Thesis (Ph. D.)--University of Chicago, Dept. of Pathaology, 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (M.S.)--California Polytechnic State University, 2009. / Title from PDF title page; viewed on January 6, 2010. Major professor: Brooke D. Humphrey, Ph.D. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Agriculture, with Specialization in Animal Science." "October 2009." Includes bibliographical references (p. 102).

Thesis (Ph. D.)--University of Virginia, 2001. / Includes bibliographical references (leaves 182-215). Also available online through Digital Dissertations.

Bakgrund: Sjuksköterskeutbildningen är treårig. I den ingår teoretisk och verksamhetsförlagd utbildning inom psykiatrisk vård. Studenter behöver förberedas med att träna för att få förmågan att möta och hantera patienter med psykisk ohälsa. Syfte: Syftet med studien var att undersöka hur sjuksköterskestudenter uppfattar akuta omhändertaganden av patienter på psykiatriska akuta vårdavdelningar. Metod: En kvalitativ induktiv metod valdes. Tio intervjuer med semistrukturerade intervjufrågor genomfördes med studenter under termin tre på sjuksköterskeprogram i Mellansverige. Datamaterialet analyserades med manifest innehållsanalys enligt Graneheim och Lundman (2004). Resultat: Ur analysen framkom två kategorier: sjuksköterskans arbetssituation och studentens reflektion över patientens situation. Vidare framkom fem subkategorier: speciellt att sätta gränser och vårda inom akut psykiatrisk vård, anpassa stöd och samtal, använda sig själv som ett redskap, etiska reflektioner och olika perspektiv. Konklusion: Studien visar att studenterna inte har tillräcklig teoretisk eller erfarenhetsmässig kompetens i rollen som sjuksköterskestudent på en psykaitrisk akutavdelning när de ska utföra VFU. Med  anledning av avdelningsinriktning, kort placering och akuta situationer de möts av inom psykiatrisk verksamhet, finns behov för studenterna att få mer psykiatrikunskap innan den kliniska praktiken utförs. Akuta omhändertaganden i psykiatriska situationer uppfattas därför mer sensitivt, svårförstådda och svåra att hantera av studenterna. / Background: Training to become a nurse is three years and includes theoretical and clinical training in psychiatric care. Students need to be prepared to practice to get the ability to meet and manage patients with mental illness. Objective: The aim of this study was to examine how nursing students perceive the emergency care order of patients in acute psychiatric wards. Method: A qualitative inductive method was chosen and ten interviews with semi-structured interview questions were conducted with students during the third semester in nursing programs in central Sweden. The data were analyzed by content analysis according Graneheim and Lundman (2004). Results: From the analysis revealed two categories: Nurses work situation and student reflection on the patient's situation. It was also found five subcategories: especially to set limits and take care in emergency psychiatric care, customize support and conversation, using her own as a tool, students' ethical reflections and different perspectives. Conclusion: The study shows that students do not have sufficient theoretical or experiential expertise in the role of a nursing student, in a psychiatric emergency department. The study shows that students do not have sufficient theoretical or experiential expertise in the role of a nurse, in a psychiatric emergency department. Because of the departments focus, where students are located and emergency situations they encounter in psychiatry, there is a need for students to gain more knowledge before psychiatry clinical practice is carried out. Acute psychiatric nursing care in situations perceived therefore more sensitive, difficult to understand and difficult to manage by the students.

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medicine / Master / Master of Philosophy

Acute myeloid leukemia (AML) is a heterogeneous disease both clinically and biologically. Approximately 55% of AML harbour karyotypic changes, and one of the most common chromosomal aberrations is the t(8;21)(q22;q22), which leads to the AML1-ETO fusion protein. Previous studies have found that this fusion protein recruits the N-CoR/mSin3A/HDAC complex, thereby acts as a transcriptional repressor. Recently, DNA methylation array studies have shown that DNA methylation patterns can stratify AML cases into different subgroups, and some of these correspond to certain chromosomal abnormalities, such as the t(8;21). These findings suggest a possible link between the fusion transcript AML1-ETO and epigenetic modifications. Additionally, c-kit mutations have emerged as an important disease modifier in the t(8;21) AML and are correlated with poor overall survival and event free survival in patients with t(8;21) AML. We therefore sought to investigate whether there are different DNA methylation patterns in t(8;21) AML with or without c-kit mutations. In our series, 52.2% of the t(8;21) AMLs harbored c-kit mutations, which were correlated with poor event free survival. We next performed pyrosequencing on a selected panel of genes and pinpointed the THBS4 and PAWR genes as hypermethylated in their promoter CpG islands in 86.4% and 59.1% of the t(8;21) AML patients, respectively. These data suggest that THBS4 and PAWR may be important in the pathogenesis of t(8;21) AML. / published_or_final_version / Pathology / Master / Master of Philosophy

Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts in circulation and/or bone marrow. Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene occurs in about 30% of AML and is associated with an inferior prognosis. Tyrosine kinase domain (TKD) mutations occur in about 5% with uncertain prognostic significance. Intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However these approaches have reached a deadlock with a cure rate of 30-40%. Targeting FLT3 in AML with multi-tyrosine-kinase inhibitors has been evaluated in Phase II/III clinical trials. Despite an initial clearance of myeloblasts, the leukemia invariably progresses despite continuous treatment. The mechanisms of drug resistance and leukemia progression, hence the effective therapeutic strategies are currently unknown, limiting its clinical application. These issues were addressed in the present study. In the first part, 13 patients with chemo-refractory or relapsed FLT3-ITD+ AML received sorafenib 200-400 mg twice daily of whom 12 patients achieved clearance or near clearance of bone marrow blasts after a median of 27 days (range 21-84 days). There was evidence of myeloid differentiation of the leukemia blasts at remission. Leukemia progression occurred in 9 patients after a median of 72 days (range 54-287 days) and in 4 out of 6 patients it was dominated by clones carrying double FLT3-ITD and -TKD mutations. Microarray studies comparing myeloblasts before sorafenib treatment (sorafenib naïve) and at subsequent progression (sorafenib resistant) demonstrated up-regulation of 64 genes including ALDH1A1, JAK3 and TESC whose functions were unknown in AML. Transplantation of sorafenib naïve and resistant myeloblasts into NOD/SCID mice recapitulated their clinical behavior when the animals were treated with sorafenib. Both ITD and TKD mutations at D835 were identified in leukemia initiating cells (LICs) from sorafenib naïve samples. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations. In the second part, the gene encoding tescalcin (TESC), that was up-regulated at sorafenib resistance and was known to activate a sodium/hydrogen exchange (NHE1), was evaluated to examine its link with TKI resistance. TESC was highly expressed in FLT3-ITD+ AML cell lines MOLM-13 and MV4-11 and its knock-down by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N,N-Hexamethylene)amiloride (HMA). Induction of sorafenib resistance in MOLM-13 cell line (MOLM-13-RE) significantly increased its sensitivity to HMA. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. Normal CD34+ cells engraftment was not affected. HMA treatment significantly enhanced suppression of FLT3 signaling by sorafenib even in sorafenib resistant cell lines. These observations provided novel information about the pathogenetic role of TESC-NHE1-pHi in sorafenib resistance in AML. In conclusion, the information derived from the present study has provided mechanistic insights to the emergence of drug resistance during sorafenib treatment and important guide for future therapeutic strategies targeting FLT3-ITD+ AML. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Acute promyelocytic leukemia (APL) is one of the subtypes of acute myeloid leukemia carrying t(15;17), and constitutes 10 to 15% of adult AMLs. One of the mechanisms of gene inactivation is hypermethylation of promoter-associated CpG islands. Cancers are characterized by global hypomethylation with locus-specific hypermethylation and hence silencing of tumor suppressor genes. Apart from tumor suppressor genes, microRNA, a class of non-coding RNA measuring 19-25 nucleotides, with tumor suppressive function is also found to be inactivated by DNA methylation in hematological malignancies. microRNAs repress target gene translation and hence expression by binding to 3'-untranslated region of corresponding mRNA. Because TP53 mutation is frequently involved in solid cancer carcinogenesis but is rarely found in APL, TP53 network may be dysregulated through epigenetic inactivation of tumor suppressor gene/miRNAs engaged in TP53 tumor suppressor network. This thesis aimed to study DNA methylation of tumor suppressor genes and miRNAs engaged in TP53 tumor suppressor network in APL. Overall survival (OS) and event free survival (EFS) of patients with or without candidate gene/miRNA hypermethylation were compared to examine their prognostic significances. Promoter methylation of DAPK1, p14ARF, miR-34a, miR-34b/c and miR-605 were studied in 10 normal bone marrow samples, NB4 cell line and 60 APL primary samples at diagnosis by methylation-specific PCR (MSP). DAPK1, miR-34a, miR-34b/c and miR-605 were completely unmethylated in normal bone marrow samples but completely methylated in NB4. Treatment of NB4 by 5'-Aza-2'-deoxyctidine (5-azadC) resulted in promoter demethylation together with re-expression of DAPK1, miR-34a, miR-34b/c and miR-605. Promoter methylation of DAPK1, p14ARF, miR-34a were absent while miR-34b/c and miR-605 methylation were detected in 43% and 10% APL samples respectively. However, methylation of miR-34b/c and miR-605 bore no prognostic significance. Overexpression of miR-34b in NB4 resulted in inhibition of proliferation. In short, methylation of DAPK1, miR-34a, miR-34b/c and miR-605 is associated with gene/miRNAs silencing. miR-34b/c is frequently methylated whereas miR-605 is methylated in small number of APL patients. miR-34b/c is a tumor suppressive miRNA in APL. Methylation of miR-34b/c may contribute to APL leukemogenesis. / published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine