In Reply

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139931/1/oncoe14.pd

Use of Prednisone With Abiraterone Acetate in Metastatic Castration‐Resistant Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140033/1/onco1231.pd

Mathematical modeling of bone marrow – peripheral blood dynamics in the disease state based on current emerging paradigms, part II

The cancer stem cell hypothesis has gained currency in recent times but concerns remain about its scientific foundations because of significant gaps that exist between research findings and comprehensive knowledge about cancer stem cells (CSCs). In this light, a mathematical model that considers hematopoietic dynamics in the diseased state of the bone marrow and peripheral blood is proposed and used to address findings about CSCs. The ensuing model, resulting from a modification and refinement of a recent model, develops out of the position that mathematical models of CSC development, that are few at this time, are needed to provide insightful underpinnings for biomedical findings about CSCs as the CSC idea gains traction. Accordingly, the mathematical challenges brought on by the model that mirror general challenges in dealing with nonlinear phenomena are discussed and placed in context. The proposed model describes the logical occurrence of discrete time delays, that by themselves present mathematical challenges, in the evolving cell populations under consideration. Under the challenging circumstances, the steady state properties of the model system of delay differential equations are obtained, analyzed, and the resulting mathematical predictions arising therefrom are interpreted and placed within the framework of findings regarding CSCs. Simulations of the model are carried out by considering various parameter scenarios that reflect different experimental situations involving disease evolution in human hosts. Model analyses and simulations suggest that the emergence of the cancer stem cell population alongside other malignant cells engenders higher dimensions of complexity in the evolution of malignancy in the bone marrow and peripheral blood at the expense of healthy hematopoietic development. The model predicts the evolution of an aberrant environment in which the malignant population particularly in the bone marrow shows tendencies of reaching an uncontrollable equilibrium state. Essentially, the model shows that a structural relationship exists between CSCs and non-stem malignant cells that confers on CSCs the role of temporally enhancing and stimulating the expansion of non-stem malignant cells while also benefitting from increases in their own population and these CSCs may be the main protagonists that drive the ultimate evolution of the uncontrollable equilibrium state of such malignant cells and these may have implications for treatment.Evans Afenya is thankful to Elmhurst College for summer research support. Rachid Ouifki would like to thank the DST/NRF SARChI Chair in Mathematical Models and Methods in Bioengineering and Biosciences for its financial support.http://www.elsevier.com/locate/yjtbi2020-01-07hj2018Mathematics and Applied Mathematic

Volunteerism, social context and health impacts: a qualitative study of Glasgow Commonwealth Games event volunteers

Volunteer engagement is crucial to the effective delivery of mega-sporting events. While evidence points to reported motivations and wellbeing benefits for individual participants during and post event, there is less evidence on how this type of civic participation relates to the social context in which it occurs and the wider social determinants of health. This qualitative study sought to understand impacts on wellbeing and the determinants of health resulting from the experience of volunteering at the Glasgow 2014 Commonwealth Games. Focus groups and interviews were conducted one-year post-Games to gather the perspectives of 46 volunteers and 7 unsuccessful applicants on their experiences. Participants provided insight into the volunteer journey, contributions and associated outcomes. Wider social impacts were also reported including a renewed sense of pride in the city. The qualitative analysis suggested an important non-linear relationship between volunteer contributions, impacts and rewards, and the outcome of enhanced social connections. The emergent ‘people and place’ framework identifies some critical factors around city life and volunteer assets that planners could consider in developing and evaluating sustainable volunteering and its wider impacts beyond a mega-event

Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes

<p>Abstract</p> <p>Background</p> <p>Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations.</p> <p>Methods</p> <p>GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes.</p> <p>Results</p> <p>Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg⁺⁺, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-<it>Myc </it>and <it>Trp53 </it>were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in <it>Ras </it>and genes encoding adhesion or cytoskeleton proteins such as integrin, β-catenin, α-catenin, and actin.</p> <p>Conclusion</p> <p>The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.</p