Emerging tumor spheroids technologies for 3D in vitro cancer modeling

"Article in Press, Available online 31 October 2017" ; "S0163-7258(17)30268-1"Cancer is a leading cause of mortality and morbidity worldwide. Around 90% of deaths are caused by metastasis and just 10% by primary tumor. The advancement of treatment approaches is not at the same rhythm of the disease; making cancer a focal target of biomedical research. To enhance the understanding and promts the therapeutic delivery; concepts of tissue engineering are applied in the development of in vitro models that can bridge between 2D cell culture and animal models, mimicking tissue microenvironment. Tumor spheroid represents highly suitable 3D organoid-like framework elucidiating the intra and inter cellular signaling of cancer, like that formed in physiological niche. However, spheroids are of limited value in studying critical biological phenomenon such as tumor-stroma interactons involving extra cellular matrix or immune system. Therefore, a compelling need of tailoring spheroid technologies with physiologically relevant biomaterials or in silico models, is ever emerging. The diagnostic and prognostic role of spheroids rearrangements within biomaterials or microfluidic channel is indicative of patient management; particularly for the decision of targated therapy. Fragmented information on available in vitro spheroid models and lack of critical analysis on transformation aspects of these strategies; pushes the urge to comprehensively overview the recent technological advancements (e.g. bioprinting, micro-fluidic technologies or use of biomaterials to attain the third dimension) in the shed of tranlationable cancer research. In present article, relationships between current models and their possible exploitation in clinical success is explored with the highlight of existing challenges in defining therapeutic targets and screening of drug efficacy.The authors are thankful to European Union (Horizon 2020) funded project FoReCaST (No. 668983), the FCT fellowship to J. Silva-Correia (Grant No. SFRH/BPD/100590/2014), distinctions to J.M.O. under the Investigator FCT program (IF/00423/2012) and V.M.C. under the Investigator FCT program (IF/01214/2014) for supporting this work financially.info:eu-repo/semantics/publishedVersio

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies

Performance evaluation of Norwegian and global mutual funds : 1999 - 2006

In this study I evaluate the performance of a sample of eight Norwegian mutual funds and eight global mutual funds over the period January 1999 to June 2006. Norwegian mutual funds invest in companies, which are listed on the Oslo Stock Exchange and global mutual funds invest in companies in USA, Europe, Asia and South America. This study examines the riskadjusted returns using Sharpe’s ratio, Treynor’s ratio, Jensen’s measure, Appraisal Ratio and Modigliani and Modigliani measure for these Norwegian and Global mutual funds. The analysis will focus on the funds performances in the form of risk-adjusted return. In the empirical examination, I have used arithmetic risk-adjusted monthly return. The purpose is to compare the performances of global mutual funds and domestic mutual funds and seeks to test whether the mutual funds achieve a higher risk-adjusted excess return than the market and if the mutual funds have the same risk profile and investment strategy as they claim. On the basis of the results I found in the empirical analysis, I conclude that only a few funds managed to generate a risk-adjusted excess return corresponding to the fund’s investment strategy and profile and few funds have the same risk profile as they claim. The performance evaluation methods, which are used to rank the mutual funds in this thesis, have strong positive correlation. This adds robustness to my results. Different fund management companies charge different management fee from their customers. The results based on the empirical analysis indicate that the mutual funds, which have lower subscription cost and management fee, obtain higher risk adjusted returns than the mutual funds with high subscription cost and management fee

How well is the electronic health record supporting the clinical tasks of hospital physicians? A survey of physicians at three Norwegian hospitals

Abstract Background The electronic health record is expected to improve the quality and efficiency of health care. Many novel functionalities have been introduced in order to improve medical decision making and communication between health care personnel. There is however limited evidence on whether these new functionalities are useful. The aim of our study was to investigate how well the electronic health record system supports physicians in performing basic clinical tasks. Methods Physicians of three prominent Norwegian hospitals participated in the survey. They were asked, in an online questionnaire, how well the hospital’s electronic health record system DIPS supported 49 clinical tasks as well as how satisfied they were with the system in general, including the technical performance. Two hundred and eight of 402 physicians (52%) submitted a completely answered questionnaire. Results Seventy-two percent of the physicians had their work interrupted or delayed because the electronic health record hangs or crashes at least once a week, while 22% had experienced this problem daily. Fifty-three percent of the physicians indicated that the electronic health record is cumbersome to use and adds to their workload. The majority of physicians were satisfied with managing tests, e.g., requesting laboratory tests, reading test results and managing radiological investigations and electrocardiograms. Physicians were less satisfied with managing referrals. There was high satisfaction with some of the decision support functionalities available for prescribing drugs. This includes drug interaction alerts and drug allergy warnings, which are displayed automatically. However, physicians were less satisfied with other aspects of prescribing drugs, including getting an overview of the ongoing drug therapy. Conclusions In the survey physicians asked for improvements of certain electronic health record functionalities like medication, clinical workflow support including planning and better overviews. In addition, there is apparently a need to focus on system stability, number of logins, reliability and better instructions on available electronic health record features. Considerable development is needed in current electronic health record systems to improve usefulness and satisfaction. </jats:sec

Abstract 5229: Single, pre-labeled metastatic melanoma cells can be detected in the mouse brain using MRI

Abstract In metastatic melanoma, brain metastases are clinically diagnosed in 40-60% of patients during the disease, but can be found in up to 90% at autopsy. The prognosis for these patients is poor, due to ineffective treatments and development of multiple brain metastasis. There is a limited knowledge about the biological mechanisms behind this development of multiple metastasis in the brain, which necessitates the development of clinically more relevant animal models. The purpose of this study was to develop a multiple brain metastasis animal model which closely reflects the clinical setting, and specifically to determine the number of single melanoma cells able to arrest in the animal brain. The H1 brain metastatic melanoma cell line was established from a patient melanoma brain metastases obtained during surgery. The H1 cells were pre-labeled with superparamagnetic iron oxide particles (Fedex; Babic et al, Bioconjugate Chem 2008) at a concentration of 10 μg/ml for 24 hrs. The viability of labeled cells was studied in vitro using cell proliferation assays, and Scanning/Transmission Electron Microscopy (SEM/TEM). One million pre-labeled tumor cells were then injected into the left ventricle of the heart in nod scid mice. 24 hrs after injections, T1 weighted (T1w), T2 weighted (T2w) and T2* weighted (T2*w) MR imaging were performed. In addition, T1w and T2w MR images were obtained 5 weeks after injections. We also transfected the H1 melanoma cells with luciferase, and monitored the animals for up to 6 weeks using bioluminescence imaging (OI). Pre-labeling of melanoma cells with Fedex did not affect cell proliferation. The SEM and TEM studies showed iron oxide particle attachment to the tumor cell membrane, as well as localisation of the labelling agents within vesicles in the cytoplasm. By encapsulating pre-labeled tumor cells at various concentrations in soft agar, we were able to detect less than 50 cell/μl using T2 mapping MRI. By pre-labeling the melanoma cells with Fedex, we were able to detect single tumour cells in the animal brains. Imaging studies (OI, MR) 4-6 weeks after injections confirmed multiple metastatic spread to the brain. In conclusion, we have developed a melanoma metastasis model in immunodeficient mice, which reflects the metastatic tumor spread seen in patients. By using pre-labeling with Fedex, we were able to detect single tumour cells in the brain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5229. doi:10.1158/1538-7445.AM2011-5229</jats:p

Automated Tracking of Nanoparticle-labeled Melanoma Cells Improves the Predictive Power of a Brain Metastasis Model

Abstract Biologic and therapeutic advances in melanoma brain metastasis are hampered by the paucity of reproducible and predictive animal models. In this work, we developed a robust model of brain metastasis that empowers quantitative tracking of cellular dissemination and tumor progression. Human melanoma cells labeled with superparamagnetic iron oxide nanoparticles (SPION) were injected into the left cardiac ventricle of mice and visualized by MRI. We showed that SPION exposure did not affect viability, growth, or migration in multiple cell lines across several in vitro assays. Moreover, labeling did not impose changes in cell-cycle distribution or apoptosis. In vivo, several SPION-positive cell lines displayed similar cerebral imaging and histologic features. MRI-based automated quantification of labeled cells in the brain showed a sigmoid association between metastasis frequency and doses of inoculated cells. Validation of this fully automated quantification showed a strong correlation with manual signal registration (r2 = 0.921, P &amp;lt; 0.001) and incidence of brain metastases (r2 = 0.708, P &amp;lt; 0.001). Metastasis formation resembled the pattern seen in humans and was unaffected by SPION labeling (histology; tumor count, P = 0.686; survival, P = 0.547). In summary, we present here a highly reproducible animal model that can improve the predictive value of mechanistic and therapeutic studies of melanoma brain metastasis. Cancer Res; 73(8); 2445–56. ©2013 AACR.</jats:p

Supplementary Figure Legends from Automated Tracking of Nanoparticle-labeled Melanoma Cells Improves the Predictive Power of a Brain Metastasis Model

&lt;p&gt;PDF file - 47K, Includes movie legends&lt;/p&gt;</jats:p