No / The use of nanoparticles have provided numerous of advantages in medicine due to their unique physiochemical characteristics such as size, charge, shape and surface reactivity [1-4]. Understanding the interaction between engineered nanomaterials and living matter has attracted increasing attention in recent years. Toxicity of nanoparticles was studied in different cell types and cell lines. Nano-SiO2 has good stability, easy dispensability, and melting degeneration, and is widely used in rubber, paints, biomedical and biotechnology fields [5]. In this study, the LDH assay and the MTT assay were applied to evaluate the cytotoxicity of in vitro Silicon dioxide nanoparticles (SiO2-NP, 20nm) on cultured cell lines. Human lung adenocarcinoma epithelial cell line (A549) were used as a lung related cell line and human keratinocyte cell line (HaCaT) as a skin related cell line representing different uptake routes. The percentage cytotoxicity of the silicon dioxide nanoparticles was measured once cultured in a 24 hour incubation period. The concentration of the SiO2 nanoparticles chosen was 10, 50, 100 and 200µg/ml. To measure the cytotoxicity of nanoparticle on cultured cell lines, we used 104*cells/100 µl of cell culture media being placed in a 96 well rounded bottom plate with the LDH assay. The extracellular lactate dehydrogenase release was measured by using a colorimetric CytoTox 96 non-radioactive assay kit and the absorbance was recorded at 492nm. The MTT assay was used to evaluate mitochondrial activity which includes cell growth and cell death. This has been performed by inserting a premixed optimized dye solution in the culture wells. The Absorbance was recorded at 570 nm, from the recorded absorbance is directly proportional to the number of live cells. In order to maintain the cell lines, they were placed in a plastic T-75cm² tissue culture flasks grown in Dulbecco's Modified Eagle's Medium. Studies were performed in the absence of serum. Cytotoxicity was found in both cells the A549 and HaCaT cells and cytotoxicity increased as concentration of the silicon dioxide increased. The percentage cytotoxicity calculated was higher in HaCaT cells compared to the A549 cells. A cell count assay was plated in order to display the cell number of both the HaCaT and A549 cells. The cell count reaffirmed that cytotoxicity did occur as the cell count decreased as the concentration of the silicon dioxide increased compared to the control. These results show that silicon dioxide nanoparticles acted differently in two different cell types and that the metabolic rate of a cell can be used to determine the nanoparticles affect. Further understanding of the mechanism involving the ROS generation could provide more information on how silicon dioxide nanoparticles increase cytotoxicity. / Physiology 2015 conference abstract

Introduktion Lungcancer är den tredje vanligaste cancersjukdomen i Sverige och den främsta orsaken till cancerrelaterade dödsfall i världen. Den har en dålig prognos med en 5 års överlevnad på under 25%. Detta främst på grund av att den ofta upptäcks i ett sent skede då bot inte längre är möjligt. Den vanligaste orsaken till lungcancer är rökning. Ungefär 90% av alla som drabbats av lungcancer är eller har varit rökare. Med hjälp av screening av individer med en hög konsumtion av rökning “högriskindivider” kan lungcancer hittas i ett tidigt skede och förhindra att individer dör av sjukdomen. Syfte Syftet med detta examensarbete är belysa högriskindividers upplevelser av deltagande i lungcancerscreening samt deras eventuella behov av stöd från sjukvården för att öka motivationen till att delta i lungcancerscreening. Metod En allmän litteraturstudie baserat på 18 vetenskapliga artiklar med kvalitativ ansats varav 3 med mixad-metod Resultat Resultatet baseras på 18 vetenskapliga artiklar. Fyra kategorier och tio subkategorier blev syntesen av dessa studier. De fyra kategorier som presenteras är: 1. Fördelar med screening, 2. Nackdelar med screening, 3. Delaktighet i beslutsprocessen och förtroendet för vården samt 4. Personcentrerad individanpassad information. Resultatet visar på vikten av personcentrerad och individanpassad information samt betydelsen av förtroendet för vården inför och under screeningprocessen. Slutsats Fördelarna med att screenas för lungcancer övervägde nackdelarna. Det kunde även motivera individer att sluta röka och behålla kontrollen över sin hälsosituation och minska rädslan för det okända. Nackdelarna var att individer kunde uppleva psykisk oro och stress under screeningprocessen och en rädsla för en cancerdiagnos. Bemötandet från vårdpersonalen var 3av stor betydelse och behovet av individanpassad information var stort. Pilotstudier pågår i Sverige för en eventuell implementering av lungcancerscreening i Sverige i framtiden. / BackgroundLung cancer is the leading cause of cancer-related deaths worldwide and the third most common in Sweden. It has a poor prognosis with a 5-year survival rate of below 25%. This is mainly due to the fact that it is often discovered at a late stage where cure is no longer possible. The most common cause of lungcancer is smoking. Approximately 90% of all people affected by lungcancer are or have been smokers. With the help of screening "highrisk individuals" lung cancer can be found at an early stage and thus prevent individuals from dying of the disease. Research questionThe purpose of this thesis is to illustrate high-risk individuals' experiences of participation in lung cancer screening and their possible need for support from health care to increase the motivation to participate in lung cancer screening. MethodA general literature review based on 18 scientific articles with a qualitative approach, of which 3 with mixed-method ResultsThe result is based on 18 scientific articles. Four categories and ten subcategories became the synthesis of these studies. The four categories presented are: 1. Advantages of screening, 2. Disadvantages of screening, 3. Participation in the decision-making process and trust in health care, and 4. Person-centered personalized information. The results show the importance of person-centered and individualized information as well as the importance of trust from the healthcare system before and during the screening process. ConclusionThe advantages of being screened for lung cancer outweighed the disadvantages. It could also motivate individuals to quit smoking and maintain control over their health situation and reduce fear of the unknown. The disadvantages were that individuals could experience 4psychological anxiety and stress during the screening process and a fear of a cancer diagnosis. How the individual was treated by the care staff was of great importance and the need for individually tailored information was great.Pilotstudies are ongoing in Sweden for a possible implementation of lung cancer screening in Sweden in the future.

Cancer is one of the main causes of death in the US. Lung cancer remains the highest killing form of cancer. Lung screening rates are low amongst the general population and even lower in minority populations. It is not well known what the barriers are for lung cancer screening. In order to investigate barriers, I created questions to add onto an existing questionnaire survey for an ongoing lung cancer screening research project. These questions focused on social determinants of health and the survey was administered to patients who were non-adherent to lung cancer screening. Patients reported cost concerns for screening, potential medical care costs, and ability to attend medical appointments as barriers to lung cancer screening. Both non-white and female patients reported more difficulties attending appointments than their white and male counterparts. Patient physician relationship and perceived racial discrimination were not barriers to lung cancer screening in the patient population surveyed. Further research needs to investigate specific details on these barriers to create interventions to increase lung cancer screening rates. / Urban Bioethics

Introduction Neutropenia is a life-threatening and dose-limiting toxicity of palliative lung cancer chemotherapy. Whilst some neutropenias are inevitable, evidence suggests that patients with a previous neutropenic event are 50% more likely to have a further neutropenic event. The aim of this research is to evaluate the variables associated with the risk of secondary neutropenic events and the role of chemotherapy dose reductions. Methods A retrospective analysis was carried out on 361 biochemical neutropenic events in palliative lung cancer patients across 5 sites in South Yorkshire and Bassetlaw. Predictors for a secondary neutropenic event were investigated in univariate and multivariate logistic regression analysis. The predictive model was validated through discrimination statistics, described by Receiver Operating Characteristic Area Under Curve (ROC-AUC). Results The incident rate for secondary neutropenic events was 32.7%. Patients with a successful intervention received a higher mean Relative Dose Intensity (RDI) of 75.65% compared to 65.05%, across the 2 chemotherapy cycles. The univariate analysis found that the biochemical type of neutropenia (depth and length of suppression) (p=0.003), dose reduction of drug 1 (p=0.042), average dose reduction (p=0.019), and cumulative dose reduction (p=0.018) were significant at reducing the risk of secondary neutropenia. Granulocyte-Colony Stimulating Factor did not offer a protective effect. The final logistic regression model evaluated 357 events and included all variables due to significant interrelationship. The model had a ROC-AUC of 0.76 (0.71-0.81) (p= 0.0021), explaining 27% of the variance. Conclusion Appropriate dose reductions play a vital role in preventing secondary neutropenic events and delivering optimal RDIs. The results of this study can aid in identifying high-risk patients.

Yes / The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25190号 / 医博第5076号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 貴浩, 教授 藤田 恭之, 教授 武藤 学 / 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・課程博士 / 博士(薬科学) / 甲第25230号 / 薬科博第192号 / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 掛谷 秀昭, 教授 樋口 ゆり子, 教授 二木 史朗 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Contexte. Le cancer bronchopulmonaire (CBP) demeure la première cause de mortalité par cancer dans le monde. Malgré l’espoir suscité par le développement des thérapies ciblées, son pronostic demeure sombre, particulièrement dans les cas de CBP à petites cellules (CBP-PC) et de CBP non à petites cellules (CBP-NPC) présentant une activation de l’oncogène KRAS. Matériel et Méthodes. Nous avons mené 3 études successives, visant à (i) radiosensibiliser des modèles de CBP-PC par l’ajout d’un inhibiteur de BCL2, (ii) cibler des modèles de CBP-NPC mutés KRAS par l’association d’un inhibiteur de mTOR et d’un inhibiteur de RAF, et (iii) créer un modèle préclinique orthotopique murin de CBP reproduisant la progression tumorale observée en clinique. Résultats. Dans la première étude, l’inhibiteur de BCL2 oblimersen a présenté un effet radiosensibilisant sur des modèles de CBP-PC, in vitro et in vivo. Dans la seconde étude, l’association de l’inhibiteur de mTOR everolimus et de l’inhibiteur de RAF/VEGFR RAF265 a présenté un effet synergique sur des lignées cellulaires de cancers présentant la double mutation de KRAS et de PIK3CA, in vitro et in vivo. Dans la troisième étude, l’injection orthotopique d’une lignée bioluminescente de CBP-NPC chez des souris nude a permis d’établir des tumeurs intra pulmonaires évoluant vers une extension métastatique ganglionnaire et hématogène, et de détecter la présence de cellules tumorales circulantes. Conclusion. L’association d’un inhibiteur de BCL2 à la radiothérapie est une stratégie intéressante dans le CBP-PC, l’association d’un inhibiteur de mTOR et d’un inhibiteur de RAF/VEGFR est une stratégie intéressante dans le CBP-NPC présentant une double mutation KRAS-PIK3CA, mais ces données doivent être confirmées sur des modèles orthotopiques afin de gagner en pertinence avant d’envisager un transfert en clinique. / Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the conséquences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model.

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