High Grade Serous Carcinoma is the most aggressive tubal/ovarian histotype. The Rb pathway, which functions to preserve cell cycle regulation and genomic stability, is frequently deregulated in HGSC. The aim of this study was to identify non-redundant mechanisms of Rb pathway deregulation with clinical relevance. Immunohistochemistry analysis of P16 and RB1 expression identified a P16 homogeneous/RB1+ subgroup with the shortest recurrence free survival, while P16 heterogeneous/RB1+ and P16 homogenous/RB1- subgroups showed longer recurrence free survival. These P16/RB1 categories were shared between precursor lesions and the associated HGSC. Characterization of the Rb pathway in the three subgroups revealed CCNE1 amplification and highest protein expression in the P16 homogeneous/RB1+, high cyclin D1 protein expression in P16 heterogeneous/RB1+, and E2F3 amplification and highest Ki67 protein expression in P16 homogeneous/RB1- subgroup. Rb pathway deregulation is common in HGSC, occurs early in tumor development, and results from multiple non-redundant mechanisms that correlate with clinical outcome.

High Grade Serous Carcinoma is the most aggressive tubal/ovarian histotype. The Rb pathway, which functions to preserve cell cycle regulation and genomic stability, is frequently deregulated in HGSC. The aim of this study was to identify non-redundant mechanisms of Rb pathway deregulation with clinical relevance. Immunohistochemistry analysis of P16 and RB1 expression identified a P16 homogeneous/RB1+ subgroup with the shortest recurrence free survival, while P16 heterogeneous/RB1+ and P16 homogenous/RB1- subgroups showed longer recurrence free survival. These P16/RB1 categories were shared between precursor lesions and the associated HGSC. Characterization of the Rb pathway in the three subgroups revealed CCNE1 amplification and highest protein expression in the P16 homogeneous/RB1+, high cyclin D1 protein expression in P16 heterogeneous/RB1+, and E2F3 amplification and highest Ki67 protein expression in P16 homogeneous/RB1- subgroup. Rb pathway deregulation is common in HGSC, occurs early in tumor development, and results from multiple non-redundant mechanisms that correlate with clinical outcome.

No description available.

<p>Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects. </p><p>Polymorphisms in serotonin 2A and 2C receptor coding genes (<i>HTR2A</i> and <i>HTR2C</i>) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and <i>HTR2C</i> polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with <i>CYP1A2</i> but not with <i>CYP2D6</i> polymorphisms. Furthermore, <i>HTR2C</i> and <i>HTR2A</i> polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (<i>ABCB1</i>) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of <i>ABCB1 </i>genotype on 9-hydroxyrisperidone and active moiety C/Ds, while <i>CYP2D6</i> genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D. </p><p>We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for <i>HTR2A</i>, <i>HTR2C</i>, <i>CYP1A2</i>, <i>CYP2D6</i> and <i>ABCB1</i> polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.</p>

Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects. Polymorphisms in serotonin 2A and 2C receptor coding genes (HTR2A and HTR2C) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and HTR2C polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with CYP1A2 but not with CYP2D6 polymorphisms. Furthermore, HTR2C and HTR2A polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of ABCB1 genotype on 9-hydroxyrisperidone and active moiety C/Ds, while CYP2D6 genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D. We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for HTR2A, HTR2C, CYP1A2, CYP2D6 and ABCB1 polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23795号 / 医博第4841号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 石見 拓, 教授 湊谷 謙司, 教授 山本 洋介 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25179号 / 医博第5065号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 石見 拓, 教授 大鶴 繁 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Distal radius fracture (DRF) is the most common fracture encountered in clinical practice. Every year, more than 20000 people in Sweden suffer from this injury. It has been shown that there is a correlation between malalignment and function following distal radial fractures and malunion may cause persistent pain and disability. A problem has been in making a correct initial assessment of the fracture. Many fractures are unstable despite an acceptable position on the initial radiographic examination or following a successful closed fracture reduction. Numerous classification systems have been developed for evaluation of DRF in order to predict the outcome. However, the values of these are limited since they have not shown satisfactory reliability. Furthermore, the utility of these systems to predict radiographic or clinical outcome is not yet proven. These shortcomings may be one reason why optimal DRF management is still controversial. Requests for a new classification system of DRF, predictive of outcome and easy to use, have been made. Improvement in initial assessment of DRF will benefit a large group of patients, as well as the society, by reducing persistent symptoms and disability. Study I: In this study we evaluated the interobserver and intraobserver reliability of a new classification system (the Buttazzoni classification). Two hundred and thirty-two patients with acute DRF were blindly evaluated using the new classification by three orthopaedic surgeons twice with a 1-year interval. The new classification showed fair to substantial interobserver and intraobserver reliability, i.e., results comparable with other commonly used classification systems. Study II: This was a prospective multicenter study of fracture stability in 428 DRF. The study investigated whether cortical comminution and intra-articular involvement, as well as the new classification system, could predict displacement in DRF. Logistic regression analysis showed that initial position of the fracture and volar or dorsal comminution predicted later displacement, while intra-articular involvement did not. Volar comminution was the strongest predictor of displacement. The new classification system, which is the first to include volar comminution as a separate parameter, was highly predictive of fracture instability. Furthermore we found that it is quite common for non-operatively treated fractures to displace at a later stage than two weeks. Study IV: In study II it was found that late displacement of DRF, still in acceptable radiologic position after 10-14 days, occurred in approximately 1/3 of cases. Despite this, we have not been able to find any study focusing on evaluating the clinical outcome in patients with late displacement. Two hundred and nine unilateral DRF from study II were still in good position after 10-14 days and were included in the study. One hundred and seventy five patients had radiographs taken at a minimum of 3 months and a clinical examination 1 year after the fracture. Late displaced distal radius fractures had significantly higher loss of ROM and grip strength compared to fractures that didn’t displace. No significant differences were seen in subjective outcome. In conclusion, initial position of the fracture predicted later displacement and was the most important parameter in predicting clinical outcome. Comminution of the fracture also affected radiological stability and clinical outcome. Volar comminuted fractures are highly unstable and need surgical intervention if displacement is to be avoided. Intra-articular involvement affected clinical outcome. Late displacement is common in DRF and may result in loss of range of motion and grip strength. To detect late displacement, DRF should be followed for more than 2 weeks. The new classification system had a moderate reliability and reproducibility. The classification was found predictive of radiologic and objective clinical outcome. However, it was not predictive of subjective outcome. The classification system was also predictive of fractures at risk for late displacement.

Background: Abdominal solid organ transplantation has evolved from an experimental procedure to a well-established therapy within a few decades. This success is largely due to the introduction of calcineurin inhibitor immunosuppression. Tacrolimus is the most widely used calcineurin inhibitor but has a narrow therapeutic range which requires close drug monitoring to prevent both toxicity and inadequate immunosuppression. Previous studies in renal transplantation have shown that genetic polymorphisms, CYP3A5, CYP3A4*22 and ABCB1 can influence the bioavailability and pharmacokinetics of tacrolimus. These polymorphisms are closely linked to ethnicity and have never been studied in a Scottish population before. Additionally, increasing evidence suggests that high variability of tacrolimus is linked to increased graft loss in kidney transplant patients. Methods: 5889 subjects were genotyped for the genetic polymorphisms CYP3A5 A > G allele transition, CYP3A4*22 C > T and ABCB1 C > T transition. This included 4899 healthy individuals from Generation Scotland bio-resource and 990 patients who underwent renal, liver, or simultaneous pancreas kidney transplants or were organ donors. Tacrolimus dose, trough level and renal function were measured at 11 time points from date of transplant up to and including 12 months post-transplant. Clinical data including episodes of acute rejection, graft and patient survival were compared between the different genotypes. Separate analyses were undertaken for kidney, SPK transplants, as well as liver transplants, the latter looking at recipient and liver donor genotype. A separate cohort of 103 renal transplant patients converted from twice-daily to once-daily tacrolimus had their tacrolimus variability calculated and compared with graft survival. Results: The distribution of the 3 different genotypes of CYP3A5, CYP3A4*22 and ABCB1 were comparable with other Caucasian populations studied previously. In renal transplant recipient expression of the A allele (GA/AA) led to significantly increased dose requirements of tacrolimus and initially lower tacrolimus trough levels. The different genotypes of ABCB1 had no effect. Expression of a CYP3A4*22 T allele trended towards a lower tacrolimus dose requirement but this was not significant. There was no difference in renal function, graft survival or patient survival with any of the polymorphisms. SPK patients had comparable results. In the liver transplant patients, the donor genotype had a greater influence than the recipient one. The donors with CYP3A5 A allele expression had significantly higher tacrolimus dose requirements and lower initial tacrolimus levels. This was apparent to a lesser extent with the recipient expression of CYP3A5 and did not reach statistical significance at all time points. There was no significant difference in tacrolimus dose requirements or level with either donor or recipient expression of ABCB1 or CYP3A4*22. There was a significantly higher incidence of acute rejection in donor CYP3A5 A allele expressers of liver transplant patients in univariate and multivariate analysis. There was no significant different in acute rejection with ABCB1 or CYP3A4*22 genotype. No differences in graft or patient survival with either donor or recipient genotype of any of the 3 polymorphisms were noted. Conversion from twice-daily to once-daily tacrolimus in the first 12 months post-transplant reduced tacrolimus variability. Patients with high tacrolimus variability pre and post conversion had significantly greater graft loss than patients with low tacrolimus variability. Conclusion: CYP3A5 expression results in increased tacrolimus requirements to achieve adequate immunosuppression in renal transplant and SPK patients. Donor rather than recipient CYP3A5 expression is relevant for liver transplantation and dose requirements. There may be an association with donor CYP3A5 expression in liver transplant patients and acute rejection which needs further evaluation. ABCB1 and CYP3A4*22 do not appear to have a significant impact in any of the organ transplants. High tacrolimus variability is associated increased graft loss in renal transplant patients.