京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21990号 / 医博第4504号 / 新制||医||1037(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 武藤 学, 教授 松田 文彦, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22321号 / 医博第4562号 / 新制||医||1041(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 川上 浩司, 教授 浅野 雅秀, 教授 岩田 想 / 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・論文博士 / 博士(医学) / 乙第13442号 / 論医博第2241号 / 新制||医||1054(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 羽賀 博典, 教授 藤田 恭之, 教授 伊藤 貴浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Bakgrund: Gastric bypass är en operationsmetod som leder till en fysiologisk förändring i magtarmkanalen av perorala läkemedel, i syfte till att främja viktnedgång. Tidigare studier har stärkt teorin om att ett förändrat upptag av två vanligt förekommande läkemedel i kliniken, levotyroxin och omeprazol, sker som en följd av gastric bypass operation. Absorptionen av dessa läkemedel är kliniskt relevanta då den terapeutiska effekten är avgörande för behandlingen och därmed hälsan hos en bred patientgrupp inom sjukvården.  Syfte: Syftet med denna litteraturstudie är att reda ut hur absorptionen av levotyroxin och omeprazol påverkas efter en gastric bypass operation.  Metod: Detta är en litterturstudie baserat på åtta orginalstudier, fyra om läkemedlet omeprazol och fyra studier om läkemedlet levotyroxin. Artiklarna identifierades efter sökningar i PubMed och Embase under april 2021. Inklusionskriterier var gastric bypass som operationsmetod samt att publikationsdatumet är inom de senaste 20 åren. Barn, äldre och patienter med samtidigt vitaminkonsumtion exkluderades.  Resultat: Av levotyroxinartiklarna konkluderar två av dessa att en minskad absorption av läkemedlet sker efter gastric bypass. De två resterande artiklar redovisade ingen förändring gällande absorptionen. Artiklar som studerade levotyroxin upptaget i form av flytande beredning efter gastric bypass, påvisade ökat läkemedelsupptag i flytande form gentemot tablettform. I de fyra artiklar som studerades omeprazol och dess absorption, styrktes en minskad läkemedlsabsorption i två av de artiklarna, samt en observerad avsaknad av signifikant skillnad i de två resterande artiklarna.  Slutsats: Ett fullständigt svar till frågeställningen om levotyroxin coh omeprazol leder till minskat läkemedelsupptag efter gastric bypass, kan inte återfås av denna litterturstudie på grund av motstridiga resultat. Detta resultat indikerar däremot behovet av en individuell farmakoterapi då variationen mellan olika individer gällande faktorer såsom BMI och kön, kan påverka läkemedelsupptaget.

Background: Gastric cancer is often diagnosed in the metastatic stage, and only 10% of patients survive for as long as 2 years. Current chemotherapy regimens show significant treatment-related toxicities. It is crucial to identify the patients that will benefit most from certain chemotherapy regimens in order to avoid unnecessary side effects. Patients and Methods: 2 patients with advanced gastric cancer repeatedly received 5-FU/cisplatin combination chemotherapy. Genomic DNA was extracted from tumor tissue and mononuclear blood cells. Genotype analysis of genes of metabolizing and DNA repair enzymes was carried out using a PCR-RFLP technique. Direct sequencing was used to identify mutations of the gene dihydropyrimidine dehydrogenase (DPD). Results: Prolonged survival of 51 and 29 months, respectively were observed in our 2 patients. Both patients were positive for genotypes of thymidylate synthase - the target enzyme of 5-FU - that are associated with improved drug response. DPD variants connected with increased toxicity were not observed. However, both patients also showed genotypes in cisplatin metabolizing enzymes which enhance the effect of the drug. Conclusion: Genotype analysis in drug metabolizing enzymes of 5-FU and cisplatin provide a possible explanation for extraordinary therapy effects observed in 2 patients with advanced gastric cancer. / Hintergrund: Das Magenkarzinom wird häufig im fortgeschrittenen Stadium diagnostiziert, und nur etwa 10% der Patienten überleben 2 Jahre. Aktuelle Chemotherapien zeigen eine hohe therapiebedingte Toxizität. Es ist daher von großer Bedeutung, diejenigen Patienten zu identifizieren, die von einer bestimmten Therapie profitieren, um anderen Patienten die Nebenwirkungen einer solchen Therapie zu ersparen. Patienten und Methoden: 2 Patienten mit fortgeschrittenem Magenkarzinom erhielten wiederholt eine Kombinationschemotherapie aus 5-FU/Cisplatin. Genomische DNS wurde aus Tumorgewebe und Leukozyten isoliert. Genotypanalysen von Genen, die am Metabolismus der Substanzen und am DNS-Reparaturprozess beteiligt sind, wurden mithilfe einer PCRRFLP-Methode durchgeführt. Das Gen der Dihydropyrimidindehydrogenase (DPD) wurde direkt sequenziert. Ergebnisse: Beide Patienten zeigten ein deutlich verlängertes Überleben von 51 bzw. 29 Monaten. Genotypen des 5-FU-Zielenzyms Thymidylatsynthase, die mit einem verbesserten Ansprechen assoziiert sind, konnten in beiden Patienten nachgewiesen werden. DPD-Varianten, die mit einer erhöhten Toxizität verbunden sind, wurden nicht beobachtet. Zusätzlich konnten bei beiden Patienten Genotypen in Cisplatin metabolisierenden Genen gefunden werden, die eine prolongierte Wirkung der Substanz bedingen. Schlussfolgerungen: Durch Genotypanalysen in Genen des 5-FU- und Cisplatin-Metabolismus konnte ein spezifisches pharmakogenetisches Profil identifiziert werden, das möglicherweise die Ursache eines außergewöhnlich guten Therapieeffektes in 2 Patienten mit fortgeschrittenem Magenkarzinom ist. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

<p>  </p> <p>The world has experienced an unprecedented change in the systems responsible for food production, distribution, and commercialization with concurrent changes in diets. In developed and developing countries, the shift in consumption patterns has moved towards a Western diet pattern which has been linked to negative health outcomes including obesity, diabetes and associated non-communicable diseases. Traditional African diets have previously been associated with protective effects against the development of the above-mentioned conditions. Yet, the underlying reasons for this is not clear. One dietary factor that may contribute to its protective effect is the principal available carbohydrate, starch, which in traditional African staples is considered to contain slowly digestible carbohydrates (SDCs) and some amount of resistant starch (RS). We reported that traditional African staple starchy foods (sorghum and millet) had markedly slower gastric emptying than introduced modern starchy foods (rice, pasta and potatoes). This response was attributed to activation of enteroendocrine cells of the small intestine (L-cells) with potential to trigger physiological, hormonal, and neurological processes that affect digestion time and perception of hunger; effect known as the ileal brake. Moreover, at least in mice models, consumption of SDCs has shown to have beneficial effects on the rate and type of fuel (e.g. carbohydrate vs fat) used for metabolic processes.</p> <p>The first thesis study compared the effect of diets (cohorts in the USA and Kenya) on gastric half-emptying time and metabolic fuel utilization in healthy adults. Our findings showed that gastric emptying time was not different between cohorts and that diet did not influence gastric emptying time; however, calculated respiratory exchange ratio (RER) (which is a measure of metabolic fuel utilization at the cellular level, e.g. carbohydrate vs fat) and metabolic flexibility (which is the ability to switch between metabolic fuel sources upon demand or need) was higher for the Kenyan cohort. Multivariant models were developed and corrected for multicollinearity of some diet variables. Carbohydrate and protein in multivariate model 1; total fiber, added sugars and starch in multivariate model 2; and diet quality (measured as the Healthy Eating Index based on 2015-2020 dietary guidelines, or HEI-2015) in multivariate model 3, were significantly and independently correlated with RER and metabolic flexibility.   </p> <p>The second study assessed if slow gastric emptying and improve metabolic fuel utilization could be induced through SDC supplementation. The objective of this study was to determine if continual consumption of SDC for 21 days delayed the rate of gastric emptying, moderated postprandial glycemic response, decreased hunger, and/or improved metabolic fuel utilization in subjects with low diet quality (HEI-2015<65). Our results indicated that supplementation with SDC did not slow gastric emptying time or acute measures of metabolic fuel utilization; however, continuous consumption of SDC had a modest but significant effect on improving metabolic flexibility and decreasing hunger scores. </p> <p>The last two chapters of this thesis focused on the use of a low-cost, high-pressure, high temperature extruder suitable for processing in Africa of whole grain pearl millet (<em>Pennisetum glaucum</em>). In Africa, emerging, entrepreneurial companies are increasingly gaining share of local markets by manufacturing and distributing high-quality locally sourced processed foods made with indigenous grains. Whole pearl millet is particularly susceptible to development of rancidity. The objective of our third study was to assess the use of the extruder on the stability and sensory attributes of whole grain pearl millet extruded flours to be used for instant thin and thick porridges. Findings showed that extrusion fully gelatinized the starch in pearl millet and prevented hydrolytic rancidity in the instant flour products. However, extrusion cooking did not stop oxidative rancidity. We concluded that while extrusion cooking is a versatile technology for whole grain processing, refinement of extrusion conditions used in the experiment and the evaluation of other unit operations (e.g. steeping, germination) in combination with extrusion cooking may improve the sensory properties of final products.</p> <p>Finally, extrusion cooking has been showed to promote the formation of beneficial amylose-lipid complexes (ALCs). The objective of the last study was to evaluate the formation of ALCs in whole grain pearl millet extruded flours, characterize their composition, and assess their ability to slowly digest <em>in vitro</em>. Extrusion promoted the formation ALCs and these flours exhibited a slow enzymatic digestion <em>in vitro</em>. The findings from this thesis provide insights into the role of diets and metabolic fuel utilization, and improvement of processed pearl millet foods in Africa.</p>

Recently, there has been an increase in the number of proton beam therapy (PBT) centers operating worldwide. For certain cases, proton beams have been shown to provide dosimetric and radiobiological advantages when used for cancer treatment, compared to the regular photon-beam based treatments. Under ideal circumstances, the dose given to the tissues surrounding a target can be reduced with PBT. The risk for side effects following treatment is then expected to decrease. Until present, mainly stationary targets, e.g. targets in the brain, have been treated with PBT. There is currently a growing interest to treat also target volumes in other parts of the body with PBT. However, there are sources of uncertainties, which must be more carefully considered when PBT is used, especially for PBT carried out with scanned proton beams. PBT is more sensitive to anatomical changes, e.g. organ motion or a variable gas content in the intestines, which requires that special precautions are taken prior to treating new tumour sites. In photon beam radiotherapy (RT) of moving targets, the main consequence of organ motion is the loss of sharpness of the dose gradients (dose smearing). When scanned proton beams are used, dose deformation caused by the fluctuations in the proton beam range, due to varying tissue heterogeneities (e.g., the ribs moving in and out of the beam path) and the so-called interplay effect, can be expected to impact the dose distributions in addition to the dose smearing. The dosimetric uncertainties, if not accounted for, may cause the planned and accurately calculated dose distribution to be distorted, compromising the main goal of RT of achieving the maximal local disease control while accepting certain risks for normal tissue complications. Currently there is a lack of clinical follow-up data regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumour sites in moving organs. On the other hand, the use of photon beams for this kind of cancer treatment is well-stablished. A treatment planning comparison between RT carried out with photons and with protons may provide guidelines for when PBT could be more suitable. New clinical applications of particle beams in cancer therapy can also be transferred from photon-beam treatments, for which there is a vast clinical experience. The evaluation of the different uncertainties influencing RT of different tumour sites carried out with photon- and with proton-beams, will hopefully create an understanding for the feasibility of treating cancers with scanned proton beams instead of photon beams. The comparison of two distinct RT modalities is normally performed by studying the dosimetric values obtained from the dose volume histograms (DVH). However, in dosimetric evaluations, the outcome of the treatments in terms of local disease control and healthy tissue toxicity are not estimated. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. In this thesis, different factors that should be taken into consideration in PBT, for treatments influenced by organ motion and density heterogeneities, were studied and their importance quantified. This thesis consists of three published articles (Articles I, II and III). In these reports, the dosimetric and biological evaluations of photon-beam and scanned proton-beam RT were performed and the results obtained were compared. The studies were made for two tumour sites influenced by organ motion and density changes, gastric cancer (GC) and liver metastases. For the GC cases, the impact of changes in tissue density, resulting from variable gas content (which can be observed inter-fractionally), was also studied. In this thesis, both conventional fractionations (implemented in the planning for GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. In this work, it was found that proton therapy provided the possibility to reduce the irradiations of the normal tissue located near the target volumes, compared to photon beam RT. However, the effects of density changes were found to be more pronounced in the plans for PBT. Furthermore, with proton beams, the reduction of the integral dose given to the OARs resulted in reduced risks of treatment-induced secondary malignancies.

Gastric aspirate specimens were collected from patients w~th clinically diagnosed gastric carcinoma and from non-carcinoma patients. The nitrite concentration and pH values of the aspirates were measured, the microorganisms present in selected specimens were isolated and identified, and the mutagenicity ratios of the aspirates were determined. The median nitrite concentration of the gastric aspirates from the carcinoma patients was significantly higher than that obtained for the non-carcinoma patients. A positive correlation was found between the nitrite concentration and the pH values of all the specimens tested, and a marked increase in nitrite levels at pH values above 6,0 was evident in specimens from the coloured ethnic "normal" subgroup. Gastric aspirate nitrite concentrations did not correlate with salivary values. The presence of microorganisms in gastric aspirates was shown to be pH dependent. Gastric aspirates with a pH &lt; 2,0 were sterile, below pH 4,0 only acidophilic bacteria survived, whereas above pH 4,0, numerous species, predominantly members of the oral microflora, were isolated. The mean mutagenicity ratio of the gastric aspirates from the carcinoma patients was found to be significantly higher than that found for the control group. There was a positive correlation between the mutagenicity ratios of all the gastric specimens and pH with a maximum at a pH value of approximately 6,0.