Radiation and medical drugs are used to fight head and neck cancer, but unfortunately in some cases these treatments cause development of other diseases and injuries. Osteoradionecrosis (ORN) and medical-related osteonecrosis of the jaw (MRONJ) are dreaded late complications in jaws from radiation therapy and medical drugs and cause great suffering to those affected. The full extent of ORN and MRONJ may be difficult to diagnose due to visualizing problems in quantifying boundaries of osteonecrosis and healthy tissues. Maxillofacial surgeons now use radiology and clinical appearance to differ affected bone, which may result in unprecise estimation of the area that is affected. As a possible adjuvant diagnostic procedure, visualizing osteonecrosis by examining neutrophil elastase (NE) activity in jaws was tested in patients. A newly developed positron emission tomography (PET) tracer specific for NE was used for observation and measurement in PET/CT images. An image processing software was used for visualization, segmentation, and analysis. Areas with osteonecrosis were identified in the ORN patients, but not in their entirety and all activity could not be equated with osteonecrosis as undiagnosed areas as well absorbed the tracer. Visualization of MRONJ displayed unexpectedly low activity in the diagnosed area.    The conclusion drawn from the results and the analysis is that NE activity can be found in osteonecrosis patients, but the activity itself does not provide complete information to visualize and quantify the diseased area and it cannot be equated with osteonecrosis. To verify NE activity as osteonecrosis, tissue samples from the affected area need to be collected for histological examination

<p dir="ltr">Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadliest cancer and despite advancements in cancer therapy, remain highly refractory to treatment, largely due to its desmoplastic tumor microenvironment (TME) characterized by complex interactions among cancer cells and stromal components. Particularly, the PDAC associated coagulation system due to leaky tumor vasculatures plays a pivotal role in reshaping the PDAC stroma and its pathogenesis. Understanding the intricate interplay between tumor cells, stromal cells, and the elevated coagulation pathway elements, including tissue factor, thrombin, and fibrin, is essential for developing effective therapeutic strategies. To address these challenges, this research proposes the engineering of a novel PDAC-associated coagulation system using a microfluidic technology, known as coagulation-on-tumor-microenvironment-on-chip (cT-MOC). The study aims to integrate key coagulation pathways in cT-MOC to investigate pivotal interactions in the PDAC stroma: <i>i)</i> thrombin-protease-activated receptors (PARs) mediated promotion of PDAC fibrosis via activation of cancer-fibroblast cross-talk; <i>ii)</i> in-depth analysis of transport and mechanical properties of collagen-fibrin microstructure; <i>iii)</i> inhibited drug delivery in reprogrammed PDAC stroma due to pronounced fibrin deposition on collagen. By leveraging innovative microfluidic technologies and comprehensive experimental approaches, the research endeavors to provide a novel platform that bridges traditional <i>in vitro</i> and <i>in vivo</i> models to overcome the challenges posed by the desmoplastic TME and enhance therapeutic strategies for treatment by targeting the coagulation at the PDAC TME.</p>

Depuis quelques années, il y a un intérêt de la communauté en dosimétrie d'actualiser les protocoles de dosimétrie des faisceaux larges tels que le TG-51 (AAPM) et le TRS-398 (IAEA) aux champs non standard qui requièrent un facteur de correction additionnel. Or, ces facteurs de correction sont difficiles à déterminer précisément dans un temps acceptable. Pour les petits champs, ces facteurs augmentent rapidement avec la taille de champ tandis que pour les champs d'IMRT, les incertitudes de positionnement du détecteur rendent une correction cas par cas impraticable. Dans cette étude, un critère théorique basé sur la fonction de réponse dosimétrique des détecteurs est développé pour déterminer dans quelles situations les dosimètres peuvent être utilisés sans correction. Les réponses de quatre chambres à ionisation, d'une chambre liquide, d'un détecteur au diamant, d'une diode, d'un détecteur à l'alanine et d'un détecteur à scintillation sont caractérisées à 6 MV et 25 MV. Plusieurs stratégies sont également suggérées pour diminuer/éliminer les facteurs de correction telles que de rapporter la dose absorbée à un volume et de modifier les matériaux non sensibles du détecteur pour pallier l'effet de densité massique. Une nouvelle méthode de compensation de la densité basée sur une fonction de perturbation est présentée. Finalement, les résultats démontrent que le détecteur à scintillation peut mesurer les champs non standard utilisés en clinique avec une correction inférieure à 1%. / In recent years, the radiation dosimetry community has shown a keen interest in extending broad beam dosimetry protocols such as AAPM's TG-51 and IAEA's TRS-398 to nonstandard fields which involve the use of an additional correction factor. Yet, these correction factors are difficult to determine precisely in a time frame that is acceptable. For small fields, these factors increase rapidly with field size, whereas for composite IMRT fields, detector positioning uncertainties render a case-by-case correction impractical. In this study, a theoretical criterion based on radiation detectors' dose response functions is used to determine in which situations a given dosimeter can be used without correction. The responses of four ionization chambers, a liquid-filled chamber, a diamond detector, an unshieded diode, an alanine dosimeter and a plastic scintillator detector are characterized at 6 MV and 25 MV. Several strategies are also suggested to reduce/eliminate correction factors such as reporting the absorbed dose to a volume and modifying the non-sensitive components of a detector to compensate for mass density effects. A new method of density compensation based on a perturbation function is presented. Finally, results show that the scintillator detector can measure nonstandard fields used in the clinic with corrections under 1%.

Avec près de 25 000 cas en 2015, le cancer du sein est de loin le cancer le plus fréquent chez les femmes canadiennes. En termes de mortalité, le cancer du sein se place au deuxième rang (13,8%), derrière le cancer du poumon (26,5%). Suite au diagnostic, 70% des femmes avec un cancer de stade avancé et 30% des femmes avec cancer précoce choisiront de subir une mastectomie totale. Plusieurs options de reconstructions mammaires sont ensuite offertes. Plus de 70% des reconstructions se feront par la mise en place d’implants mammaires (plutôt que par reconstruction autologue utilisant les tissus de la patiente). Parmi les complications survenant après cette intervention, la contracture capsulaire en est une des plus fréquente. La contracture capsulaire se définit comme la contraction anormale de la capsule fibreuse se formant autour des implants mammaires, pouvant causer des douleurs en plus d’un mauvais résultat sur le plan esthétique. Les études cliniques ont démontré un risque accru de développer une contracture capsulaire chez les femmes ayant du suivre un protocole de radiothérapie. Si plusieurs études ont cherché à démontré l’influence des radiations sur l’histologie et l’immunologie du tissu capsulaire, aucune étude ne s’était intéressée à leur effet sur l’ultrastructure capsulaire. Notre équipe a récemment démontré que l’ultrastructure capsulaire dépendait de plusieurs facteurs, notamment de la texture prothétique et du délai de reconstruction. L’objectif de ce mémoire était de décrire l’impact de la radiothérapie sur l’ultrastructure capsulaire en comparant des capsules irradiées et non-irradiées en utilisant la microscopie éléctronique à balayage. Nous avons observé, chez les échantillons issus de capsules irradiés, une perte de relief au niveau de l’interface prothèse-capsule par rapport au échantillons non irradiés. Nous avons aussi démontré que cette caractéristique ultrastructurale est associée à la présence de contracture capsulaire. Enfin, ces effets néfastes de la radiothérapie semblent altérer la capacité de la capsule à adhérer à la prothèse mammaire. En conclusion, mon projet de maîtrise aura permis de décrire pour la première fois l’impact de la radiothérapie sur l’ultrastructure des capsules périprothétiques. Bien que nos résultats ne nous permettent pas d’expliquer de façon certaine le lien potentiel avec l’évolution vers un état de contracture capsulaire, ils laissent croire que cela serait associé avec un diminution de la stabilité de la capsule sur son implant, facteur auparavant évoqué comme ayant une rôle protecteur sur la contracture capsulaire. / With around 25,000 cases in 2015, breast cancer is the most common cancer among Canadian women. In term of mortality, breast cancer is second (13.8%), only behind lung cancer (26.5%). As part of the therapeutic approaches, around 70% and 30% of women with advanced and early breast cancer (respectively) will chose to have a total mastectomy. Following a mastectomy, few options of breast reconstruction are offered to the patients. More than 70% of breast reconstructions are implant-based. Among the complications following this surgery, capsular contracture (CC) is one of the most common. CC is defined as the abnormal, and sometimes painful, contraction of the fibrous capsule that normally grows aroung breast implants, resulting in a aesthetic failure and associated with a higher surgical revision rate. Many studies have demonstrated that the incidence of CC was higher among women who had undergone radiotherapy prior to their implant-based breast breast reconstruction procedure. Most of published studies focus on the influence of radiotherapy on capsular tissue at the immune-histological level but no study has described its influence on capsular architecture. As our team recently demonstrated that capsular ultrastructure is influenced by many factors (prosthetic texture, expansion timing). The main purpose was to describe the impact of radiotherapy on periprosthetic capsule ultrastructural features by comparing irradiated and non-irradiated capsules using scanning electron microscopy (SEM). We observed a significant loss of tridimensional texture at the implant-capsule interface in irradiated capsular samples. This feature was also found to be associated with CC. Finally, our results tend to show that radiotherapy impaires the stability of capsules by preventing them to grow withing their surrounding implant texure. In conclusion, the present research project offers the first description of the capsular response following exposiong to radiations. Even though our results do not allow us to conlude to a clear relation between loss of capsular architecture and a higher risk of CC, we think that the impairement of capsular stability might be part of the answer

Depuis quelques années, il y a un intérêt de la communauté en dosimétrie d'actualiser les protocoles de dosimétrie des faisceaux larges tels que le TG-51 (AAPM) et le TRS-398 (IAEA) aux champs non standard qui requièrent un facteur de correction additionnel. Or, ces facteurs de correction sont difficiles à déterminer précisément dans un temps acceptable. Pour les petits champs, ces facteurs augmentent rapidement avec la taille de champ tandis que pour les champs d'IMRT, les incertitudes de positionnement du détecteur rendent une correction cas par cas impraticable. Dans cette étude, un critère théorique basé sur la fonction de réponse dosimétrique des détecteurs est développé pour déterminer dans quelles situations les dosimètres peuvent être utilisés sans correction. Les réponses de quatre chambres à ionisation, d'une chambre liquide, d'un détecteur au diamant, d'une diode, d'un détecteur à l'alanine et d'un détecteur à scintillation sont caractérisées à 6 MV et 25 MV. Plusieurs stratégies sont également suggérées pour diminuer/éliminer les facteurs de correction telles que de rapporter la dose absorbée à un volume et de modifier les matériaux non sensibles du détecteur pour pallier l'effet de densité massique. Une nouvelle méthode de compensation de la densité basée sur une fonction de perturbation est présentée. Finalement, les résultats démontrent que le détecteur à scintillation peut mesurer les champs non standard utilisés en clinique avec une correction inférieure à 1%. / In recent years, the radiation dosimetry community has shown a keen interest in extending broad beam dosimetry protocols such as AAPM's TG-51 and IAEA's TRS-398 to nonstandard fields which involve the use of an additional correction factor. Yet, these correction factors are difficult to determine precisely in a time frame that is acceptable. For small fields, these factors increase rapidly with field size, whereas for composite IMRT fields, detector positioning uncertainties render a case-by-case correction impractical. In this study, a theoretical criterion based on radiation detectors' dose response functions is used to determine in which situations a given dosimeter can be used without correction. The responses of four ionization chambers, a liquid-filled chamber, a diamond detector, an unshieded diode, an alanine dosimeter and a plastic scintillator detector are characterized at 6 MV and 25 MV. Several strategies are also suggested to reduce/eliminate correction factors such as reporting the absorbed dose to a volume and modifying the non-sensitive components of a detector to compensate for mass density effects. A new method of density compensation based on a perturbation function is presented. Finally, results show that the scintillator detector can measure nonstandard fields used in the clinic with corrections under 1%.

<p>The realm of molecular physical chemistry ranges from the structure of matter and the fundamental atomic and molecular interactions to the macroscopic properties and processes arising from the average microscopic behaviour.</p><p>Herein, the conventional electrodic problem is recast into the simpler molecular problem of finding the electrochemical, real chemical, and chemical potentials of the species involved in redox half-reactions. This molecular approach is followed to define the three types of absolute chemical potentials of species in solution and to estimate their standard values. This is achieved by applying the scaling laws of statistical mechanics to the collective behaviour of atoms and molecules, whose motion, interactions, and properties are described by first principles quantum chemistry. For atomic and molecular species, calculation of these quantities is within the computational implementations of wave function, density functional, and self-consistent reaction field theories. Since electrons and nuclei are the elementary particles in the realm of chemistry, an internally consistent set of absolute standard values within chemical accuracy is supplied for all three chemical potentials of electrons and protons in aqueous solution. As a result, problems in referencing chemical data are circumvented, and a uniform thermochemical treatment of electron, proton, and proton-coupled electron transfer reactions in solution is enabled.</p><p>The formalism is applied to the primary and secondary radiation damage to DNA bases, e.g., absorption of UV light to yield electronically excited states, formation of radical ions, and transformation of nucleobases into mutagenic lesions as OH radical adducts and 8-oxoguanine. Based on serine phosphate as a model compound, some insight into the direct DNA strand break mechanism is given.</p><p>Psoralens, also called furocoumarins, are a family of sensitizers exhibiting cytostatic and photodynamic actions, and hence, they are used in photochemotherapy. Molecular design of more efficient photosensitizers can contribute to enhance the photophysical and photochemical properties of psoralens and to reduce the phototoxic reactions. The mechanisms of photosensitization of furocoumarins connected to their dark toxicity are examined quantum chemically.</p>

The realm of molecular physical chemistry ranges from the structure of matter and the fundamental atomic and molecular interactions to the macroscopic properties and processes arising from the average microscopic behaviour. Herein, the conventional electrodic problem is recast into the simpler molecular problem of finding the electrochemical, real chemical, and chemical potentials of the species involved in redox half-reactions. This molecular approach is followed to define the three types of absolute chemical potentials of species in solution and to estimate their standard values. This is achieved by applying the scaling laws of statistical mechanics to the collective behaviour of atoms and molecules, whose motion, interactions, and properties are described by first principles quantum chemistry. For atomic and molecular species, calculation of these quantities is within the computational implementations of wave function, density functional, and self-consistent reaction field theories. Since electrons and nuclei are the elementary particles in the realm of chemistry, an internally consistent set of absolute standard values within chemical accuracy is supplied for all three chemical potentials of electrons and protons in aqueous solution. As a result, problems in referencing chemical data are circumvented, and a uniform thermochemical treatment of electron, proton, and proton-coupled electron transfer reactions in solution is enabled. The formalism is applied to the primary and secondary radiation damage to DNA bases, e.g., absorption of UV light to yield electronically excited states, formation of radical ions, and transformation of nucleobases into mutagenic lesions as OH radical adducts and 8-oxoguanine. Based on serine phosphate as a model compound, some insight into the direct DNA strand break mechanism is given. Psoralens, also called furocoumarins, are a family of sensitizers exhibiting cytostatic and photodynamic actions, and hence, they are used in photochemotherapy. Molecular design of more efficient photosensitizers can contribute to enhance the photophysical and photochemical properties of psoralens and to reduce the phototoxic reactions. The mechanisms of photosensitization of furocoumarins connected to their dark toxicity are examined quantum chemically.

科学研究費補助金 研究種目:基盤研究(C)(2) 課題番号:07680528 研究代表者:青山 隆彦 研究期間:1995-1996年度

Advances in breast cancer detection and oncology treatment modalities have prolonged the survival time for the cancer population, which is officially the largest group of cancer survivors among women in the western world, including South Africa (Brem & Kumar, 2011; Fisher, Dolbeault, Sultan & Bredart, 2014; Herbst, 2011; Reyes-Gibby, et al., 2012). In the light of shocking statistics and ever rising numbers of cancer, especially breast cancer, the time is ripe for further research in the domain of psycho-oncology and has motivated the researcher, due to her interest and involvement in breast cancer, to make this her field of research. Despite the need for a bio-psycho-social approach when treating cancer patients there is little literature available on the psychological interventions in South Africa where the majority of research studies previously conducted in South Africa have generally focused on the bio-medical aspects of cancer (Albrecht, 2009; Venter, 2014). To comprehend the paradigm of psycho-oncology, which is the backbone of this study, a theoretical framework was attained from Engel’s humanistic or psychological model (caring) and Pasteur’s biomedical model (curing) (Borrel-Carrio, Suchman, & Epstein, 2004). The primary aim of this study was to explore the lived experiences of breast cancer patients concerning their diagnosis, treatment and survivorship and unique needs for psycho-oncological interventions through their own “voices”. The research was conducted within a qualitative framework with a case study method of inquiry employing open-ended style interviews and psychotherapeutic sessions with five purposely sampled breast cancer patients. Two qualitative questionnaires were also used for triangulation purposes. Transcripts of all the therapeutic sessions were analysed using interpretive analysis where categories and themes were developed and described in full. Findings indicated that in spite the extensive proof that breast cancer causes numerous sexual and psychological complications during active treatment and afterwards, patients still feel that they have no “platform” to express their emotions and sexual issues within the oncology framework, or that there is enough and sufficient assistance to attend to their needs. e The researcher hopes that this study will make a valuable contribution to research in the field of psycho-oncology in South Africa and to indicate new realities of the chronicity of breast cancer and treatment complications that demand psychotherapeutic interventions in cancer care and that the study will initiate new ways of understanding the role of psychology and the psychologist in the medical world of cancer. The researcher hopes that by offering an understanding of participants’ unique experiences of this process, practitioners will have insight when working therapeutically with this population and empower them to have a quality of life, even within the boundaries of their illness. / Psychology / D. Litt. et Phil. (Psychology)

<div>Cancer is responsible for the second highest cause of death in the United States, and lung cancer accounts for 13% of new cancer diagnoses, with the highest rate of cancer death at 24%. Almost 85% of these cases represent non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma, the most common NSCLC subtype. Traditional cancer treatments often only temporarily stop the spread of the disease, but immunotherapies, which are becoming a standard of care, are much more promising. Natural killer (NK) cells are powerful effectors of innate immunity, and genetically engineered NK cells as immunotherapies have had encouraging clinical responses in the treatment of various cancers. However, more progress is needed for solid tumor treatment, especially for lung adenocarcinoma. The activation of cancer-associated ectoenzymes, CD39 and CD73 catalyze the phosphorylation of ATP to AMP to produce extracellular adenosine (ADO), which is a highly immunosuppressive mechanism contributing to the pathogenesis of solid tumors. Understanding adenosine effects on NK cells will help develop more robust immunotherapeutic treatments to improve cytotoxicity against solid tumors. Here, we established that tumor microenvironment ADO results in impaired metabolic and anti-tumor functions of cytokine-primed NK cells. Specifically, peripheral blood-derived NK cells stimulated with IL-2, IL-15, or a combination of IL-12 and IL-15 showed suppressed anti-tumor immunity due to ADO. This was observed by the downregulation of activation receptor expression, cytotoxicity inhibition, impairment of metabolic activity, and alterations in gene expression. To target ADO-producing CD73 on cancer cells, we redirected NK cells by fusing CD73 ScFv with intracellular and transmembrane regions of NK cell specific signaling components derived from FCyRIIIa (CD16). Engineered NK cells were shown to be cytotoxic against lung adenocarcinoma <i>in vitro</i> and impede tumor growth in a lung adenocarcinoma mouse model <i>in vivo</i>. Engineered cells also had higher levels of degranulation and cytokine release, as well as more infiltration into tumors and longer survival time in mice. In summary, the microenvironment of solid tumors is highly immunosupressive, and redirecting NK cell function using a NK-specific anti-CD73 targeting construct will help to promote anti-tumor immunity and</div><div>inhibit cancer growth for a potentially powerful new immunotherapy against solid tumors.</div>