京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21704号 / 人健博第70号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 青山 朋樹, 教授 黒木 裕士, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.

Grasping, the skill to hold objects and tools while doing in-hand manipulation, still is in many cases an unsolvable problem for robotics, but a natural act for humans. An efficient grasping requires not only human-like robotic hands with articulated fingers but also tactile, force, and kinesthetic sensors for the precise control of the forces and motions exerted during the manipulation. As a fully autonomous robotic dexterous manipulation is too difficult to develop for changing and unstructured environments, an alternative approach is to combine the low-level robot computer control with the higher-level perception and task planning abilities of a human operator equipped with an adequate human-computer interface (HCI). This thesis presents theoretical and experimental contributions to the development of an upgraded haptic-enabled anthropomorphic Ring Ada dexterous robotic hand and a biology-inspired synergistic real-time control system for teleoperated grasping of different objects using a CyberTouch HCI data glove. A fuzzy logic controller module was developed to efficiently control the underactuated Ring Ada’ robotic hand during grasping. A machine learning classification system was developed to recognize grasped objects. Experiments have convincingly demonstrated that our novel Ring Ada robotic hand equipped with kinematic position sensors and touch sensors is able to efficiently grasp different lightweight objects through teleoperation.

No description available.

Powered exoskeletons can assist patients suffering from motor dysfunctions. Recent researches are focused on how to improve the communication system between patient and device. Further research is needed in order to design an EMG based robotic assistive device able to convey intended motions to the patient. The primary need is the understanding of how EMG patterns from different muscles contribute to motions. Studies on muscle synergy have shown how different muscles of lower limbs contribute to gait. This study is aimed to expand the analysis to motions other than gait by analysing ten muscles around the right knee joint. The chosen muscle were soleus, gastrocnemius medialis, gastrocnemius lateralis, peroneus longus, tibialis anterior, rectus femoris, vastus medialis, vastus lateralis, biceps femoris and semitendinosus. The main hypothesis is that specific movements are controlled by specific muscle synergies. Motion data and EMG data of eight healthy subjects have been compared in order to outline a coordination pattern specific to four different movements: gait, gait stop and balance, sit to stand and stand to sit. Through the analysis of EMG signals, three muscle synergies have been identified including muscles from the same group, i.e. four plantar flexors, three quadriceps and two hamstrings. It was possible to conclude that the four movements were controlled by the same muscle synergies with different coordination patterns. Further research is recommended to expand the knowledge about muscle synergies.

Aspergillus fumigatus is a globally present pathogen capable of inflicting debilitating and life-threatening opportunistic infections in individuals, primarily those who are immunocompromised. Diagnosing A. fumigatus infections is often difficult, leading to a delay in treatment which can greatly impact patient outcomes. Furthermore, our lessening of antifungal development combined with increasing resistance generates a feasible scenario where only last resort options are viable. This has prompted the World Health Organization (WHO) to declare this pathogen a "critical priority" due to increased resistance and rising mortality rates. Azoles are utilized as primary treatment options for Aspergillus fumigatus infections such as voriconazole (VRC), itraconazole (ITC), and posaconazole (POS) with a reserve of Amphotericin B (AmB). In the past two decades, the emergence of resistance to azoles has contributed to a 90% mortality rate in resistant cases globally. In this report, we investigated the MedChem Express (MCE) Drug Repurposing Compound Library (4,226 compounds) in conjunction with itraconazole at 0.06 µg/mL against A. fumigatus CDC #738. After the initial screening, we identified compounds known to be antifungals or antiseptics and deselected them. The remaining thirty selected compounds were evaluated through published literature and clinical trial data to determine those candidates with favorable characteristics/properties. Criteria for candidate selection consisted of evaluating the compounds; plasma concentration peak, the time to reach peak, protein binding, oral availability, and drug class. Six candidates were ranked the highest of the previous round –surprisingly 50% of those compounds were HIV drugs, cobicistat, elvitegravir, lopinavir. The remaining three selected compounds are penfluridol, rilapladib, and rolapitant. The combination of itraconazole (ITC), posaconazole (POS), and voriconazole (VRC), with the identified compounds demonstrated promising amounts of synergy, in resistant and susceptible isolates. Further investigation revealed novel properties of ITC and POS when in combination with our compounds of interest. Rilapladib was able to reverse POS, ITC, and VRC resistant strain(s) to a sensitive profile. Growth kinetic assays demonstrate potent anti-germination properties not seen before in the sub-inhibitory doses of azoles. This work demonstrates that high-throughput screening as a viable technique to identify robust antifungal synergizers, allowing for tenable translation to a clinical setting. / Master of Science / Aspergillus fumigatus is a worldwide fungal organism capable of causing disease, particularly in immunocompromised individuals. Infections primarily occur when individuals inhale spores that can remain dormant until the person's immune system is weakened, via disease, cancer, or prescribed drug for surgery. When the immune system is weakened, the spores are more effective at lung colonization. Aspergillus fumigatus infections can be combatted with voriconazole (VRC), itraconazole (ITC), or posaconazole (POS). However, in the past two decades, some fungi have started to develop resistance to azoles, necessitating the use of amphotericin B (AmB), a highly intolerable and final treatment option. In this report, we challenged A. fumigatus CDC isolate #738 with compounds from the MedChem Express (MCE) Drug Repurposing Compound Library (4,226 compounds) with itraconazole at 0.06 µg/mL, an ineffective concentration. We selected combinations and compounds that negated 90% of fungal growth those combinations that contained a known antifungal or antiseptic agent; once identified we deselected any known antifungal or antiseptic agents. The remaining selected compounds were evaluated for favorable drug properties, by reviewing published literature and clinical reports to determine those candidates with favorable characteristics/properties. The combination of ITC, POS, and VRC with the identified compounds demonstrated antifungal enhancement in resistant and susceptible isolates. We observed the reversal of resistance to POS, ITC, and VRC in several isolates when the drug combinations were applied. This demonstrates the importance of evaluating approved and under current review drugs to identify novel properties to aid our dwindling number of effective antifungals. This study provides promising combinational therapies for further evaluation in combating resistant A. fumigatus infections.

No description available.

The Construction industry has had a relatively low increase in the efficiency rates over the recent years. Two developments of Lean construction and Building Information Modelling(BIM) have been introduced that have each shown improvements in the efficiency rates in construction. These two individual concepts of Lean and BIM have been applied each independent of the other and because of their similarities and overlapping benefits, it is thought that them being applied together improves the efficiency in a greater way than them being applied individually. This study looks at the synergy that is possible due to the overlapping benefits in applying Lean Construction and BIM. The study is a Literature review aimed at understanding Lean and BIM and their overlaps. The Literature looks at past research studies that have investigated this area. The clear look at these studies shows that when the two concepts are combined, then that collaboration leads to a more integrated process in construction that in turn yields higher efficiency rates. / Byggindustrin har haft en relativt låg ökning i effektivitetstalen de senaste åren. Utvecklingen inom två nya områden, Lean Construction och Building Information Modelling (BIM), där man kunnat visa ökad effektivitet genom båda åtgärder. De två begreppen Lean Construction och BIM har introducerats oberoende av varandra på grund av deras likheter och överlappande fördelar men det är vid användningen av båda åtgärder samtidigt som den bästa effekten har kunnat visas i motsats mot om varje åtgärd hade använts separat. Denna studie undersöker synergieffekterna som är möjliga genom överlappande fördelar vid användandet av Lean Construction och BIM. Det är en litteraturstudie som syftar till att förstå Lean och BIM och deras överlappning. Litteraturen tittar på tidigare forskning som har undersökt detta område. En noggrann betraktelse av dessa studier visar att när de två åtgärderna kombineras leder det till en mer integrerad byggprocess som i sin tur ger högre effektivitetstal.

Chemotherapy, employing single-molecule or multidrug concoctions inspired by the diverse repository of plant chemicals, has been the mainstay of cancer treatment for years. However, isolating single molecules has proven to be expensive along with limited therapeutic window and toxicity. On the other hand, whole foods, while preserving the natural complex balance between their constituent phytochemicals and being non-toxic, have proven to impart better disease-fighting efficacies, thus leading to an increased focus on dietary interventions to both treat and prevent cancer. Owing to the complex interactions between their constituent phytochemicals, several dietary agents have been investigated for their therapeutic and preventive efficacies. However, due to lack of emphasis on confounding factors like bioavailability, absorption, metabolism, and excretion, essentially driven by phytocomplexity, incorporation of whole foods in therapeutic regimen has not been successful. This thesis exemplifies the need to investigate factors associated with the limitations in the current approach with respect to dietary agents. Bioactivity-guided fractionation of sweet potato greens extract (SPGE) led to the identification of ~100-fold more potent fraction in vitro. However, this efficacy could not be translated in vivo. We also studied whole ginger extract (GE) for its in vitro and in vivo prostate tumor growth-inhibitory and apoptosis-inducing effects. In addition, GE proved to be more efficacious as compared to its individual most-active constituents owing to the differences in their pharmacokinetic (PK) and bioavailability measurements. Hence, these studies emphasize the crucial role of synergistic/additive interactions among the constituents of whole foods in successful translation of their therapeutic benefits. Another factor that seeks further attention is the unique cellular mechanisms engaged by these phytochemicals to confer their remarkable effects. Phenolic compounds, the most-abundant of all phytochemicals, are well known for their antioxidant properties and act via reactive oxygen species (ROS)-mediated mechanisms. We however assert the underappreciated xenohormetic prooxidant role of phenolics, where cancer cell death is caused by induction of intolerable levels of ROS. We demonstrated that a Piper betel constituent, hydroxychavicol (HC), mediates cytotoxicity via ROS-induced DNA-damage. This thesis thus provides compelling grounds for future preclinical studies to validate their potential usefulness for cancer management.

Submitted by JOSIANE SANTOS DE OLIVEIRA (josianeso) on 2018-10-05T12:02:20Z No. of bitstreams: 1 Marcos André Müller_.pdf: 9700367 bytes, checksum: 1b66014939603064d8e738b504a9cbab (MD5) / Made available in DSpace on 2018-10-05T12:02:21Z (GMT). No. of bitstreams: 1 Marcos André Müller_.pdf: 9700367 bytes, checksum: 1b66014939603064d8e738b504a9cbab (MD5) Previous issue date: 2011-08-03 / Nenhuma / A evolução do conhecimento, dos modelos econômicos e da gestão organizacional torna cada vez mais relevante a agilidade das informações, a cooperação, coordenação e uma forte interação entre todos os envolvidos na busca de melhores resultados. É neste contexto que o presente estudo busca identificar e diagnosticar a sinergia empresarial, tendo como alvo melhorar o seu desempenho global. A possibilidade de obter ganhos globais maiores que a soma dos ganhos locais – efeito “2 + 2 = 5” anima as pesquisas e as Organizações na busca dos caminhos que levam a este efeito, bem como na busca de ferramentas que auxiliem no diagnóstico e na tomada de decisão estratégica. É nesse sentido que esta pesquisa visa contribuir, tendo como objetivo medir a percepção do grau de sinergia empresarial em instituições constituídas de multiunidades de negócio por intermédio da via da integração, desenvolvendo, aplicando e avaliando um instrumento de medição. A pesquisa foi desenvolvida partindo-se de um estudo bibliográfico para identificar ferramentas já validadas no meio acadêmico e empresarial, a fim de compor um instrumento de medição que congregue cinco dimensões de sinergia e que seja adequado à Organização objeto de estudo de caso. Uma vez selecionadas as ferramentas, partiu-se para a construção de uma nova ferramenta, validando e aplicando a mesma em uma instituição confessional de ensino composta por várias Unidades de Negócio. A pesquisa é de natureza aplicada, de abordagem qualitativa tendo seus objetivos orientados à descrição das características de um determinado fenômeno. Quanto aos procedimentos técnicos para a obtenção dos dados, está alicerçada no estudo de caso, avançando para a proposição de um instrumento de medição da percepção do grau de sinergia. Quanto aos resultados obtidos, considera-se que a pesquisa cumpriu seu objetivo, uma vez que foi possível identificar a percepção do grau de sinergia da Organização, das dimensões e dos itens de medição, sinalizando, através desse desdobramento, quais pontos poderão ser abordados pela Organização para melhorar o seu desempenho através das variáveis contempladas no escopo desta pesquisa. Compreende-se, também, que a pesquisa possibilitou disponibilizar uma ferramenta que indique a percepção dos respondentes perante: i) a prontidão das Unidades de Negócio para a cooperação; ii) a qualidade da gestão à luz das redes de cooperação; iii) a intenção para a adoção das boas práticas de governança corporativa; iv) a gestão e operacionalização integrada de ações de impacto social e ambiental; e v) a adoção do compartilhamento de serviços como uma forma de implementar ganhos através de sinergias. A pesquisa também possibilita evidenciar a assimetria das percepções entre a alta administração e a operação no que tange à integração e cooperação entre as Unidades de Negócio. E, por fim, a pesquisa deixa à disposição uma ferramenta de apoio ao monitoramento das ações estratégicas das Organizações perante a busca de melhores resultados através de Sinergias. / The evolution of knowledge, economic models and organizational management makes increasingly important the agility of information, cooperation, coordination and a strong interaction between everyone involved in the search for better results. In this context, this study seeks to identify and diagnose business synergy, targeting at the improvement of its overall performance. The possibility of global gains greater than the sum of local gains – the “2 + 2 = 5” effect - encourages researchers and organizations in the pursuit of this effect, as well as in the search for tools that aid in the diagnosis and strategic decision making. That is what this research aims to contribute with, parallel with the objective of measuring the perceived degree of synergy in business institutions composed of multi-unit business by means of integration, development, implementation and evaluation of a measuring instrument. The research started out with a bibliographical study viewing to identify tools already validated in the academic and business environment in order to obtain a measuring instrument that could bring together five dimensions of synergy and that should be appropriate to the Organization, which was the object of the case study. Once the tools were selected, we decided to build a new tool, validating and applying it in a confessional educational institution composed of several Business Units. The research is of an applied nature, of a qualitative approach, and has its goals oriented to the description of the characteristics of a particular phenomenon. As to the technical procedures for obtaining data, it is based on case study, advancing towards the proposition of an instrument for measuring the perception of the degree of synergy. As to the results obtained, it is considered that the research reached its goal, since it was possible to identify the perception of the Organization’s level of synergy, of its dimensions and of the measuring items, thus signaling which points the Organization may have to focus on in order to improve their performance through the variables covered in the scope of this research. It is also believed that the research has provided a possible tool capable of indicating the perception of respondents regarding: i) the readiness of the Business Units for cooperation, ii) the quality of management in the light of cooperation networks; iii) the intention to adopt good corporate governance practices; iv) the management and the integrated application of actions of social and environmental impact, and v) the adoption of shared services as a way to implement gains through synergies. The research also provides evidence of the asymmetry of perceptions between top management and operational levels regarding the integration and cooperation between business units. Finally, the research makes available a support tool that aids the monitoring of the strategic actions of organizations towards better results through synergies.