Danazol as a Steroid Enzyme Inhibitor in Rat Adrenal Glands

A thesis presented to the faculty of the School of Sciences and Mathematics at Morehead State University in partial fulfillment of the requirements for the Degree of Master of Science in Biology by Frank A. Miklavcic on August 1, 1979

Brewing of filter coffee

We report progress on mathematical modelling of coffee grounds in a drip filter coffee machine. The report focuses on the evolution of the shape of the bed of coffee grounds during extraction with some work also carried out on the chemistry of extraction. This work was sponsored by Philips who are interested in understanding an observed correlation between the final shape of the coffee grounds and the quality of the coffee. We used experimental data gathered by Philips and ourselves to identify regimes in the coffee brewing process and relevant regions of parameter space. Our work makes it clear that a number of separate processes define the shape of the coffee bed depending on the values of the parameters involved e.g. the size of the grains and the speed of fluid flow during extraction. We began work on constructing mathematical models of the redistribution of the coffee grounds specialised to each region and on a model of extraction. A variety of analytic and numerical tools were used. Furthermore our research has progressed far enough to allow us to begin to exploit connections between this problem and other areas of science, in particular the areas of sedimentology and geomorphology, where the processes we have observed in coffee brewing have been studied

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development

The influence of skeletal muscle anisotropy on electroporation: in vivo study and numerical modeling

The aim of this study was to theoretically and experimentally investigate electroporation of mouse tibialis cranialis and to determine the reversible electroporation threshold values needed for parallel and perpendicular orientation of the applied electric field with respect to the muscle fibers. Our study was based on local electric field calculated with three-dimensional realistic numerical models, that we built, and in vivo visualization of electroporated muscle tissue. We established that electroporation of muscle cells in tissue depends on the orientation of the applied electric field; the local electric field threshold values were determined (pulse parameters: 8 × 100 μs, 1 Hz) to be 80 V/cm and 200 V/cm for parallel and perpendicular orientation, respectively. Our results could be useful electric field parameters in the control of skeletal muscle electroporation, which can be used in treatment planning of electroporation based therapies such as gene therapy, genetic vaccination, and electrochemotherapy

Effectiveness of a Community Program for Older Adults with Type 2 Diabetes and Multimorbidity: A Pragmatic Randomized Controlled Trial

Background Type II diabetes mellitus (T2DM) affects upwards of 25% of Canadian older adults and is associated with high comorbidity and burden. Studies show that lifestyle factors and self-management are associated with improved health outcomes, but many studies lack rigour or exclude older adults, particularly those with multimorbidity. More evidence is needed on the effectiveness of community-based self-management programs in older adults with T2DM and multimorbidity. The study purpose is to evaluate the effect of a community-based intervention versus usual care on physical functioning, mental health, depressive symptoms, anxiety, self-efficacy, self-management, and healthcare costs in older adults with T2DM and 2 or more comorbidities. Methods Community-living older adults with T2DM and two or more chronic conditions were recruited from three Primary Care Networks (PCNs) in Alberta, Canada. Participants were randomly allocated to the intervention or control group in this pragmatic randomized controlled trial comparing the intervention to usual care. The intervention involved up to three in-home visits, a monthly group wellness program, monthly case conferencing, and care coordination. The primary outcome was physical functioning. Secondary outcomes included mental functioning, anxiety, depressive symptoms, self-efficacy, self-management, and the cost of healthcare service use. Intention-to-treat analysis was performed using ANCOVA modeling. Results Of 132 enrolled participants (70-Intervention, 62-Control), 42% were 75 years or older, 55% were female, and over 75% had at least six chronic conditions (in addition to T2DM). No significant group differences were seen for the baseline to six-month change in physical functioning (mean difference: -0.74; 95% CI: − 3.22, 1.74; p-value: 0.56), mental functioning (mean difference: 1.24; 95% CI: − 1.12, 3.60; p-value: 0.30), or other secondary outcomes.. Conclusion No significant group differences were seen for the primary outcome, physical functioning (PCS). Program implementation, baseline differences between study arms and chronic disease management services that are part of usual care may have contributed to the modest study results. Fruitful areas for future research include capturing clinical outcome measures and exploring the impact of varying the type and intensity of key intervention components such as exercise and diet

Data for Improvement and Clinical Excellence: a report of an interrupted time series trial of feedback in home care

Abstract Background There is substantial evidence about the effectiveness of audit with feedback, but none that we know have been conducted in home care settings. The primary purpose of the Data for Improvement and Clinical Excellence – Home Care (DICE-HC) project was to evaluate the effects of an audit and feedback delivered to care providers on home care client outcomes. The objective of this paper is to report the effects of feedback on four specific quality indicators: pain, falls, delirium, and hospital visits. Methods A 10-month audit with feedback intervention study was conducted with care providers in seven home care offices in Alberta, Canada, which involved delivery of four quarterly feedback reports consisting of data derived from the Resident Assessment Instrument – Home Care (RAI-HC). The primary evaluation employed an interrupted time series design using segmented regression analysis to assess the effects of feedback reporting on the four quality indicators: pain, falls, delirium, and hospitalization. Changes in level and trend of the quality indicators were measured before, during, and after the implementation of feedback reports. Pressure ulcer reporting was analyzed as a comparator condition not included in the feedback report. Care providers were surveyed on responses to feedback reporting which informed a process evaluation. Results At initiation of feedback report implementation, the percentage of clients reporting pain and falls significantly increased. Though the percentage of clients reporting pain and falls tended to increase and reporting of delirium and hospital visits tended to decrease relative to the pre-intervention period, there was no significant effect of feedback reporting on quality indicators during the 10-month intervention. The percentage of clients reporting falls, delirium, and hospital visits significantly increased in the 6-month period following feedback reporting relative to the intervention period. About 50% of the care providers that read and understand the feedback reports found the reports useful to make changes to the way clients are cared for. Conclusions Routinely collected data used over time for feedback is feasible in home care settings. A high proportion of care providers find feedback reports useful for informing how they care for clients. Since reporting on the frequency of quality indicators increased in the post-intervention period, this study suggests that ongoing use of audit with feedback to enhance health outcomes in home care may promote improved reporting on standardized instruments.https://deepblue.lib.umich.edu/bitstream/2027.42/136777/1/13012_2017_Article_600.pd

Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma

Electrochemotherapy has a direct cytotoxic effect on tumour cells, and presumably, a vascular disrupting effect. In this study, on the basis of the prediction of the mathematical model, histological evaluation and physiological measurements of the tumours were carried out to confirm that electroporation and electrochemotherapy of tumours have a vascular disrupting action. In the study, SA-1 solid subcutaneous sarcoma tumours in A/J mice were treated by bleomycin (BLM) given intravenously (1 mg kg−1), application of electric pulses (8 pulses, 1040 V, 100 μs, 1 Hz) or a combination of both – electrochemotherapy. The vascular effect was determined by laser Doppler flowmetry, power Doppler ultrasonographic imaging and Patent blue staining. The extent of tumour hypoxia was determined immunohistochemically by hypoxia marker pimonidazole and partial pressure of oxygen (pO2) in tumours by electron paramagnetic resonance oximetry. Electrochemotherapy with BLM induced good antitumour effect with 22 days, tumour growth delay and 38% tumour cures. The application of electric pulses to the tumours induced instant but transient tumour blood flow reduction (for 70%) that was recovered in 24 h. During this tumour blood flow reduction, we determined an increase in hypoxic tumour area for up to 30%, which was also reflected in reduced tumour oxygenation (for 70%). According to the described mathematical model, endothelial cells lining in tumour blood vessels are exposed to a ∼40% higher electric field than the surrounding tumour cells, and therefore easily electroporated, allowing access of high BLM concentration to the cytosol. Consequently, electrochemotherapy has, besides the immediate vascular disrupting action, also a delayed one (after 24 h), as a consequence of endothelial cell swelling and apoptosis demonstrated by extensive tumour necrosis, tumour hypoxia, prolonged reduction of tumour blood flow and significant tumour growth delay, and tumour cures. Our results demonstrate that in addition to the well-established direct cytotoxic effect on tumour cells, electrochemotherapy also has an indirect vascular disrupting action resulting altogether in extensive tumour cell necrosis leading to complete regression of tumours

Calcium electroporation and electrochemotherapy for cancer treatment:Importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy

Abstract Calcium electroporation is a novel anti-cancer treatment investigated in clinical trials. We explored cell sensitivity to calcium electroporation and electroporation with bleomycin, using viability assays at different time and temperature points, as well as heat calorimetry, lipidomics, and flow cytometry. Three cell lines: HT29 (colon cancer), MDA-MB231 (breast cancer), and HDF-n (normal fibroblasts) were investigated for; (a) cell survival dependent on time of addition of drug relative to electroporation (1.2 kV/cm, 8 pulses, 99 µs, 1 Hz), at different temperatures (37 °C, 27 °C, 17 °C); (b) heat capacity profiles obtained by differential scanning calorimetry without added calcium; (c) lipid composition by mass spectrometry; (d) phosphatidylserine in the plasma membrane outer leaflet using flow cytometry. Temperature as well as time of drug administration affected treatment efficacy in HT29 and HDF-n cells, but not MDA-MB231 cells. Interestingly the HT29 cell line displayed a higher phase transition temperature (approximately 20 °C) versus 14 °C (HDF-n) and 15 °C (MDA-MB231). Furthermore the HT29 cell membranes had a higher ratio of ethers to esters, and a higher expression of phosphatidylserine in the outer leaflet. In conclusion, lipid composition and heat capacity of the membrane might influence permeabilisation of cells and thereby the effect of calcium electroporation and electrochemotherapy

Two-dimensional nanosecond electric field mapping based on cell electropermeabilization

Nanosecond, megavolt-per-meter electric pulses cause permeabilization of cells to small molecules, programmed cell death (apoptosis) in tumor cells, and are under evaluation as a treatment for skin cancer. We use nanoelectroporation and fluorescence imaging to construct two-dimensional maps of the electric field associated with delivery of 15 ns, 10 kV pulses to monolayers of the human prostate cancer cell line PC3 from three different electrode configurations: single-needle, five-needle, and flat-cut coaxial cable. Influx of the normally impermeant fluorescent dye YO-PRO-1 serves as a sensitive indicator of membrane permeabilization. The level of fluorescence emission after pulse exposure is proportional to the applied electric field strength. Spatial electric field distributions were compared in a plane normal to the center axis and 15-20 μm from the tip of the center electrode. Measurement results agree well with models for the three electrode arrangements evaluated in this study. This live-cell method for measuring a nanosecond pulsed electric field distribution provides an operationally meaningful calibration of electrode designs for biological applications and permits visualization of the relative sensitivities of different cell types to nanoelectropulse stimulation. PACS Codes: 87.85.M