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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23785号 / 医博第4831号 / 新制||医||1057(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 伊達 洋至, 教授 中本 裕士, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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With the recent increase in the threat of biological terrorism as well as the continual risk of other diseases, the research in public health surveillance and disease monitoring has grown tremendously. There is an abundance of data available in all sorts of forms. Hospitals, federal and local governments, and industries are all collecting data and developing new methods to be used in the detection of anomalies. Many of these methods are developed, applied to a real data set, and incorporated into software. This research, however, takes a different view of the evaluation of these methods. We feel that there needs to be solid statistical evaluation of proposed methods no matter the intended area of application. Using proof-by-example does not seem reasonable as the sole evaluation criteria especially concerning methods that have the potential to have a great impact in our lives. For this reason, this research focuses on determining the properties of some of the most common anomaly detection methods. A distinction is made between metrics used for retrospective historical monitoring and those used for prospective on-going monitoring with the focus on the latter situation. Metrics such as the recurrence interval and time-to-signal measures are therefore the most applicable. These metrics, in conjunction with control charts such as exponentially weighted moving average (EWMA) charts and cumulative sum (CUSUM) charts, are examined. Two new time-to-signal measures, the average time-between-signal events and the average signal event length, are introduced to better compare the recurrence interval with the time-to-signal properties of surveillance schemes. The relationship commonly thought to exist between the recurrence interval and the average time to signal is shown to not exist once autocorrelation is present in the statistics used for monitoring. This means that closer consideration needs to be paid to the selection of which of these metrics to report. The properties of a commonly applied scan method are also studied carefully in the strictly temporal setting. The counts of incidences are assumed to occur independently over time and follow a Poisson distribution. Simulations are used to evaluate the method under changes in various parameters. In addition, there are two methods proposed in the literature for the calculation of the p-value, an adjustment based on the tests for previous time periods and the use of the recurrence interval with no adjustment for previous tests. The difference in these two methods is also considered. The quickness of the scan method in detecting an increase in the incidence rate as well as the number of false alarm events that occur and how long the method signals after the increase threat has passed are all of interest. These estimates from the scan method are compared to other attribute monitoring methods, mainly the Poisson CUSUM chart. It is shown that the Poisson CUSUM chart is typically faster in the detection of the increased incidence rate. / Ph. D.

We examine some of the methodologies implemented by the Centers for Disease Control and Prevention's (CDC) BioSense program. The program uses data from hospitals and public health departments to detect outbreaks using the Early Aberration Reporting System (EARS). The EARS method W2 allows one to monitor syndrome counts (W2count) from each source and the proportion of counts of a particular syndrome relative to the total number of visits (W2rate). We investigate the performance of the W2r method designed using an empiric recurrence interval (RI) in this dissertation research. An adaptive threshold monitoring method is introduced based on fitting sample data to the underlying distributions, then converting the current value to a Z-score through a p-value. We compare the upper thresholds on the Z-scores required to obtain given values of the recurrence interval for different sets of parameter values. We then simulate one-week outbreaks in our data and calculate the proportion of times these methods correctly signal an outbreak using Shewhart and exponentially weighted moving average (EWMA) charts. Our results indicate the adaptive threshold method gives more consistent statistical performance across different parameter sets and amounts of baseline historical data used for computing the statistics. For the power analysis, the EWMA chart is superior to its Shewhart counterpart in nearly all cases, and the adaptive threshold method tends to outperform the W2 rate method. Two modified W2r methods proposed in the dissertation also tend to outperform the W2r method in terms of the RI threshold functions and in the power analysis. / Ph. D.

<p dir="ltr">Proper development of hypersonic vehicles requires knowledge of thermal loads, which are primarily dictated by the turbulent kinetic energy [1]. Accurate measurements of these values require measurements of velocity fluctuations, which are difficult to obtain using conventional seeded velocimetry methods [2]. However, molecular tagging velocimetry methods such as femtosecond laser electronic excitation tagging (FLEET) have been shown to be capable of measuring mean velocity within highly varying flows [3].</p><p dir="ltr">This work extends the available measurements provided by FLEET, through combination with optical thermometry and novel analysis methods of the signal. By performing FLEET velocimetry alongside thermometry, this shows capability to make instantaneous measurements of Mach number within supersonic flows [4]. Additionally, by tracking multiple characteristics of FLEET image signals, the ability to both capture instantaneous velocity fluctuations and improve measurement of mean velocity are demonstrated.</p><p dir="ltr">Furthermore, the uncertainty intrinsic to the analysis of FLEET signals is investigated. This is done using a combination of both classical statistical methods and uncertainty calculation methods commonly used in particle imaging velocimetry [5]. This is necessary to provide the best possible estimate of velocity fluctuations for the validation of computational fluid dynamic (CFD) models of boundary layer heat transfer.</p><p dir="ltr">Beyond simply improving the quality of velocity measurements, frequency analysis tools are developed and extended to analysis of fluid dynamic problems. These tools have been used prior for detecting extreme transitions within a signal [6], but are applied here to demonstrate their ability to detect physics captured within flow fields. These tools show promise in the ability to detect frequency couplings in time and can potentially be implemented to improve current control strategies in the field of fluid dynamics.</p>

Cancer remains the second leading cause of death in the United States and the world, despite years of research and the development of different treatments. One reason for this is cancer cells are able to survive through adaptation to their environment and aberrantly activated growth signaling. As such, developing new therapies that overcome these hurdles are necessary to combat cancer. Previous work in our laboratory using RNA interference screening identified genes that regulate the survival of glioblastoma (GBM) or autophagy in chronic myelogenous leukemia (CML) cancer cells. One screen identified Phosphatidylinositol-4,5-bisophosphate 3-kinase catalytic subunit beta (PIK3CB) in the family of Phosphatidylinositol 3-kinases (PI3K) as a survival kinase gene in GBM. Work contained in this dissertation set out to study PIK3CB mediated GBM cell survival. We report that only PIK3CB, in its family of other PI3K genes, is a biomarker for GBM recurrence and is selectively important for GBM cell survival. Another screen identified the long non-coding RNA, Linc00467, as a gene that regulates autophagy in CML. Autophagy is a dynamic survival process used by all cells, benign and cancerous, where cellular components are broken down and re-assimilated to sustain survival. Work contained in this dissertation set out to characterize the role that Linc00467 serves in regulating autophagy in a myriad of cancers. Collectively our data have showed Linc00467 to actively repress levels of autophagy in cancer cells. Further, our data revealed an important role for Linc00467 in regulating the stability of the autophagy regulating protein serine-threonine kinase 11 (STK11). Because of the unique role that Linc00467 serves in regulating autophagy we renamed it as, autophagy regulating long intergenic noncoding RNA or ARLINC. Taken together the work in this dissertation unveils the inner-workings of two important cancer cell survival pathways and shows their potential for development into therapeutic targets to treat cancer. / Ph. D. / Cancer remains the second leading cause of death in the United States and the world, despite years of research and the development of different treatments. One reason for this is cancer cells are able to survive through adaptation to their environment and aberrantly activated growth signaling. As such, developing new therapies that overcome these hurdles are necessary to combat cancer. Previous work in our laboratory using high throughput genetic screens identified genes that regulate the survival of cancer cells from a deadly type of brain cancer called glioblastoma (GBM). Another screen revealed genes that regulate a process called autophagy in cancer cells from a type of leukemia called chronic myelogenous leukemia (CML). Autophagy is a process that cancer cells can use to survive through chemotherapy. One screen identified the gene Phosphatidylinositol-4,5-bisophosphate 3-kinase catalytic subunit β (PIK3CB) in the family of Phosphatidylinositol 3-kinases (PI3K) as a survival gene in GBM. Work contained in this dissertation set out to study PIK3CB mediated GBM cell survival. We report that only PIK3CB, in its family of other PI3K genes, is a biomarker for GBM recurrence and is selectively important for GBM cell survival. Another screen identified the long non-coding RNA, Linc00467, as a gene that regulates autophagy in CML. Autophagy is a dynamic survival process used by all cells, normal and cancerous, where cellular components are broken down and reassimilated to sustain survival. Work contained in this dissertation set out to characterize the role that Linc00467 serves in regulating autophagy in different types of cancer. Collectively our data have showed Linc00467 to actively repress levels of autophagy in cancer cells. Further, our data revealed an important role for Linc00467 in regulating the stability of the autophagy regulating protein serine-threonine kinase 11 (STK11). Because of the unique role that Linc00467 serves in regulating autophagy we renamed it as, autophagy regulating long intergenic noncoding RNA or ARLINC. Taken together the work in this dissertation unveils the inner-workings of two important cancer cell survival pathways and shows their potential for development into therapeutic targets to treat cancer.

Tesis por compendio / [ES] La tesis "Teoría Combinatoria de Números, Recurrencia de Operadores y Dinámica Lineal" se sitúa dentro del estudio de la dinámica de operadores lineales, o Dinámica Lineal. El objetivo de este trabajo es estudiar múltiples nociones de recurrencia, que pueden presentar los sistemas dinámicos lineales, y que clasificaremos mediante la Teoría Combinatoria de Números. La Dinámica Lineal estudia las órbitas generadas por las iteraciones de una transformación lineal. Las propiedades más estudiadas en esta rama durante los últimos 30 años han sido la hiperciclicidad (existencia de órbitas densas) y el caos (con sus múltiples definiciones), siendo esta un área de investigación muy activa y obteniéndose un considerable número de resultados profundos e interesantes. Nosotros nos centraremos en la recurrencia, propiedad muy estudiada para sistemas dinámicos clásicos no lineales, pero prácticamente nueva en Dinámica Lineal pues no es hasta 2014, con el artículo de Costakis, Manoussos y Parissis titulado "Recurrent linear operators", cuando se empieza a estudiar esta noción de manera sistemática en el contexto de operadores actuando en espacios de Banach. La situación básica de la que parte nuestro estudio es la siguiente: "T : X ---> X" será un operador lineal y continuo actuando sobre un F-espacio "X" , aunque a veces necesitaremos que el espacio subyacente "X" sea un espacio de Fréchet, de Banach o de Hilbert. Dado un vector "x" y un entorno "U" de "x" estudiaremos el conjunto de retorno "N_T(x,U) = { n : T^n(x) está en U }" y dependiendo de su tamaño, observado mediante la Teoría Combinatoria de Números, diremos que el vector "x" presenta una propiedad de recurrencia u otra. La memoria de la tesis se ha realizado por compendio de artículos y consta de cuatro capítulos y un apéndice: 1. Adaptación de la "versión de autor" del artículo "Frequently recurrent operators. Journal of Functional Analysis, 283 (12) (2022), artículo núm. 109713, 36 páginas". En este se definen por primera vez las fuertes nociones de recurrencia reiterada, U-frecuente y frecuente, y sus propiedades básicas son estudiadas. Finalmente se generaliza el estudio mediante el concepto de F-recurrencia, que se conecta con la noción de F-hiperciclicidad. 2. Adaptación al formato de la tesis de la "versión de autor" revisada del artículo "Recurrence properties: An approach via invariant measures. Journal de Mathématiques Pures et Appliquées, 169 (2023), 155-188". En este se relaciona la recurrencia de operadores con la Teoría Ergódica y los sistemas dinámicos que conservan la medida. 3. Adaptación de la "versión de autor" del preprint "Questions in linear recurrence: From the T+T-problem to lineability". Se resuelve negativamente un problema abierto de 2014: Sea "T : X ---> X" un operador recurrente. ¿Es cierto que el operador "T+T" es recurrente en "X+X"? Para resolverlo introducimos la casi-rigidez, que será, para la recurrencia, la noción análoga a la propiedad débil-mezclante (topológica) para la transitividad/hiperciclicidad; y luego construimos operadores recurrentes pero no casi-rígidos en todo espacio de Banach infinito-dimensional y separable. 4. Adaptación de la "versión de autor" revisada del preprint " Recurrent subspaces in Banach spaces". En este se estudia la propiedad de espaciabilidad (existencia de un subespacio vectorial cerrado y de dimensión infinita) para el conjunto de vectores recurrentes. - Apéndice. Para conseguir un carácter auto-contenido hemos añadido un apéndice con los resultados básicos de Teoría Combinatoria de Números que se han utilizado en los trabajos que componen la memoria. Siguiendo la normativa establecida por la Escuela de Doctorado también se incluye: - Introducción; - Discusión general de los resultados; - Conclusiones. / [CAT] La tesi "Teoria Combinatòria de Nombres, Recurrència d'Operadors i Dinàmica Lineal" se situa dins de l'estudi de la dinàmica d'operadors lineals, o simplement Dinàmica Lineal. L'objectiu d'aquest treball és estudiar múltiples nocions de recurrència, que poden presentar els sistemes dinàmics lineals, i que classificarem mitjançant la Teoria Combinatòria de Nombres. La Dinàmica Lineal estudia les òrbites generades per les iteracions d'una transformació lineal. Les propietats més estudiades en aquesta branca de les matemàtiques als darrers 30 anys han estat la hiperciclicitat (existència d'òrbites denses) i el caos (amb les seves múltiples definicions), sent aquesta una àrea de recerca molt activa i obtenint-se un considerable nombre de resultats profunds i interessants. Nosaltres ens centrarem en la recurrència, propietat molt estudiada per a sistemes dinàmics clàssics no lineals, però, pràcticament nova en Dinàmica Lineal doncs no és fins al 2014, amb l'article de Costakis, Manoussos i Parissis titulat "Recurrent linear operators", quan es comença a estudiar aquesta noció de manera sistemàtica en el context d'operadors actuant en espais de Banach. La situació bàsica de la qual parteix el nostre estudi és la següent: "T : X ---> X" serà un operador lineal i continu actuant sobre un F-espai "X", encara que de vegades necessitarem que l'espai subjacent X siga un espai de Fréchet, de Banach o de Hilbert. Llavors, donat un vector "x" i un entorn "U" de "x" estudiarem el conjunt de retorn "N_T(x,U) = { n : T^n(x) està en U }" i depenent de la seva mida, observada des del punt de vista de la Teoria Combinatòria de Nombres, direm que el vector "x" presenta una o altra propietat de recurrència. La memòria de la tesi s'ha realitzat per compendi d'articles i consta de quatre capítols i un apèndix: 1. Adaptació de la "versió d'autor" revisada de l'article "Frequently recurrent operators. Journal of Functional Analysis, 283 (12) (2022), article núm. 109713, 36 pàgines". En aquest es defineixen per primera vegada les nocions de recurrència reiterada, U-freqüent i freqüent, i les seves propietats bàsiques són estudiades. Finalment es generalitza l'estudi mitjançant el concepte de F-recurrència, que es connecta amb la noció de F-hiperciclicitat. 2. Adaptació al format de la tesi de la "versió d'autor" revisada de l'article "Recurrence properties: An approach via invariant measures. Journal de Mathématiques Pures et Appliquées, 169 (2023), 155-188". Es relaciona la recurrència d'operadors amb la Teoria Ergòdica i els sistemes dinàmics que conserven la mesura. 3. Adaptació de la "versió d'autor" del preprint "Questions in linear recurrence: From the T+T-problem to lineability". En aquest es resol un problema obert de l'any 2014: Siga "T : X ---> X" un operador recurrent. És cert que l'operador "T+T" és recurrent en "X+X"? Per resoldre'l introduïm la quasi-rigidesa, que serà, per a la recurrència, la noció anàloga a la propietat feble-barrejant (topològica) per a la transitivitat/hiperciclicitat; i després construïm operadors recurrents però no quasi-rígids en tot espai de Banach infinit-dimensional i separable. 4. Adaptació de la "versió d'autor" del preprint "Recurrent subspaces in Banach spaces". S'inclou l'estudi de la propietat d'espaiabilitat (existència d'un subespai vectorial tancat i de dimensió infinita) per al conjunt de vectors recurrents. - Apèndix:Per aconseguir un caràcter auto-contingut hem afegit un apèndix amb resultats bàsics de Teoria Combinatòria de Nombres que es donen per suposats en els treballs que componen la memòria. Seguint la normativa establerta per l'Escola de Doctorat també s'inclou: - Introducció; - Discussió general dels resultats; - Conclusions. / [EN] The thesis "Combinatorial Number Theory, Recurrence of Operators and Linear Dynamics" is part of the study of the dynamics of linear operators, simply called Linear Dynamics. The objective of this work is to study multiple notions of recurrence, that linear dynamical systems can present, and which will be classified through Combinatorial Number Theory. Linear Dynamics studies the orbits generated by the iterations of a linear transformation. The two most studied properties in this branch of mathematics during the last 30 years have been hypercyclicity (existence of dense orbits) and chaos (with its multiple definitions), being this a very active research area with a considerable number of exceptionally deep but also interesting results. We will focus on recurrence, a property widely studied in the classical setting of non-linear dynamical systems, but practically new with respect to Linear Dynamics since it was not until 2014, with the article by Costakis, Manoussos and Parissis entitled "Recurrent linear operators", when this notion started to be systematically studied in the context of operators acting on Banach spaces. The basic situation from which our study starts is the following: "T : X ---> X" will be a continuous linear operator acting on an F-space "X", although sometimes we will need the underlying space X to be a Fréchet, Banach or Hilbert space. Given a vector "x" and a neighbourhood "U" of "x" we will study the return set "N_T(x,U) = { n : T^n(x) is in U }" and depending on its size, observed from the Combinatorial Number Theory point of view, we will say that the vector "x" presents one property of recurrence or another. The thesis memoir is a compendium of articles and it has four chapters and one appendix: 1. Adaptation of the revised "author version" of article "Frequently recurrent operators. Journal of Functional Analysis, 283 (12) (2022), paper no. 109713, 36 pages". Here, the strong notions of reiterative, U-frequent and frequent recurrence are defined for the first time, and their basic properties are studied. The theory is finally generalized through the concept of F-recurrence, which is connected to the notion of F-hypercyclicity. 2. Adaptation of the revised "author version" of article "Recurrence properties: An approach via invariant measures. Journal de Mathématiques Pures et Appliquées, 169 (2023), 155-188". In this chapter the recurrence properties for linear operators are related to Ergodic Theory and measure preserving systems. 3. Adaptation of the revised "author version" of the preprint "Questions in linear recurrence: From the T+T-problem to lineability". We solve in the negative an open problem posed in 2014: Let "T : X ---> X" be a recurrent operator. Is it true that the operator "T+T" is recurrent on "X+X"? In order to do that we establish the analogous notion, for recurrence, to that of (topological) weak-mixing for transitivity/hypercyclicity, namely quasi-rigidity; and then we construct recurrent but not quasi-rigid operators on every separable infinite-dimensional Banach space. 4. Adaptation of the revised "author version" of the preprint "Recurrent subspaces in Banach spaces". In this chapter we study the spaceability (existence of an infinite-dimensional closed subspace) for the set of recurrent vectors. - Appendix. Looking for a self-contained text we have added an appendix with some of the basic Combinatorial Number Theory results that are taken for granted along the different chapters/articles forming this memoir. Following the regulations established by the Doctoral School the next sections are also included: - Introduction; - General discussion of the results; - Conclusions. / This thesis has been written at the “Institut Universitari de Matemàtica Pura i Aplicada” (IUMPA) of the “Universitat Politècnica de València” (UPV), during the period of enjoyment of a scholarship of the “Programa de Formación de Profesorado Universitario” granted by the “Ministerio de Ciencia, Innovación y Universidades”, reference number: FPU2019/04094. The research exposed has also been partially funded by the project “Dinámica de operadores” (MCIN/AEI/10.13039/501100011033, Project PID2019-105011GB-I00), thanks to which the author carried out a 3-month research stay in Lille, France (September-December 2021), that was supervised by Professor Sophie Grivaux; and also by the travel grant awarded by the “Fundació Ferran Sunyer i Balaguer” which allowed the author to carry out a 3-month research stay in Mons, Belgium (April-June 2023), supervised by Professor Karl Grosse-Erdmann. / López Martínez, A. (2023). Combinatorial Number Theory, Recurrence of Operators and Linear Dynamics [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/196101 / Compendio

Background Current studies indicate that fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography ([18F]FDG PET/CT) is the most accurate imaging modality for the detection of relapsed locally advanced non-small cell lung cancer (NSCLC) after curatively intended chemoradiotherapy. To this day, there is no objective and reproducible definition for the diagnosis of disease recurrence in PET/CT, the reading of which is relevantly influenced by post radiation inflammatory processes. The aim of this study was to evaluate and compare visual and threshold-based semi-automated evaluation criteria for the assessment of suspected tumor recurrence in a well-defined study population investigated during the randomized clinical PET-Plan trial. Methods This retrospective analysis comprises 114 PET/CT data sets of 82 patients from the PET-Plan multi-center study cohort who underwent [18F]FDG PET/CT imaging at different timepoints for relapse, as suspected by CT. Scans were first analyzed visually by four blinded readers using a binary scoring system for each possible localization and the associated reader certainty of the evaluation. Visual evaluations were conducted repeatedly without and with additional knowledge of the initial staging PET and radiotherapy delineation volumes. In a second step, uptake was measured quantitatively using maximum standardized uptake value (SUVmax), peak standardized uptake value corrected for lean body mass (SULpeak), and a liver threshold-based quantitative assessment model. Resulting sensitivity and specificity for relapse detection were compared to the findings in the visual assessment. The gold standard of recurrence was independently defined by prospective study routine including external reviewers using CT, PET, biopsies and clinical course of the disease. Results Overall interobserver agreement (IOA) of the visual assessment was moderate with a high difference between secure (ĸ = 0.66) and insecure (ĸ = 0.24) evaluations. Additional knowledge of the initial staging PET and radiotherapy delineation volumes improved the sensitivity (0.85 vs 0.92) but did not show significant impact on the specificity (0.86 vs 0.89). PET parameters SUVmax and SULpeak showed lower accuracy compared to the visual assessment, whereas threshold-based reading showed similar sensitivity (0.86) and higher specificity (0.97). Conclusion Visual assessment especially if associated with high reader certainty shows very high interobserver agreement and high accuracy that can be further increased by baseline PET/CT information. The implementation of a patient individual liver threshold value definition, similar to the threshold definition in PERCIST, offers a more standardized method matching the accuracy of experienced readers albeit not providing further improvement of accuracy.