Untersuchungen zur transkriptionellen Regulation des Chromogranin A Gens und seine Anwendung zum zellspezifischen therapeutischen Gentransfer in neuroendokrine Pankreastumorzellen

Die Therapieoptionen zur Behandlung metastasierter neuroendokriner Tumore sind bisher ineffektiv. Der regulierte Gentransfer könnte eine weitere Möglichkeit eröffnen, metastasierte neuroendokrine Tumore zu behandeln. In der vorliegenden Arbeit wurde daher die transkriptionelle Regulation von Chromogranin A als Basis zur Gentherapie durch eine regulierte Genexpression in neuroendokrinen Tumorzellen untersucht. Chromogranin A (CgA) besitzt vielfältige Funktionen in der regulierten Sekretion von Peptidhormonen und Neurotransmittern. Es wird spezifisch in nahezu allen endokrinen und neuroendokrinen Zellen exprimiert und diagnostisch als Marker bei neuroendokrinen Tumorerkrankungen eingesetzt. Zur Identifizierung wichtiger cis-regulatorischer Elemente im humanen Chromogranin A Promotor wurde die 5'-flankierende Sequenz des hCgA Gens auf putative Transkriptionsfaktorbindungsseiten untersucht und eine Interspezieshomologie des humanen, bovinen, murinen und des Rattenchromogranin A Promotors erstellt. Es fand sich eine konservierte Sequenzhomologie in den proximalen Chromogranin A Promotorbereichen mit den putativen Transkriptionsfaktor-Bindungsseiten Egr-1/Sp1, CRE und TATA-Box. Untersuchungen zur zelltypspezifischen Regulation des Chromogranin A Promotors ergaben eine starke Expression von Chromogranin A in neuroendokrinen Pankreastumorzellen BON-1 und der Lungenkarzinomzelllinie EPLC 32M1, während sich nur eine geringe Expression in nicht neuroendokrinen Zelllinien wie z.B. der Fibroblastenzelllinie MSTO-211H zeigte. Die neuroendokrin-spezifische Regulation wurde im hCgA Promotor durch das im proximalen Promotorbereich gelegene CRE vermittelt. Ebenso konnte gezeigt werden, dass Gastrin und cAMP den hCgA Promotor über das CRE regulieren. Unter Anwendung des charakterisierten hCgA Promotors konnte die funktionelle Expression des Natriumjodidsymporters unter der Kontrolle des humanen CgA Promotors in BON 1 Zellen nachgewiesen werden. Dies bildet einen vielversprechenden neuen Therapieansatz, durch einen regulierten Gentransfer neuroendokrine Tumorzellen mittels einer Radiojodtherapie in Analogie zu Schilddrüsenkarzinomen zu behandeln

Effects of acute and sub-chronic ammonium nitrate exposure on rat liver and blood tissues

Use of fertilizers like ammonium nitrate (NH4NO3) for agricultural purposes has increasingly contaminated the ecosystem with nitrate and/or nitrites. Nitrite is a toxic substance that can cause multiple physiological effects if allowed to build up to high concentrations in animals such as methemoglobinemia. This work is concerned with the study of short term (3 days intoxication) and midterm (over 21 days) NH4NO3 exposure to wistar rats at the dose of 250 mg/Kg. Under these conditions, some hematological and biochemical parameters were affected. Methemoglobinemia, increase in serum nitrates as well as a hepatic cytotoxicity indicated by an increase in bilirubin and transaminases levels were observed

Negotiating the Maze: Case based, Collaborative Distance Learning in Dentistry

The module was developed as an elective to give motivated senior dental students an opportunity to expand their horizons in planning oral rehabilitation. It comprised one tutor and 12 students, from five universities world-wide, communicating on the World Wide Web (WWW), to develop oral rehabilitation plans for simulated patients. Trigger material came from one of two Case Profiles and consisted of diagnostic casts and details of the clinical and radiographic examination in WWW/CD-ROM form. No background material was supplied as to the "patient's" age, sex, history or main concern(s). Students worked in groups of three, each student from a different location. Individual students were given a role within the group: "Patient", who developed a "personal background" belonging to the trigger examination material, "Academic" who identified state-of-the-art treatment options available for the dental treatment needs identified by the group and "General Practitioner" who tailored these options to the "patient's" needs and wants. Student feedback focused on their perception of their experience with the program in response to a questionnaire comprising 11 structured and four "open" questions. All students felt that the program increased their confidence in planning oral rehabilitation. Ten students felt that the "best thing about the program" was the interaction with students from other universities and the exposure to different philosophies from the different schools. Eight students mentioned their increased awareness of the importance of patient input into holistic planning. Under the heading "What was the worst thing", students cited some technical hitches and the snowball effect of two sluggish students who were not identified early enough and thus impacted negatively on the working of their groups. Student feedback showed that the module succeeded in its aims but needed modification to improve the logistics of working with an extended campu

Navigating Scholarly Development Through a CoP: #generational-lenses

CoPs provide opportunity for professional identity exploration. Extant research neglects how multiple identities, including generational memberships, influence development. This study explores professional identity development of scholars within a multigenerational CoP