京都大学 / 新制・課程博士 / 博士(医学) / 甲第24878号 / 医博第5012号 / 新制||医||1068(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 萩原 正敏, 教授 湊谷 謙司, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Yes / Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research in the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystal and compare the performance of ball mill and jet mill, using caffeine-glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I; whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size but ball milling was unable to reduce the particle beyond certain limit even with increasing milling intensity. Heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general.

No / Knowledge and control of the polymorphic phases of chemical compounds are important aspects of drug development in the pharmaceutical industry. Salmeterol xinafoate, a long acting β-adrenergic receptor agonist, exists in two polymorphic Forms, I and II. Raman and near infrared spectra were obtained of these polymorphs at selected wavelengths in the range of 488–1064 nm; significant differences in the Raman and near-infrared spectra were apparent and key spectral marker bands have been identified for the vibrational spectro-scopic characterisation of the individual polymorphs which were also characterised with X ray diffractometry. The solid-state transition of salmeterol xinafoate polymorphs was studied using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry isothermally between transitions. This method assisted in the unambiguous characterisation of the two polymorphic forms by providing a simultaneous probe of both the thermal and vibrational data. The study demonstrates the value of a rapid in situ analysis of a drug polymorph which can be of potential value for at-line in-process control.

Video applications are becoming ubiquitous in recent times due to an explosion in the number of devices with video capture and display capabilities. Traditionally, video applications are implemented on a variety of devices with each device targeting a specific application. However, the advances in technology have created a need to support multiple applications from a single device like a smart phone or tablet. Such convergence of applications necessitates support for interoperability among various applications, scalable performance meet the requirements of different applications and a high degree of reconfigurability to accommodate rapid evolution in applications features. In addition, low power consumption requirement is also very stringent for many video applications. The conventional custom hardware implementations of video applications deliver high performance at low power consumption while the recent MPSoC implementations enable high degree of interoperability and are useful to support application evolution. In this thesis, we combine the best features of custom hardware and MPSoC approaches to design a Polymorphic ASIC. A Polymorphic ASIC is an integrated circuit designed to meet the requirements of several applications belonging to a particular domain. A polymorphic ASIC consists of a fabric of computation, storage and communication resources, using which applications are composed dynamically. Although different video applications differ widely in the internal de-tails of operation, at the heart of almost every video application is a video codec (encoder and decoder). The requirements of scalability, high performance and low power consumption are very stringent for video decoding. Therefore this thesis focuses mainly on the architectural design of a Polymorphic ASIC for video decoding. We present an unified software and hardware architecture (USHA) for Polymorphic ASIC. USHA is a tiled architecture which uses loosely coupled processor and hardware tiles that are software programmable and hardware reconfigurable respectively. The distinctive feature of Polymorphic ASIC is the static partitioning of the application and dynamic mapping of ap-plication processes onto the computational tiles. Depending on the application scenarios, a process may be mapped onto one of the hardware or processor tiles. Polymorphic ASIC incor-porates a network–on–chip (NoC) to achieve flexible communication across different tiles. Formulation of a programming framework for Polymorphic ASIC requires an implementation model that captures the structure of video decoder applications as well as the properties of the Polymorphic ASIC architecture. We derive an implementation model based on a combination of parametric polyhedral process networks, stream based functions and windowed dataflow models of computation. The implementation model leads to a process network oriented compilation flow that achieves realization agnostic application partitioning and enables seamless migration across uniprocessor, multi–processor, semi hardware and full hardware configurations of a video decoder. The thesis also presents an application QoS aware scheduler that selects a decoder configuration that best meets the application performance requirements, thereby enabling dynamic performance scaling. The memory hierarchy of Polymorphic ASIC makes use of an application specific cache. Through a combined analysis of miss rate and external memory bandwidth, we show that the degradation in decoder performance due to memory stall cycles depends on the properties of the video being decoded as well as the behavior of the external memory interface. Based on this observation, we present the design of a reconfigurable 2–D cache architecture which can adjust its parameters in accordance with the characteristics of the video stream being decoded. We validate the Polymorphic ASIC using a proof–of–concept implementation on an FPGA. The performance of H.264 decoder on Polymorphic ASIC is evaluated for uniprocessor, multi processor, hardware accelerated and full hardware configurations. The scaling in performance delivered by these configurations shows that the Polymorphic ASIC enables the application to achieve super linear speedups [1]. The experimental results show that different implementations of a H.264 video decoder on the Polymorphic ASIC can deliver performance comparable to a wide spectrum of devices ranging from embedded processor like ARM 9 to MPSoCs like IBM Cell. We also present the energy consumption of various configurations of video decoders on Polymorphic ASIC and an application to configuration mapping aimed at minimizing the overall energy consumption of a Polymorphic ASIC.

Video applications are becoming ubiquitous in recent times due to an explosion in the number of devices with video capture and display capabilities. Traditionally, video applications are implemented on a variety of devices with each device targeting a specific application. However, the advances in technology have created a need to support multiple applications from a single device like a smart phone or tablet. Such convergence of applications necessitates support for interoperability among various applications, scalable performance meet the requirements of different applications and a high degree of reconfigurability to accommodate rapid evolution in applications features. In addition, low power consumption requirement is also very stringent for many video applications. The conventional custom hardware implementations of video applications deliver high performance at low power consumption while the recent MPSoC implementations enable high degree of interoperability and are useful to support application evolution. In this thesis, we combine the best features of custom hardware and MPSoC approaches to design a Polymorphic ASIC. A Polymorphic ASIC is an integrated circuit designed to meet the requirements of several applications belonging to a particular domain. A polymorphic ASIC consists of a fabric of computation, storage and communication resources, using which applications are composed dynamically. Although different video applications differ widely in the internal de-tails of operation, at the heart of almost every video application is a video codec (encoder and decoder). The requirements of scalability, high performance and low power consumption are very stringent for video decoding. Therefore this thesis focuses mainly on the architectural design of a Polymorphic ASIC for video decoding. We present an unified software and hardware architecture (USHA) for Polymorphic ASIC. USHA is a tiled architecture which uses loosely coupled processor and hardware tiles that are software programmable and hardware reconfigurable respectively. The distinctive feature of Polymorphic ASIC is the static partitioning of the application and dynamic mapping of ap-plication processes onto the computational tiles. Depending on the application scenarios, a process may be mapped onto one of the hardware or processor tiles. Polymorphic ASIC incor-porates a network–on–chip (NoC) to achieve flexible communication across different tiles. Formulation of a programming framework for Polymorphic ASIC requires an implementation model that captures the structure of video decoder applications as well as the properties of the Polymorphic ASIC architecture. We derive an implementation model based on a combination of parametric polyhedral process networks, stream based functions and windowed dataflow models of computation. The implementation model leads to a process network oriented compilation flow that achieves realization agnostic application partitioning and enables seamless migration across uniprocessor, multi–processor, semi hardware and full hardware configurations of a video decoder. The thesis also presents an application QoS aware scheduler that selects a decoder configuration that best meets the application performance requirements, thereby enabling dynamic performance scaling. The memory hierarchy of Polymorphic ASIC makes use of an application specific cache. Through a combined analysis of miss rate and external memory bandwidth, we show that the degradation in decoder performance due to memory stall cycles depends on the properties of the video being decoded as well as the behavior of the external memory interface. Based on this observation, we present the design of a reconfigurable 2–D cache architecture which can adjust its parameters in accordance with the characteristics of the video stream being decoded. We validate the Polymorphic ASIC using a proof–of–concept implementation on an FPGA. The performance of H.264 decoder on Polymorphic ASIC is evaluated for uniprocessor, multi processor, hardware accelerated and full hardware configurations. The scaling in performance delivered by these configurations shows that the Polymorphic ASIC enables the application to achieve super linear speedups [1]. The experimental results show that different implementations of a H.264 video decoder on the Polymorphic ASIC can deliver performance comparable to a wide spectrum of devices ranging from embedded processor like ARM 9 to MPSoCs like IBM Cell. We also present the energy consumption of various configurations of video decoders on Polymorphic ASIC and an application to configuration mapping aimed at minimizing the overall energy consumption of a Polymorphic ASIC.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science. Pretoria 1991. / Remote sensing can be used to produce maps of land-cover, but to be of use to the GIS community these maps must first be vectorized in an intelligent manner. Existing algorithms suffer from the defects of being slow, memory intensive and producing vast quantities of very short vectors. Furthermore if these vectors are thinned via standard algorithms, errors are introduced. The process of vectorizing raster maps is subject to major ambiguities. Thus an infinite family of vector maps ccrresponds to each raster map. This dissertation presents an algorithm for converting raster maps in a rapid manner to accurate vector maps with a minimum of vectors. The algorithm converts raster maps to vector maps using local information only, (a two by two neighbourhood). the method is "exact" in the sense that rasterizing the resulting polygons would produce exactly the same raster map, pixel for pixel. The method is "near optimal" in that it produces, in a local sense, that "exacb" vector map having the least number of vectors. The program is built around a home-grown object oriented Programming System (OOPS) for the C programming language. The main features of the OOPS system, (called OopCdaisy), are virtual and static methods, polymorphism, generalized containers, container indices and thorough error checking, The following general purpose objects are implemented with a large number of sophistiated methods :- Stacks, LIFO lists, scannable containers with indices, trees and 2D objects like points, lines etc. / AC2017

Made available in DSpace on 2016-08-10T10:29:34Z (GMT). No. of bitstreams: 1 Wilma Gomes Galvao.pdf: 1683869 bytes, checksum: fab2810f336fcca017df31d20e4619cc (MD5) Previous issue date: 2009-06-25 / Many pharmaceutical products are in solid state for reasons of stability or ease of handling during the stages of drug development. The polymorphism is the crystallization of the same substance in different crystalline architectures. This phenomenon is very common in pharmaceuticals and is associated with differences in packing arrangements of crystalline. The presence of different crystalline forms for the same drug can change some of its physicochemical properties such as solubility, which can directly affect their bioavailability and therapeutic efficacy. In this context, carbamazepine has served as a model compound for the study of polymorphism, where an analysis of its structural diversity has sought to evaluate the susceptibility polymorphic. Significant differences between the polymorphic forms of anhydrous carbamazepine were characterized by spectroscopic methods and difratometria, especially the X-ray diffraction, the important structural information provided. Where Polymorphic susceptibility to the more stable form can be observed due to several factors including the energy content is highlighted. / Muitos produtos farmacêuticos encontram-se no estado sólido por motivos de estabilidade ou por facilidade no manuseio durante as etapas de desenvolvimento da droga. O polimorfismo é a cristalização de uma mesma substância em diferentes arquiteturas cristalinas. Este fenômeno é muito comum em produtos farmacêuticos e está associado às diferenças nos arranjos da embalagem cristalina. A presença de diferentes formas cristalinas para um mesmo fármaco pode alterar algumas das suas propriedades físico-químicas, tais como a solubilidade, o que pode afetar diretamente sua biodisponibilidade e sua eficácia terapêutica. Neste contexto, a carbamazepina tem servido de composto modelo para o estudo do polimorfismo, onde uma análise de sua multiplicidade estrutural tem buscado avaliar a susceptibilidade polimórfica. Significantes diferenças entre as formas polimórficas anidras da carbamazepina foram caracterizadas por métodos espectroscópicos e difratométricos, em especial a difração de raios X, pelas importantes informações estruturais fornecidas. Onde a suscetibilidade polimórfica para forma mais estável pode ser observada em função de vários fatores entre eles se destaca o conteúdo energético.

O melanoma é uma lesão maligna da pele, com alta taxa de mortalidade cuja incidência vem aumentando nos últimos anos. Os principais fatores de risco são a história familial da doença, presença de nevos benignos múltiplos ou nevos atípicos e melanoma prévio. Imunossupressão, sensibilidade ao sol e exposição intermitente e intensa à radiação UV da luz solar, sem proteção, são fatores de risco adicionais. O objetivo deste estudo caso-controle de base hospitalar foi avaliar a contribuição de polimorfismos de genes de metabolização de xenobióticos (CYP1A1/MspI, CYP2E1/PstI, GSTM1, GSTT1 e GSTP1/Bsma), de genes de reparo do DNA (XRCC1/MspI, XRCC3/NcoI e XPD/PstI) e do gene do receptor de vitamina D (VDR/FokI e VDR/TaqI) no risco de melanoma. Consentiram em participar 193 pacientes com melanoma (49,7% homens e 50,3% mulheres, média de 52 ± 14,28 anos) e 208 controles (51,4% homens e 48,6% mulheres, média de 48 ± 15,24 anos) que após responderem a um questionário detalhado sobre hábitos e tipos de exposição a fatores de risco cederam amostras biológicas para análsie do DNA por PCR-RFLP. Os principais fatores de risco para o melanoma foram ascendência européia (p<0,001), cor de olhos claros (p<0,001), presença de nevos (p<0,001), histórico de queimadura grave na adolescência (p<0,001), falta de filtro solar (p<0.034) e exposição à lâmpadas fluorescentes (p=0,001). Quanto à análise dos polimorfismos de genes de metabolização de xenobióticos somente o GSTT1 nulo revelou associação inversamente positiva com o risco de melanoma maligno (OR ajustado = 0,60; IC95% = 0,37-0,97). Entretanto, essa associação não se manteve após a análise de regressão múltipla escalonada. Os polimorfismos VDR/FokI e VDR/TaqI não modificaram a susceptibilidade ao melanoma maligno na comparação entre os grupos. Na análise conjunta do fenótipo-genótipo, indivíduos com olhos verdes e genótipo VDR/FokI polimórfico, apresentaram risco praticamente seis vezes maior de melanoma (OR ajustado = 5,93; IC95% = 1,49-23,59). A associação entre os polimorfismos em pelo menos um dos alelos dos genes de reparo do DNA, XRCC3/NcoI e XPD/PstI aumentou praticamente duas vezes o risco de melanoma tanto na análise estatística multivariada (OR ajustado = 1,84; IC95% = 1,08-3,14) quanto na regressão logística múltipla escalonada (OR ajustado = 2,32; IC95% = 1,01-5,36). Na interação genemeio ambiente a falta do uso de filtro solar dobrou o risco de melanoma em indivíduos com polimorfismo XPD/PstI (OR ajustado = 2,17; IC95% = 1,12- 4,17). A identificação de polimorfismos genéticos associados com doenças multifatorias como o caso do melanoma maligno devem ser estimuladas em nosso meio, principalmente por vivermos em um país tropical com alta incidência solar em praticamente todo seu território. A identificação de marcadores genéticos de susceptibilidade pode propiciar medidas precoces e eficazes de prevenção do câncer. / Melanoma is a malignant skin lesion, with high mortalitty rate and its incidence has been rising in the last years. The main risk factors are melanoma family history, presence of multiple benign or atypical nevi and previous melanoma. Immunosuppression, sun sensitivy and intermittent and intense exposure to UV sunlight radiation, without protection, are additional risk factors. The aim of this hospital based case-control study was to evaluate the contribution of genetic polymorphisms of xenobiotic metabolizing enzymes (CYP1A1/MspI, CYP2E1/PstI, GSTM1, GSTT1 and GSTP1/Bsma), DNA repair genes (XRCC1/MspI, XRCC3/NcoI and XPD/PstI) and vitamin D receptor genes (VDR/FokI and VDR/TaqI) to the risk of melanoma. All participants, including 193 melanoma patients (49.7% men and 50.3% women, mean age 52 ± 14.28 years old) and 208 controls (51.4% men and 48.6% women, mean age 48 ± 15.24 years old) gave written informed consent to participate in the study and agreed to donate a sample of bloody to analysis of DNA by PCR-RFLP and answer a questionarie regarding phenotypic characteristics, personal habits and questions regarding sun exposure that could be associated to the disease. The main risk factors to melanoma were European ancestries (p<0.001), light colored eyes (p<0.001), presence of nevi (p<0.001), history of sunburns during the adolescence (p<0.001), no use of sunblock (p<0.034) and exposure of fluorescent lamps (p<0.001). Regarding the genes polymorphisms, only GSTT1 null genotype showed as an inversely positivefactor (OR adjusted = 0.60; 95%CI = 0.37-0.97) to malignant melanoma. However, this association disappeared with multiple regression analysis. The VDR/FokI and VDR/TaqI polymorphisms did not alter the susceptibility to malignant melanoma in the comparison between groups. A joint analysis of phenotype-genotype, individuals with green eyes and polymorphic genotype VDR/FokI, presented almost six times more risk to melanoma (OR adjusted = 5.93, 95% CI = 1.49-23.59). The association between polymorphisms, in at least one polymorphic allele of DNA repair genes XRCC3/NcoI and XPD/PstI increased almost twice the risk of melanoma in the multivariate statistic analysis (OR adjusted = 1.84, 95%CI = 1.08-3.14) and in multiple logistic regression (OR adjusted = 2.32, 95%CI = 1.01-5.36). In the interaction gene-environment the lack of sunscreen doubled the risk of melanoma in individuals with polymorphisms of XPD/PstI (OR adjusted = 2.17, 95%CI = 1.12-4.17). The identification of genetic polymorphisms associated with diseases such as multi factorial case of malignant melanoma should be encouraged in our country, mainly because we live in a tropical country with high solar irradiation in almost all its territory. The identification of genetic markers of susceptibility may provide early and effective prevention of cancer.

O melanoma é uma lesão maligna da pele, com alta taxa de mortalidade cuja incidência vem aumentando nos últimos anos. Os principais fatores de risco são a história familial da doença, presença de nevos benignos múltiplos ou nevos atípicos e melanoma prévio. Imunossupressão, sensibilidade ao sol e exposição intermitente e intensa à radiação UV da luz solar, sem proteção, são fatores de risco adicionais. O objetivo deste estudo caso-controle de base hospitalar foi avaliar a contribuição de polimorfismos de genes de metabolização de xenobióticos (CYP1A1/MspI, CYP2E1/PstI, GSTM1, GSTT1 e GSTP1/Bsma), de genes de reparo do DNA (XRCC1/MspI, XRCC3/NcoI e XPD/PstI) e do gene do receptor de vitamina D (VDR/FokI e VDR/TaqI) no risco de melanoma. Consentiram em participar 193 pacientes com melanoma (49,7% homens e 50,3% mulheres, média de 52 ± 14,28 anos) e 208 controles (51,4% homens e 48,6% mulheres, média de 48 ± 15,24 anos) que após responderem a um questionário detalhado sobre hábitos e tipos de exposição a fatores de risco cederam amostras biológicas para análsie do DNA por PCR-RFLP. Os principais fatores de risco para o melanoma foram ascendência européia (p<0,001), cor de olhos claros (p<0,001), presença de nevos (p<0,001), histórico de queimadura grave na adolescência (p<0,001), falta de filtro solar (p<0.034) e exposição à lâmpadas fluorescentes (p=0,001). Quanto à análise dos polimorfismos de genes de metabolização de xenobióticos somente o GSTT1 nulo revelou associação inversamente positiva com o risco de melanoma maligno (OR ajustado = 0,60; IC95% = 0,37-0,97). Entretanto, essa associação não se manteve após a análise de regressão múltipla escalonada. Os polimorfismos VDR/FokI e VDR/TaqI não modificaram a susceptibilidade ao melanoma maligno na comparação entre os grupos. Na análise conjunta do fenótipo-genótipo, indivíduos com olhos verdes e genótipo VDR/FokI polimórfico, apresentaram risco praticamente seis vezes maior de melanoma (OR ajustado = 5,93; IC95% = 1,49-23,59). A associação entre os polimorfismos em pelo menos um dos alelos dos genes de reparo do DNA, XRCC3/NcoI e XPD/PstI aumentou praticamente duas vezes o risco de melanoma tanto na análise estatística multivariada (OR ajustado = 1,84; IC95% = 1,08-3,14) quanto na regressão logística múltipla escalonada (OR ajustado = 2,32; IC95% = 1,01-5,36). Na interação genemeio ambiente a falta do uso de filtro solar dobrou o risco de melanoma em indivíduos com polimorfismo XPD/PstI (OR ajustado = 2,17; IC95% = 1,12- 4,17). A identificação de polimorfismos genéticos associados com doenças multifatorias como o caso do melanoma maligno devem ser estimuladas em nosso meio, principalmente por vivermos em um país tropical com alta incidência solar em praticamente todo seu território. A identificação de marcadores genéticos de susceptibilidade pode propiciar medidas precoces e eficazes de prevenção do câncer. / Melanoma is a malignant skin lesion, with high mortalitty rate and its incidence has been rising in the last years. The main risk factors are melanoma family history, presence of multiple benign or atypical nevi and previous melanoma. Immunosuppression, sun sensitivy and intermittent and intense exposure to UV sunlight radiation, without protection, are additional risk factors. The aim of this hospital based case-control study was to evaluate the contribution of genetic polymorphisms of xenobiotic metabolizing enzymes (CYP1A1/MspI, CYP2E1/PstI, GSTM1, GSTT1 and GSTP1/Bsma), DNA repair genes (XRCC1/MspI, XRCC3/NcoI and XPD/PstI) and vitamin D receptor genes (VDR/FokI and VDR/TaqI) to the risk of melanoma. All participants, including 193 melanoma patients (49.7% men and 50.3% women, mean age 52 ± 14.28 years old) and 208 controls (51.4% men and 48.6% women, mean age 48 ± 15.24 years old) gave written informed consent to participate in the study and agreed to donate a sample of bloody to analysis of DNA by PCR-RFLP and answer a questionarie regarding phenotypic characteristics, personal habits and questions regarding sun exposure that could be associated to the disease. The main risk factors to melanoma were European ancestries (p<0.001), light colored eyes (p<0.001), presence of nevi (p<0.001), history of sunburns during the adolescence (p<0.001), no use of sunblock (p<0.034) and exposure of fluorescent lamps (p<0.001). Regarding the genes polymorphisms, only GSTT1 null genotype showed as an inversely positivefactor (OR adjusted = 0.60; 95%CI = 0.37-0.97) to malignant melanoma. However, this association disappeared with multiple regression analysis. The VDR/FokI and VDR/TaqI polymorphisms did not alter the susceptibility to malignant melanoma in the comparison between groups. A joint analysis of phenotype-genotype, individuals with green eyes and polymorphic genotype VDR/FokI, presented almost six times more risk to melanoma (OR adjusted = 5.93, 95% CI = 1.49-23.59). The association between polymorphisms, in at least one polymorphic allele of DNA repair genes XRCC3/NcoI and XPD/PstI increased almost twice the risk of melanoma in the multivariate statistic analysis (OR adjusted = 1.84, 95%CI = 1.08-3.14) and in multiple logistic regression (OR adjusted = 2.32, 95%CI = 1.01-5.36). In the interaction gene-environment the lack of sunscreen doubled the risk of melanoma in individuals with polymorphisms of XPD/PstI (OR adjusted = 2.17, 95%CI = 1.12-4.17). The identification of genetic polymorphisms associated with diseases such as multi factorial case of malignant melanoma should be encouraged in our country, mainly because we live in a tropical country with high solar irradiation in almost all its territory. The identification of genetic markers of susceptibility may provide early and effective prevention of cancer.