京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24292号 / 人健博第107号 / 新制||人健||8(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 藤井 康友, 教授 岡 昌吾, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Objective: To determine the difference in effectiveness of positional release therapy (PRT) compared with therapeutic massage (TM) in treating trigger and tender points in the upper trapezius muscle. Background: Trigger points in the upper trapezius muscle are common and can be painful. Therapeutic massage is a more traditional treatment method for this condition while PRT is relatively new. Design and Setting: A randomized-group design was used to examine the differences between the 2 treatments for reducing pain and muscle tension. Subjects: Sixty healthy subjects (males = 24, females = 36; age = 27.1 ± 8.8 years; wt = 75.2 ± 17.9 kg; ht = 172.8 ± 9.7 cm) presenting with upper trapezius pain and a trigger point. Subjects were randomly assigned to the TM group or the PRT group. Measurements: Presence of upper trapezius trigger points was found via palpation by a clinician. Level of pain was measured by a visual analog scale (VAS) and pain pressure threshold (PPT) was assessed by a pressure algometer. Muscle thickness was measured by B-mode ultrasound (US) and muscle tension was measured by shear-wave elastography (SWE). Subjects were measured pretreatment and posttreatment and 48 hours later. Results: All measurements showed significant improvements for both treatments. Positional release therapy was more effective (p = 0.05) at reducing pain at day 2 and was able to maintain the pain loss. The SWE and US showed no difference between the treatment groups. There was no significant difference in PPT, but PRT PPT increased each visit while TM dropped significantly at day 2 (p = .003). Conclusion: Both treatments showed a significant ability to reduce pain and acutely decrease muscle stiffness (as measured by SWE) but there were few differences between the treatments. However, there appeared to be a slight benefit for pain reduction with PRT up to 2 days posttreatment.

Objective: To determine the difference in effectiveness of positional release therapy (PRT) compared with therapeutic massage (TM) in treating trigger and tender points in the upper trapezius muscle. Background: Trigger points in the upper trapezius muscle are common and can be painful. Therapeutic massage is a more traditional treatment method for this condition while PRT is relatively new. Design and Setting: A randomized-group design was used to examine the differences between the 2 treatments for reducing pain and muscle tension. Subjects: Sixty healthy subjects (males = 24, females = 36; age = 27.1 ± 8.8 years; wt = 75.2 ± 17.9 kg; ht = 172.8 ± 9.7 cm) presenting with upper trapezius pain and a trigger point. Subjects were randomly assigned to the TM group or the PRT group. Measurements: Presence of upper trapezius trigger points was found via palpation by a clinician. Level of pain was measured by a visual analog scale (VAS) and pain pressure threshold (PPT) was assessed by a pressure algometer. Muscle thickness was measured by B-mode ultrasound (US) and muscle tension was measured by shear-wave elastography (SWE). Subjects were measured pretreatment and posttreatment and 48 hours later. Results: All measurements showed significant improvements for both treatments. Positional release therapy was more effective (p = 0.05) at reducing pain at day 2 and was able to maintain the pain loss. The SWE and US showed no difference between the treatment groups. There was no significant difference in PPT, but PRT PPT increased each visit while TM dropped significantly at day 2 (p = .003). Conclusion: Both treatments showed a significant ability to reduce pain and acutely decrease muscle stiffness (as measured by SWE) but there were few differences between the treatments. However, there appeared to be a slight benefit for pain reduction with PRT up to 2 days posttreatment.

The capability of precisely controlling the kinetics of therapeutic delivery at the optimal location and rate for a given patient would have great potential to improve health and well-being in a range of current drug therapies (insulin, chemotherapeutics, vaccines, etc.). Indeed, if successfully developed, locally administered injectable drug delivery vehicles capable of remotely-triggered release would be the gold standard for many treatments. Multiple injectable nanocomposites have been investigated for this purpose that are generally comprised of a thermosensitive polymeric material and superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs generate heat when exposed remote alternating magnetic fields (AMFs), and the transfer of this heat to thermosensitive polymers can be used to control the release of therapeutics. Ideally, these systems would be capable of returning to their original state and basal release rate when the external AMF trigger is removed. Several novel injectable nanocomposite materials that explore interactions between SPIONs and thermosensitive polymers to mediate drug release, from the macroscale to the nanoscale, were developed and demonstrated to be capable of remotely-triggered, AMF-mediated enhanced release. The macroscale magnetic nanocomposites have thermosensitive hydrogel and/or microgel components that regulate release based on the heat produced from SPIONs in response to an external AMF. On the millimeter-scale, a microinjection system capable of producing thermosensitive hydrogel beads that could potentially incorporate SPIONs is described. On the nanoscale, nanoparticles with a glass transition temperature and thermosensitive microgels are combined with SPIONs and investigated for their remote, AMF-mediated release characteristics. The engineered macroscale and nanoscale systems are capable of up to ~4:1 and ~7:1 enhancements in release due to an AMF application, respectively, compared to the basal release rate. Collectively, these nanocomposites represent a promising stride towards improved remote-actuation of drug release and a stepping stone for future attempts at precisely controlling the site and kinetics of drug release. / Thesis / Doctor of Philosophy (PhD) / This thesis focuses on the development of nanocomposite materials that can be injected into a specific location in the body and deliver therapeutic drugs by a remote-controlled process. These nanocomposites are composed of magnetic particles and polymers that respond to changes in temperature. The combination of these materials results in nanocomposites that can change their properties in response to specific magnetic fields to switch from releasing drug slowly (or not at all) to releasing drug quickly on demand. The changes are fully reversible and solely depend on whether the external magnetic field is switched on or off. These novel systems offer an alternative to therapies that require frequent injections, such as insulin for diabetes, or therapies that need the drug to be released in very precise locations, such as cancer treatments, and could improve the safety, reduce the risk of side effects, and lower the cost of many medical treatments.

Current treatment for posterior segment ocular diseases requires intravitreal injections administered every 4-6 weeks. The potential for siRNA to be used to treat these diseases is extremely attractive due to the specificity of these molecules and their potential for making long term changes to the expression patterns of the cells. Due to physiological recognition, however siRNA undergoes rapid degradation upon application. The development of cationic nanogels using polymeric “smart” biomaterials with degradable components to transport siRNA is described. pH – sensitive N, N dimethylaminoethyl methacrylate (DMAEMA) was crosslinked with thermo-sensitive diethylene glycol methacrylate (DEGMA), by free radical emulsion-precipitation polymerization. Size, charge and morphology were analyzed to assess potential as a nanovehicle. Through modification of the particle composition, cationic nanogels, determined by zeta potential, with sizes of approximately 160 nm confirmed with dynamic light scattering (DLS), were synthesized. A composition of 55:45 (DEGMA:DMAEMA); a size and charge ideal for cellular uptake. These particles had minimal impact on cell proliferation and exhibited spherical morphology when imaged by TEM at physiological pH. The structure was maintained between pH 3.5-9. Sensitivity to pH was shown by DLS through swelling at physiological pH, which may be useful can be taken advantage of in future studies for loading and release. Degradation with a reducing agent was shown using gel permeation chromatography, DLS and turbidity analysis. The results suggest this formula will undergo degradation in the cell. Reducing environments mimicking intracellular conditions that promoted degradation of the crosslinker showed enhanced release of dexamethasone phosphate as a model drug. Ongoing work is focused on examining gene silencing using these formulations. / Thesis / Master of Applied Science (MASc)

Разработаны алгоритмы расчета температурных полей и оценки термонапряженного состояния массивных железобетонных фундаментов в стадии охлаждения. / Algorithms for calculating temperature fields and assessing the thermally stressed state of massive reinforced concrete foundations in the cooling stage have been developed.

Entangled semiflexible polymer networks are usually described by the tube model, although this concept has not been able to explain all experimental observations. One of its major shortcomings is neglecting the thermal fluctuations of the polymers surrounding the examined test filament, such that disentanglement effects are not captured. In this study, we present experimental evidence that correlated constraint release which has been predicted theoretically occurs in entangled, but not in crosslinked semiflexible polymer networks. By tracking single semiflexible DNA nanotubes embedded both in entangled and crosslinked F-actin networks, we observed different reptation dynamics in both systems, emphasizing the need for a revision of the classical tube theory for entangled polymer solutions.

INTRODUCTION: Multiple myeloma (MM) is a disease that results in the production of ineffective immunoglobulins and monoclonal proteins in the blood and urine, leading to insufficient organ function or death. Currently, there is a 5-year survival rate of 47% for patients diagnosed with MM, with a proportion of patients ultimately succumbing to the disease. The current standard of care for MM includes toxic combinations of chemotherapy. The evolution of chimeric antigen receptor (CAR) T-cell therapy for hematologic cancers such as lymphoma, leukemia, and now myeloma has provided another effective treatment option for patients who have relapsed after standard treatments for MM. Idecabtagene Vicleucel (ide-cel), was approved in March 2021 for patients with relapsed and refractory MM. While CAR T-cell treatment appears to be far less toxic than standard chemotherapy, this therapy comes with its own associated toxicities, mainly cytokine release syndrome (CRS) and neurotoxicity (NT). In clinical trials, ide-cel demonstrated to be an effective treatment in some patients, leading to the FDA approval for patients who have exhausted multiple other lines of therapy. Currently, it is unclear why patients respond differently to CAR T-cell treatment and why some patients present with more severe toxicity than others. Therefore, this study aims to examine patient factors such as demographics, age, and treatment history to determine if such characteristics may influence the CAR T-cell response; also, we assess the efficacy of ide-cel in a real-world experience outside of a clinical trial. METHODS: In this study, 14 patients’ medical records were reviewed after receiving commercial CAR T-cell therapy between August 2021 and January 2022. Eligible patients for the therapy were determined by strict inclusion criteria, including having a confirmed diagnosis of MM and exhausting at least four prior lines of therapy, as well as exclusion criteria, such as excluding individuals who have received CAR T-cells prior in a clinical trial setting. Approximately one month before preparation lymphodepletion chemotherapy, eligible patients underwent leukapheresis and had their blood sent to a laboratory to extract T-cells and genetically modify them to express the CAR for reinfusion. On 3 and 5 days prior to CAR T-cell infusion, patients underwent lymphodepletion using fludarabine and cyclophosphamide. Patients remained in the hospital for approximately one week following infusion, pending adverse reactions. After discharge, patients returned to the hospital for routine follow-ups. Data analysis was then performed on collected clinical readouts such as: prior treatments, bone marrow biopsies, response rates, laboratory values from blood samples, and pre- and post-infusion scans of various tissues within the body. RESULTS: At a median follow-up time of 15 weeks, six patients (43%) achieved a complete response (CR), three patients demonstrated a partial response (PR, 21%), and four patients showed disease progression (PD, 28%). Post-infusion scans were not available for one subject (7%) as they were still in the hospital. These results are similar to the phase I and phase II trials in which 45% and 33% of patients demonstrated a CR post-infusion, respectively. As for associated toxicities, 10 patients (71%) experienced CRS and one patient (7%) presented with ICANS. All patients that achieved a CR experienced ide-cel related toxicities, compared with only 38% of those with less favorable or unknown outcomes, which indicates that systemic immune system activation which causes CRS may be required to achieve a CR but CRS is not always linked with a CR outcome. There were 28 different chemotherapy regimens used as the standard of care treatment prior to ide-cel therapy. We assessed the most recent chemotherapeutic regimen in each patient to assess whether there is an association with most recent treatment and response. Of the six patients that achieved a CR to ide-cel, all were previously treated with RVD or CyBorD regimens, compared to the four patients who had disease progression who were mainly treated with salvage DCEP chemotherapy. Four patients (29%) received DCEP as their final chemotherapy regimen, and 3 of these 4 (75%) demonstrated progressive disease after ide-cel. Two patients received Belantamab-Mafodotin prior to ide-cel treatment, with one patient presenting with disease progression and the other patient achieving CR. 71% of patients experienced CRS following ide-cel infusion, which is resembles the phase II trial of ide-cel in which 84% of patients demonstrated CRS. In this study, only 7% of patients experienced neurological toxicity, which is comparable to the 18% of patients that demonstrated to have ICANS in the phase II study. CONCLUSIONS: We found similar performance of the ide-cel CAR-T therapy in the real world setting as in the clinical trial. Also, the complete responses were achieved by subjects with an array of characteristics, including varying recent chemotherapeutic treatments, IgG, IgA, and light-chain only subtypes of MM, and diverse demographics and other characteristics. The characteristic that demonstrated the most predictability and somewhat unique to subjects with CR was the associated toxicities from ide-cel. Development of these associated toxicities may attest that substantial immune activation, of CAR T-cells and other immune cells, leads to the efficacy of the product in eliminating cancer cells. Further analysis will need to be completed as more individuals enroll in this study to be able to determine if there are significant associations between demographics and prior lines of treatment with response to ide-cel CAR-T therapy. Lastly, future studies should assess the immune cell effector functions that are generated in CR patients that will help to specify the association between ide-cel activation, experienced associated toxicities, and its efficacy.

Climate change and its accompanying environmental issues have caused the building industry to use more environmentally friendly building materials. Wood have always been a buildingmaterial but due to the renewed interest in imparting sustainability and renewability, its usage has increased over the recent years. With a rising interest in wood, it is of great importance to enhance the knowledge of its burning behaviour in order to predict and prevent fire hazards. Fire development is often characterized in terms of heat release rate (HRR) as a function oftime. Therefore, HRR is considered one of the most important variables in the evaluation of material fire hazards. This study aims to generate greater knowledge of the HRR curve of wood when exposed to heating in the cone calorimeter and how the curve can be described quantitatively. Furthermore, it was attempted to comprehend the properties and functions of char and its effects on HRR during combustion. The study is based on laboratory tests carried out with a cone calorimeter and a Scanning Electron Microscope (SEM). The cone calorimeter was set to generate a heat flux of 35 kWm-2. Spruce wood samples of three thicknesses were analysed, namely 10, 20 and 30mm. The samples were assembled with one of three types of material on the rear side of the samples, which were Kaowool, steel plates and aluminium foil wrapped around wood. The different materials were used as they are greatly dissimilar in their thermal properties. Wood with both low and normal moisture content was also analysed. Char was analysed with SEM. The results show that there are four major points of interest in the HRR curve of wood. The first point is the initial peak heat release rate (PHRR) that occurs when the sample surface ignites causing great production of heat which increases the HRR. The second point of interest is the vast decrease in HRR soon after the first PHRR, this is due to char formation, which acts as a protective barrier preventing the exchange of volatile gases and oxygen. The third point of interest is a second PHRR close to the end of the combustion that occurs as a response to sample burn through, which means that the heat gradient reaches the rear side of the sample. The second PHRR is highly dependent on the boundary condition defined by the rear material, which determines the heat losses at the rear side of the specimen, and consequently the temperature of the specimen. The higher is the specimen temperature, the higher is the pyrolysis rate, and therefore also the higher the second PHRR. Moreover, high moisture content delays the time of occurrence of the second PHRR as more water needs to undergo phase change, which requires a high amount of energy. The final point of interest is the final decrease in HRR as a result of fuel depletion leading to the sample smouldering or the fire being extinguished. Char, formed by mainly lignin and some cellulose in wood, affects the overall HRR. The SEM analysis showed that the char cracks grew wider during the second PHRR. It is, however, observed that char cracking has no significance in the time of occurrence of the second PHRR as this is based on sample burn through, and it was difficult to determine to what extent char cracking affected the intensity of the PHRR. This systematic study is considered adequate to justify the research questions and aim of this study. It has also created new questions for further study in the area as well as provided a deeper understanding of the fundamental burning behaviour of wood. / Klimatförändringen och dess medföljande miljöfrågor har fått byggbranschen att använda mer hållbara och miljövänliga byggmaterial. Trä har alltid varit ett byggmaterial men på grund av ett förnyat intresse för hållbarhet och förnybarhet har användningen av materialet ökat under de senaste åren. Med ett stigande intresse för trä är det av stor vikt att öka kunskapen om dess förbränningsbeteende för att kunna förutse och förebygga brandrisker. Brandutveckling karakteriseras ofta i termer av värmeavgivningshastighet (HRR) som funktion av tid. Det är därför en av de viktigaste variablerna i utvärderingen av brandrisker. Denna studie syftar till att skapa större kunskap om HRR-kurvan för trä när det utsätts för värme i konkalorimetern och hur kurvan kan beskrivas kvantitativt. Vidare, att studera kollagrets egenskaper och funktioner samt hur det påverkar HRR under förbränning. Studien bygger på laborativa försök utförda med en konkalorimeter och ett svepelektronmikroskop (SEM). Konkalorimetern genererade strålning med intensitet 35 kWm-2. Tre tjocklekar av granprover testades, 10, 20 och 30 mm. Proverna placerades ovanpå en av tre typer av material i en provform, Kaowool, stålplattor och trä invirat i aluminiumfolie. Materialen användes då deras termiska egenskaper skiljer sig åt. Vidare testades även trä av både låg och normal fukthalt. Kollagret analyserades med SEM. Resultatet visar att det finns fyra intressanta områden på HRR-kurvan för trä. Det första är den initiala maximala värmeavgivningshastigheten (PHRR) som inträffar när provytan antänder vilket orsakar en stor värmeproduktion som ökar HRR. Det andra är en kraftig minskning av HRR strax efter den första PHRR. Detta beror på att kol börjat bildas på provytan, kollagret fungerar som en skyddande barriär som förhindrar utbyte av flyktiga gaser och syre. Det tredje är en andra PHRR som inträffar nära brandprovets slut. Detta sker till följd av provkroppsgenombränning som innebär att värmegradienten når provets baksida. Intensitetenav PHRR är starkt beroende av materialet bakom provet. Det bestämmer värmeförlusten på provets baksida och därmed även provkroppens temperatur. Ju högre provkroppstemperaturenär, desto högre är pyrolyshastigheten vilket leder till en högre andra PHRR. Hög fukthalt fördröjer även tidpunkten för uppkomsten av den andra PHRR eftersom fasomvandling av vatten kräver en stor mängd energi. Det sista och fjärde området av intresse är en minskning av HRR efter den andra PHRR, detta sker när allt bränsle förbränts och det som kvarstår är endast ett glödande prov. Kollagret, som främst bildas av lignin och en del cellulosa i träet, påverkar den totala HRR. SEM-analysen visade att sprickorna i kollagret blev bredare under den andra PHRR. Däremot observerades det att sprickbildningen inte har någon betydelse för tidpunkten av den andra PHRR uppkomst då denna enbart är baserad på provets genombränning. Det är även svårt att avgöra i vilken utsträckning sprickbildningen påverkar intensiteten av PHRR. Metoden som används för att besvara frågeställningarna och syftet anses vara adekvat. Studien har öppnat upp för ytterligare frågeställningar och idéer till fortsatta försök inom området. Vidare har även studien gett en djupare förståelse om förbränningsbeteendet av trä.

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