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Prevention of Organ-Specific Doxorubicin Induced Toxicity Using Physiologically-Based Pharmacokinetic Modeling and Therapeutic Drug Monitoring
Get PDFPhysiology-based pharmacokinetic models are mathematical models that characterize the behavior of a drug and have compartmental equations that are representative of specific tissues and physiological processes.[1, 2] Doxorubicin is an anthracycline antibiotic that is effective and widely used in anticancer therapy due to its potent cytotoxicity. Unfortunately, with that potency comes cardiotoxic side effects related to cumulative lifetime dose.[3] Specifically, the toxicity is related to the accumulation of the primary metabolite doxorubicinol (DOXol) in the heart.[4] Since the toxicity is organ-specific, the best way to characterize the behavior is through PBPK modeling.[2] Since PBPK models tend to be large systems of ODEs, several numerical methods were attempted for solving the model before a matrix-based approach was chosen.[5, 6] The eigenvalue/eigenvector solution was evaluated at three time points which were then included in a Composite Simpson’s Rule numerical integration for the length of some time interval.[5, 7] The PBPK model, adapted from a pig model, was fit to mouse data and scaled to predict rat, rabbit, dog, pig, and human data sets using an allometric scaling equation on the blood:plasma partition coefficient B : P .[8, 9, 10] Despite extensive investigation into dose adjustments for DOX, no covariates were consistently found to improve the efficacy and minimize toxicity except dosing schedule – infusion rate and duration.[11] The criterion for decreasing incidence of cardiotoxicity was maintaining a sub-toxic Cmax,heart,DOXol in the heart while maximizing exposure, represented by area under the concentration-time-curve (AUC). Thus, the original mouse data set was ideal since it included both DOX venous blood concentration and DOXol heart concentration.[12] The model was optimized at 10 time points between 1 minute and 72 hours with the goal of (AUC) maximization without exceeding Cmax,heart,DOXol. Using these predictions, therapeutic drug monitoring could be executed by taking the plasma concentration samples during a patient’s first DOX dose, PBPK model predictions could provide AUC and Cmax,heart,DOXol data, which could then inform the infusion parameters for the next dose. Clinical thresholds for Cmax,vb have been established for incidence of adverse effects, and in future work, perhaps a similar threshold for cardiotoxicity could also be established using tissue-specific measures
Leadership Aspirations of Preservice Teachers in Louisiana: Does Certification Pathway Matter?
Get PDFThe purpose of this study was to examine dispositions of teacher candidates, explore differences in leadership aspirations between traditional and alternative certification groups, and develop an unbiased predictive model for identifying future education leaders. Literature suggests that dispositions can be assessed, taught, and developed, but little is known about the link between the dispositions of teacher candidates and aspirations to seek leadership positions. Fourteen dispositions were identified through a Delphi method to correlate with educational leadership standards. They were then combined through factor analysis to develop four leadership constructs: collaborative, professional, inclusive, and modernistic. This study found that an existing disposition assessment can be used to predict future education leaders and identified a predictive equation for discerning potential leaders. At the time of program completion, alternative certification candidates who aspire to enter leadership positions self-reported their dispositions significantly higher than their traditional counterparts. However, there were no significant differences found between pathways for candidates who do not aspire to enter leadership positions.The relationship between leadership aspiration and the leadership dispositions of candidates is also of significance. Participants who do not aspire to leadership are likely to report higher scores in the inclusive construct, but the opposite was found for the modernistic construct
Noninvasive Traumatic Brain Injury Therapeutics Effects and Biosensor Implants Optimization in Rodents
Get PDFTraumatic brain injuries (TBI) result in impaired motor and sensory skills, which amplify over time due to the natural immune responses to trauma. Currently, there is no therapeutic on the market to treat the secondary damage from the cascading events caused by neurotrauma. In an experimental treatment method, poly(lactide-co-glycolide)-graft-polyethenimine (PgP) is used as a vector for drug delivery. This previously described method has successfully treated experimental spinal cord injury (SCI) using the nanoparticles for Rolipram (Rm) delivery, a phosphodiesterase inhibitor, to repair damage in a rat model. We proposed to utilize this same treatment to reduce secondary axonal damage after TBI. A direct injection, used for the experimental treatment of SCI, can cause additional damage to the neural tissue after diffuse TBI; thus, it is not an efficient method of administration of therapeutics for a diffuse injury. The noninvasive use of intranasal (IN) and intravenous (IV) administration would avoid additional injury. Yet, IN and IV administration of PgP complexed with Rm (PgP-Rm) has not been attempted. This work shows that IN and IV methods effectively deliver PgP to the brain. That administration of PgP-Rm via these noninvasive delivery methods reduced secondary damage, resulting in reduced astroglia activation in the caudate-putamen. Lastly, a surgical optimization was performed using a new Alcorix silicon-based shank probe for in vivo glutamate (GLU) recording. The use of implantable biosensors is of interest to allow the study of neurotransmitter activity in vivo, after TBI. Surgical optimization of the new probe led to the reinforcement of the junction between the shank and mounting board and incorporating a surgically mounted capsule to protect the probe’s reference wire. This optimized protocol resulted in a successful recording of GLU with sub-second resolution. This method can be utilized for future implant surgeries
The Role of Notch1 and Notch3 in Adult Stem Cell Osteogenic Differentiation
Get PDFHuman adipose-derived stem cells (hASCs) have significant therapeutic potential due to their ability to self-renew, differentiate down multiple lineages, and modulate the immune system. In addition to these many benefits, hASCs boast a minimally invasive harvesting procedure, making them a readily available cell source for stem cell research and tissue regeneration (Ock, et al. 2016) (Abdi, et al. 2008). Despite their broad use, very little is known about the mechanisms that control cell fate. One way to enhance our mechanistic understanding of differentiation is through the systematic examination of the signaling pathways. The Notch signaling pathway is a highly conserved, contact dependent, cell-to-cell signaling cascade known to regulate cell state and multipotent differentiation of hASCs. This pathway consists of four unique receptors and five unique ligands (Braune and Lendahl 2016). Two receptors believed to play a significant role in regulating osteogenic differentiation are Notch1 and Notch3. Here the expression of Notch1 and Notch3 are characterized during osteogenesis and the effect that siRNA-mediated knockdown of each receptor has on osteogenic differentiation is evaluated. By studying changes in osteogenic marker expression following a reduction in Notch expression and activity, we will be able to determine how each receptor individually affects the osteogenic potential of hASCs and identify potential novel therapeutic targets to treat bone damage and loss
Hello, I am Summer Adams
No full textSummer Adams is a senior biology student. The title of her project is Notch Signaling Plays a Key Role in Regulating Adult Stem Cell Osteogenic Differentiation
Hello, I am Hannah Koenig
No full textHannah Koenig is a junior in the Nutrition and Dietetics program. The title of her research project is: College Students’ Grocery Shopping Food Safety Practices During the Covid-19 Experience
Hello, I am Emily Meaney
No full textEmily Meaney is double majoring in biology and Spanish. The title of her project is: The Influence of MED12 Knockdown on Adipogenesis
08. Blood Pressure Response in Police Officers
Get PDFBackground: Law enforcement agencies have started transitioning from a traditional duty belt to load bearing vests to reduce hip and back pain. However, research has yet to examine the effect of blood pressure between the two apparatuses.
Purpose: To determine changes in systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) with a load bearing vest compared to a traditional duty belt.
Methods: Twenty-one law enforcement officers had blood pressure measured for three randomized sets of trials: seated and standing with a duty belt (13.6 kg), seated and standing with a vest (13.6 kg), and seated and standing without any apparatus.
Results: DBP was higher when seated with a vest than seated with a belt (+2.6 mmHg). After separating by Body Mass Index (BMI), the obese group (n=11) had higher SBP (control +14.9 mmHg, belt +11.4 mmHg, vest +8.7 mmHg) and MAP (control +12.4 mmHg, belt +8.3 mmHg, vest +5.9 mmHg) compared to the normal/overweight (n=10) participants when standing. Compared to no apparatus, normal/overweight officers’ SBP increased with the belt (+6.7 mmHg) when standing, and had a higher SBP and MAP with a vest (+10.6 mmHg and 8.4 mmHg). Obese officers showed no changes in blood pressure between the trials.
Conclusion: When including all participants, the duty belt and load bearing vest resulted in similar blood pressure responses. Although, a normal/overweight BMI lead to an increase in SBP and MAP while standing with a belt and vest, there was no difference in the apparatuses while standing in the obese group
08. Affect of Post-Fabrication Treatment on 3D-Printed Stainless Steels
Get PDFMost current metal production is dependent on the limitations of traditional manufacturing machinery. Traditional metal manufacturing generally limits designs, produces excessive waste, and requires lengthy processing times. Additive manufacturing allows a new era of designs to become reality by offering greater material integrity at reduced processing times and costs. In medicinal settings, 316L stainless steels (SS) are used due to the following: favorable corrosion properties, low cost, high durability, and reliability. Fabrication conditions and post-fabrication treatments of 3D-printed SS affect corrosion properties of the material. In this study, 316L SS samples were 3D printed using a 100 W laser power at 800 mm/s scan speed. One sample set was corrosion tested in simulated body fluid as received, whereas the other sample set was polished and chemically etched before testing. Polarization resistance, cyclic polarization, and impedance response comparisons were carried out to evaluate the corrosion behavior of the samples. Scanning electron microscopy and confocal imaging was collected to observe resulting surface conditions, such as pitting due to corrosion. The goal of this work was to evaluate the role of post-fabrication treatment on corrosion behavior in 3D printed 316L SS exposed to simulated body fluid and investigate: 1) pitting initiation and cessation, 2) the consistency and quality of the passive layer, and 3) repassivation kinetics. This study’s breadth will broaden the knowledge base of corrosion testing in simulated body fluid (SBF), which will grant greater understanding of corrosion behavior of 3D printed 316L stainless steel within biomedical applications