ha podido recoger de pilas situadas en ermitas, monasterios, u oratorios. Paralelamente se han estudiado pilas bautismales características, que no entran en el àmbito de este estudio; solamente a título comparativo. / Two have been the reasons moved me to develop this research work. First, I have noticed that there was not a comprehensive study on the evolution of the Baptism over time although many monographs are written on punctual subjects, partial studies, sacramental books over time, etc., that make evidence the rituals are the same or they have little changed. My interest has been to study in depth and with maximum historical rigor in order to draw conclusions, the historical periods, especially those from the beginnings of Christianity until the sixteen century. I have observed that from this century ecclesiastical studies on the baptism have suffered a decline in depth and in quantity. The general and local Councils of the Church, provide much information on matter of doctrine and discipline, interesting enough in order to know the thought of every time, and what were the problems, very often linked to social and political environment of the time. We consider that, for centuries, the society was leaving an era of Christianity that drenched everything. I have tried to give an overview of each historical period. The disagreements the Church has suffered along the centuries have led to the separation of groups of Christians. Therefore, I have studied the different Christian confessions according to their effect on history and around the Ecclesiastical Province of Barcelona, on the specific fact of the celebration of the baptism: why to celebrate and how to celebrate. The second reason that has driven me to complete this research work has been the Baptismal Fonts: the particular material object where the rite of the baptism has developed. Formerly the baptism was to be held in living waters. The practice led to celebrate it in plunge pools. These, over time, became smaller where only fit the new baptized and not the celebrant, as was norm to do so in large pools. Obliged as a matter of hygiene, baptism by immersion moved to infusion baptism; and pools or baptismal fonts, which were already reduced in size, still further reduced, and only served to place the water and, at the same time, collect the water falling from the head of the baptized. Although the Second Vatican Council has issued rules for the dignified celebration of the sacrament of Baptism, nowadays in many churches are used bowls or basins. This historical evolution is interesting because it is parallel to the evolution of artistic trends of the time. Assuming that only the dioceses and parishes have been entrusted with the celebration of Baptism, in order to make an historical and current catalog of the existing and those that have existed, baptismal fonts have been studied all there are or there have been in these places of Worship. The informations in which is based this study has been obtained from written documents collected in archives, personal interviews and field work, collecting information “in situ” and creating a comprehensive photo archive. All information collected from baptismal fonts located in chapels, monasteries, shrines, private oratories, … has been incorporated. A parallelism has been done with other artistic baptismal fonts outside the scope of this study, as a comparison.

Σκοποί της εργασίας ήταν η επιδημιολογική μελέτη της MuSK-MG (μυασθένεια με αντι-MuSK αντισώματα) στην Ελλάδα, ο προσδιορισμός των υποτάξεων των IgG αυτοαντισωμάτων της MuSK-MG, η επίδραση της χορήγησης 4 MuSK-MG ορών στον AChR (υποδοχέα ακετυλοχολίνης) των κυττάρων της μυϊκής κυτταρικής σειράς ΤΕ671 και ο προσδιορισμός των ανοσογόνων επιτόπων της MuSK. Η επιδημιολογική μελέτη της MuSK-MG έλαβε χώρα μεταξύ 1 Ιανουαρίου 1986 και 30 Ιουνίου 2006 κι αφορούσε σε 33 ασθενείς. Ο προσδιορισμός των υποτάξεων των IgG αυτοαντισωμάτων πραγματοποιήθηκε με ραδιοανοσοκατακρήμνιση στους ορούς 14 ασθενών. Ο προσδιορισμός των ανοσογόνων επιτόπων της MuSK πραγματοποιήθηκε συνθέτοντας το εξωκυτταρικό κομμάτι της MuSK με τη μέθοδο Geysen της σύνθεσης πεπτιδίων σε στερεά φάση κι ελέγχοντας, στη συνέχεια, με τη μέθοδο ELISA, τη δέσμευση μιας σειράς MuSK-MG ορών στο τμήμα της MuSK που συνθέσαμε. Η μέση ετήσια επίπτωση της MuSK-MG στην Ελλάδα ήταν 0,32 ασθενείς/εκατομμύριο πληθυσμού/έτος. Στις γυναίκες, η έναρξη της MuSK-MG εμφανίστηκε μετά τα 30, ενώ, στους άνδρες, η νόσος εμφανίζεται σε κάθε δεκαετία. Οι περισσότεροι ασθενείς εμφάνισαν συμπτώματα από τους προσωπικούς κι αυχενικούς μύες. Η συντριπτική πλειονότητα των αυτοαντισωμάτων της MuSK-MG ήταν IgG4 υποτάξης. Σχετικά με την επίδραση των 4 MuSK-MG ορών στον AChR, οι οροί αυτοί ήταν ανίκανοι στην πρόκληση αποδόμησης του AChR των κυττάρων. Τέλος, δεν κατέστη δυνατός ο προσδιορισμός των ανοσογόνων επιτόπων της MuSK, αφού υπήρχαν αμινοξικές αλληλουχίες, στις οποίες ο αρνητικός μάρτυρας του πειράματος δεσμευόταν ισχυρότερα σε σχέση με τους MuSK-MG ορούς που δοκιμάσαμε. / The purposes of this study were to determine the epidemiological characteristics of muscle-specific kinase-myasthenia gravis (MuSK-MG) in Greece, the IgG subclass of the anti-MuSK antibodies, the effect of 4 MuSK-MG sera on the AChR of the cells of muscle cell line TE671 and the immunodominant epitopes of MuSK. This population-based study was performed on MuSK-MG patients in Greece between 1 January 1986 and 30 June 2006. Epidemiological and clinical data for 33 patients were collected. In addition, the distribution of anti-MuSK IgG autoantibody subclasses in the sera of 14 patients was determined by immunoprecipitation. The determination of the immunodominant epitopes on MuSK was performed by synthesizing the extracellular part of MuSK via Geysen method of peptide synthesis. Then, we performed ELISA method in order to determine the epitopes. The average annual incidence was 0.32 patients/million population/year. In females, onset of MuSK-MG occurred after the age of 30, whilst, in males, the disease appears in any decade. Most patients presented with involvement of the facial and bulbar muscles. The vast majority of anti-MuSK antibodies were IgG4. As far as the the effect of 4 MuSK-MG sera on the AChR of the cells is concerned, these sera were incapable of destroying the AChR effectively. Finally, we did not determine the immunodominant epitopes on MuSK, as there were amino acid sequences on which the negative control was bound with greater affinity than the MuSK-MG sera we tested.

Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat myocardial ischemia and congestive heart failure. GTN is proposed to act as a prodrug that requires bioactivation for pharmacological activity. However, continuous administration results in tolerance development, limiting its clinical usefulness. Aldehyde dehydrogenase 2 (ALDH2) has been proposed to be the primary enzyme responsible for GTN bioactivation, and ALDH2 inactivation has been proposed as the sole basis of nitrate tolerance. In the present study, we utilized an in vivo GTN tolerance model to investigate the role of ALDH2 in GTN bioactivation and tolerance. We assessed changes in ALDH2 protein, mRNA and activity levels in rat blood vessels during chronic GTN exposure (0.4 mg/hr for 6, 12, 24 and 48 hr) in relation to changes in vasodilator responses to GTN. A time-dependent decrease in both ALDH2 expression and activity occurred (80% in tolerant veins and 30% in tolerant arteries after 48 hrs exposure to GTN), concomitant with decreased vasodilator responses to GTN. However, after a 24 hr drug-free period following 48 hr GTN exposure, the vasodilator responses to GTN had returned to control values, whereas ALDH2 expression and activity were still markedly depressed. The dissociation between reduced ALDH2 activity and expression, and the duration of the impaired vasodilator responses to GTN in nitrate-tolerant blood vessels, suggest factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2008-10-03 16:14:49.313

Background: Exercise is widely recognized as the cornerstone of management of type II diabetes (T2D). However, it is also known that people with T2D have poor adherence to exercise regimens, which is largely thought to be because of poor exercise tolerance. Recent studies have suggested that this exercise intolerance may be caused by a reduction in exercising muscle blood flow. One physiological mechanism which could potentially contribute is the muscle metaboreflex (MMR). This mechanism is thought to be a pressure-based flow-improving mechanism, but as a result of reduced efficacy of vasodilators and sympatholytic agents, might in fact be restraining the flow-improvement in persons with T2D. Hypothesis: Persons with T2D would not improve exercising muscle blood flow upon MMR activation. This absence of flow-improvement will be due to an augmented vasoconstriction in the exercising muscle. Methods: T2D (n=7) and CTL (n=6) participants performed rhythmic forearm handgrip exercise at an intensity equivalent to 20% MVC for 9 minutes with and without the application of ischemic plantar flexion (IPF). Forearm blood flow (FBF), mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), total peripheral resistance (TPR) and forearm vascular conductance (FVK) were quantified for the last thirty seconds of each of four time points during the protocol. Plasma norepinephrine was measured via deep venous and arterialized venous blood sampling. Results: Steady state exercising FBF was increased in CTL but not in T2D during MMR activation (mean ± SE mL/min: CTLControl 161.16 ± 5.95, CTLMMR 212.72 ± 9.49, T2DControl 156.71 ± 13.08, T2DMMR 144.22 ± 10.55). This occurred despite similar increases in MAP, CO, HR, and TPR (across groups and treatment conditions, NS). FVK increased in CTL during the MMR protocol compared to the Control protocol, but decreased in the T2D group using the same comparison (mean ± SE mL/min/100 mm Hg: CTLControl 144.74 ± 5.63, CTLMMR 176.76 ± 11.99, T2DControl 143.29 ± 13.44, T2DMMR 103.53 ± 8.44). Conclusions: In the exercise model utilized, persons with T2D do not demonstrate the MMR-induced flow improvement seen in CTL. This impaired muscle blood flow in T2D is the result of MMR induced exercising limb vasoconstriction. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2012-01-31 09:30:42.604

Inducible LAK cell responses were studied in HIV-seropositive individuals lacking clinical symptoms, and overt AIDS patients. Inducible LAK cell responses have been operationally defined as, non-MHC-restricted and antigen-nonspecific cytotoxic activity observed following IL-2 stimulation. HIV-seropositive asymptomatic individuals exhibited an enhanced LAK cell response against HIV-infected targets while lysis of uninfected targets remained at control levels. LAK activity of AIDS patients however, was significantly diminished when compared to healthy controls. Immunomagnetic negative selection depletion experiments indicated that LAK cell activity is mediated primarily by CD56-expressing lymphocytes, both at the progenitor and effector cell level. Of interest, in HIV-seropositive asymptomatic individuals we observed the emergence of a second CD8-expressing cytotoxic population that mediates IL-2-induced non-MHC-restricted and antigen-nonspecific cytotoxicity. Overall we demonstrated that CD56-expressing LAK cells of HIV-seropositive patients exhibited a decreased ability to mediate cytotoxicity on a per cell basis against a panel of different targets. In vivo, this inhibition may be amplified by decreases in absolute numbers of CD56-expressing lymphocytes per ml of blood. HIV-infection therefore results in dramatic changes on the number, function and phenotype of the effector cells mediating IL-2 inducible LAK cell responses.

The phenomenal emergence of several heterogeneous wireless networks and technologies has allowed users to have access IP services anywhere at anytime from any network with whatever terminal they use. This computing platform has also been driven by the rapid evolution of mobile devices that are equipped with multiple network interfaces and the development of IP based applications. One of the challenging tasks with this Next-Generation Networks (NGN) computing platform is service continuity when users roam around different wireless networks e.g. Wi-Fi, Bluetooth and Cellular networks. This challenge is elevated more when dealing with applications that distribute time continuous data with stringent Quality of Service (QoS) requirements. One of the adaptation methods to ensure service continuity by minimizing flow interruptions when users are mobile is session handoff. The main contribution of the thesis is to present a handoff support system which implements a handoff decision engine using a Multi-Criteria Decision Making (MCDM) method based on a Bayesian Belief Network (BBN) and a handoff execution procedure based on buffering and doublecasting techniques. The handoff support system is built around the following features: 1) It utilises a proxy-based middleware architecture, 2) It uses a BBN based MCDM for handoff decision, 3) It is able to represent the full context information which represents the execution environment, 4) It is able to perform decision making under both certainty and uncertainty, 5) It is able to decide correctly on the target network under dynamic context, 6) It performs decision making in the midst of conflicting, interdependent and constraint criteria, and 7) It uses a profile-based handoff decision to offer personalisation to users. The experimental results showed that when compared with Analytical Hierarchy Process (AHP), the handoff decision method based on BBN performs better on: 1) Modelling of the handoff decision problem and the full representation of the context information, 2) Decision making under uncertainty, 3) Modelling of constraints and interdependent criteria and 4) Support for user preferences. When evaluating the handoff execution, further results revealed that the underlying handoff management strategies provide service continuity by minimising handoff latency and packet losses.

The challenge of parking management has increasingly posed the need for smart solutions. Motorists in today’s busy world seek the best option in locating available parking points. The need for an efficient parking system stems from increased congestion, motor vehicle pollution, driver frustration and fatigue to mention but a few. This study was conducted at a time when the world was experiencing a financial crisis and more than ever motorists needed intelligent parking systems to reduce the cost of gas spent driving around to find parking. Indeed, the time spent driving around would be beneficial if used to do work that would put one at an advantage in the credit recession. The study was also conducted at a time when South Africa was preparing to host the 2010 soccer world cup. In the preparation to manage motor vehicle congestion, this study was a viable solution to manage the expected challenge of parking. This study presents the design and illustrates the performance of an intelligent parking system based on an integrated architecture where (1) Wireless Sensor networks (WSNs) using Small Programmable Object Technology (SPOT) motes are launched into parking places to monitor the activity of the parking area through light intensity sensing and (2) the sensed information is gathered and channeled through a gateway into databases used for parking space visualization and information dissemination over the World Wide Web technology and mobile devices via a Multi Protocol label Switching (MPLS) network. Using an illustrative simulation model of a small parking system built around a new generation of SUNspot motes, the study demonstrates how a real life smart parking system can be deployed to benefit motorists in today’s busy World and serves as a foundation to future work on how this emerging generation of motes can be used to provide better ways of finding parking.