A Comprehensive Model and Modulation of Cellular Signaling Involved in Early Mammary Development and Aggressive Cancer Using a Novel Recombinant Protein of the G3 Domain of Laminin-5

The mammary gland is a unique and specialized epidermal organ; mammary organogenesis begins in the embryo but is not fully complete until puberty. As such, formation of the mammary gland depends on temporally and spatially regulated developmental steps that require coordination of multiple biological and cell signaling processes; many of which have parallels with cancer development. Research describing the events that occur between birth and puberty is lacking and little is known about human breast development of youth. Since mammary gland development requires a coordinated balance between cell growth, proliferation, and apoptosis, it is critical to understand which signaling pathways are utilized to relay developmental signals, and how these pathways and their targets interact and cooperate with age. Additionally, interactions between integrin molecules and their laminin ligands, especially Laminin-5 (Ln-5; also known as Laminin-332), regulate multiple facets of both embryonic development and tumor growth, invasion, and metastasis. α6β4 integrin serves as a marker to detect distant metastases in the early stages of specific malignancies and β4 integrin overexpression has been found in basal-like breast cancers, correlating with aggressiveness to institute a prognostic β4 signature that increases with tumor grade. The mechanism α6β4 integrin utilizes to modulate oncogenic signaling through association with Ln-5 molecules in the ECM is the basis for the recombinant protein (rG3, the third of five G domains of Ln-5) produced for the work reported in this dissertation. Here, it is shown there are specific transcriptional differences and a unique interaction of a gene set over time that contributes to postnatal mammary gland development, and this model clearly shares similarities and signaling pathways with oncogenic development. Especially important are pathways of the adaptive and innate immunities, ECM remodeling and integrin interactions, and extrinsic and intrinsic TP53-mediated apoptosis, greater understanding of which could lead to early detection of potential tumorigenic growth and identification of potential treatment avenues. Presented is a comprehensive model of early mammary development along with several panels of biomarkers that possess a role in normal mammary development, are involved in aggressive cancers, and are affected by apoptosis induced by rG3 treatment. rG3 has proven to be a valuable tool to study apoptotic pathways and the crosstalk among those pathways

Ability of Flavonoids to Mimic the Estrogen Receptor to Drive Myeloid Derived Suppressor Cell Differentiation

Flavonoids are natural compounds found in dietary elements such as soy, grains, and vegetables that have the potential to bind to the estrogen receptor. Activation of the estrogen receptor drives myeloid derived suppressor cell (MDSC) accumulation, cells that increase during cancer, inflammation, and infection. In this study, we are investigating specific flavonoids, such as epigallocatechin-3-gallate (EGCG), kaempferol, naringenin, daidzein, and genistein, for their ability to mimic estrogen. After examination, we expect that MDSC differentiation will decrease upon treatment of the chosen flavonoids, leading to reduced carcinogenic effects

Optimising tidal lagoons: an environmental focus

Tidal lagoons could help towards meeting ambitious global and national renewable energy and carbon reduction targets, contributing towards tackling climate change through the displacement of fossil fuel generation. Lagoons have additional benefits over other forms of renewable energy which include: predictability, use of proven technology, long expected life spans (100 years) and the ability to be strategically located to provide a base load supply of continuous energy. Despite these advantages there are no tidal lagoons in the world to date, the key barriers to lagoon development have been cost and environmental concerns. This research shows how to optimise tidal lagoons in terms of the environment, considering the wider socio-economic implications of lagoon developments as multi-use facilities. Through industry engagement, the research provides a snapshot of industry perspectives, allowing presentation of the key environmental impacts and benefits of tidal lagoons. It then uses systematic literature review to investigate transferable solution options from other relevant coastal and marine industries to address these key impacts. Finally, the research demonstrates use of a potential methodology to select and assess solution options which allows for consideration of the wider environmental, socio-economic implications of lagoons. Unlike many other large-scale marine energy projects tidal lagoons have the potential to be multi-use, multi-benefit facilities which are likely to have far reaching environmental, social and economic impacts, both positive and negative. The lagoon sector is in its infancy with recent political debates arising over the ‘value for money’ of lagoons and the cost of developments to both the tax payer and to the environment. Independent research addressing the uncertainty surrounding the environmental impacts of lagoons and considering how to optimise lagoons in terms of the potential value they could provide to society is now more important than ever

Changing ideas about family care for the elderly in Japan

As rapid social changes occur around the world, accompanied by increasingly larger numbers of elderly in need of care, it is crucial to gain new knowledge of the relationship between changing social institutions and the impact of such changes on the context in which care is given to the elderly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42993/1/10823_2004_Article_BF00971564.pd

Eat more beans to experience benefits to your health

Medical and dietetic students often co-author a column for the Daily Reflector under Dr. Kolasa's byline. The students research the topic a reader or patient has asked. Dr. Kolasa reviews their draft for technical accuracy, patient friendly language, and people first language. She fact checks the study or other evidence-based reference the student provides. If a physician review is appropriate, Dr. Kolasa requests a colleague from ECU physicians to review the article. The final draft is submitted to the Reflector with the editor having the final say. The headline is written by the Reflector headline writer. The food and nutrition column has run weekly since 1987. Starting in 2020, in addition to the Daily Reflector, the article is published in daily and weekly papers owned by the Adams Publishing Group East (https://adamspg.com)This is a weekly Q and A newspaper column under the byline of Dr. Kathy Kolasa. The topic of today's column is eating more beans for health benefits and advice for integrating beans into a family's regular diet.Non

Boundary of oxidative and overflow metabolism (boom) controller for CHO cell feed control

There is limited literature for CHO cell cultures with low batch glucose concentrations (Gowtham et al. 2017; Lu et al. 2005; Wong et al. 2005). Work like Xu et al. (2016) and Berry et al. (2016) have shown positive results for controlled fed-batch cultures at low glucose concentrations following standard high glucose (5-6 g/L) batch cultures. However, the Xu et al. (2016) and Berry et al. (2016) approaches still accumulate lactate. Controlling glucose earlier could potentially avoid lactate accumulation and lead to even greater improvements in culture outcomes. The objective of this project was to develop an advanced feed controller for CHO cell cultures that maximizes cell growth by maintaining the culture in a state of maximal oxidative metabolism while minimizing overflow metabolism. The Boundary of Oxidative and Overflow Metabolism (BOOM) controller periodically manipulates the feed rate while monitoring online signals to gauge the remaining oxidative “space”, in order to decide whether feed can be increased while remaining in oxidative metabolism. The Oxygen Uptake Rate (OUR) is the primary signal of interest, since it plateaus when a culture shifts from oxidative to overflow metabolism, encoding vital information about metabolic state. This project’s approach is different from past work in that the batch glucose concentrations is much lower (on the order of 1 g/L), the glucose and/or glutamine feeding begins very early in the process, and glucose feed is triggered/controlled by the off-gas sensing of the metabolic state instead of a targeted glucose concentration. During early runs several chemistry effects were observed directly due to the bolus feed additions interfering with the media-dissolved gas equilibrium. For example, a bolus feed that only contained 5 mM bicarbonate, resulted in an observed short sharp decrease in CO2 off-gas as the feed absorbed CO2 from the 5% CO2 sparge gas. Continuous feeding was introduced in subsequent runs as a means to mitigate disrupting the media-dissolved gas-equilibrium and disturbing the off-gas sensing. In order to have effective continuous feeding, the feed pump used a pulse width modulation (PWM) with a 10-minute period to allow extremely low effective feed rates required for the 1-L vessel. Two runs were used to demonstrate that the PWM feed pump could provide these very low pump feed rates for the 1-L vessel containing as little as 500 mL media. Initial glucose concentrations between 0.6 to 2.0 g/L were used (compared to 8 g/L glucose in the standard media formulation). Feedings have started between 6- and 20-hour post-inoculation. Distinct qualitative and quantitative differences have been observed in the corresponding oxygen uptake rate (OTR) responses due to the feeding spikes, suggesting that metabolic state can be detected. The development of the state estimator to control glucose feeding will be presented