Publications

PODIUM/POSTER PRESENTATIONS: 2018

Poster

Cusick JK, Khansari P, Fitzpatrick L. Use of engaging review application exercises to enhance understanding of critical concepts prior to summative examinations. Presented at the Team Based Learning Collaborative (TBLC) annual meeting, San Diego CA, March 2018.

Abstract

BACKGROUND: Review application exercises were created in an Immunology class for third-year pharmacy students that utilized Team-Based Learning (TBL) as its pedagogy. The goal was to enhance student understanding of critical concepts prior to summative examinations.

DESCRIPTION: Three distinct exercises were utilized prior to summative examinations.  For applications #1 and #2, important topics were divided amongst the teams, to ensure that all topics relevant to an upcoming exam were covered by posters that would be displayed for students to view. Application #1 was conducted over several class periods while applications #2 and #3 were conducted in a single class period. Application Exercise #1: Teams created engaging and informative posters describing assigned subject matter utilizing superheroes or other caricatures. A gallery walk was conducted the day the final posters were due, in which teams of students reviewed key concepts on posters created by fellow students, and graded the posters according to rubrics that emphasized the posters should be engaging, accurate, informative, and most importantly, were effective as a teaching tool. Application Exercise #2: Teams created mnemonics, songs or haikus to highlight assigned material and displayed their creations on a poster. Approximately half of the teams performed their song creation to the rest of the class. Application Exercise #3:  A Jeopardy® review game utilizing team clickers and a team leaderboard created a fun and friendly competition in which student teams collectively discussed and answered practice exam questions.

CONCLUSION: The review application exercises were well received by students as indicated by the course evaluations, with many students indicating that the review exercises greatly helped them solidify their knowledge in a way that was fun and engaging. Additionally, the posters served as excellent recruiting tools during the interview process, as the student creations generated positive feedback from visiting applicant candidates not familiar with TBL.

Poster

Vinall R and Kreys E. Determination of whether implementation of mini-application exercises can enhance individual student performance in a TBL setting.  Presented at the Team Based Learning Collaborative (TBLC) annual meeting, San Diego CA, March 2018.

Abstract

Introduction: A common concern of TBL is a tendency of some students to depend on team members to answer application exercise questions resulting in inadequate preparation for higher Bloom’s taxonomy questions on exams. The objective of this study was to determine whether implementation of individual applications (iBATs) improves student performance.

Methods: Ninety-eight first year pharmacy students taking the Cell and Molecular Biology & Biochemistry course  participated in an unblinded, randomized, controlled, cross-over study. The course consisted of three blocks: block 1 served as a control, iBATs were administered for the two randomized groups in a cross-over manner for only blocks 2 and 3.  An independent t-test was used to compare average block exam scores between groups. A paired t-test was used to compare average group z-scores between block 1 exam results and results of the block coinciding with iBAT implementation. A subgroup analysis based on the Bloom’s taxonomy of exam questions was performed.  A questionnaire assessed students’ impression of iBAT impact after each block exam.  

Results: Exam scores for block 1, 2, or 3 were not significantly different between randomized groups (p-value = 0.35, 0.11, and 0.82, respectively). Subgroup analysis revealed similar results. Implementation of iBATs resulted in an increase of 0.091 z-scores, but was not statistically significant (p= 0.35). Limited to critical thinking questions, an increase of 0.102 z-scores was observed (p= 0.36). Majority of students reported that iBATs increased their ability to identify knowledge gaps (88%), determine their proficiency of critical thinking questions (91%), and increased studying following poor iBAT performance (83%), while few felt that iBATs increased stress (30%), or reduced enjoyment of the course (46%).

Conclusions: Implementation of iBATs did not significantly improve student performance on examinations or specifically on critical thinking exam questions. Generally students felt that iBATs had a positive impact their learning.

Poster

Westrick T and Malhotra A.  Integrating an Audiology-focused Interprofessional Teaching Activity Into a Pharmacy Curriculum. Presented at American  Academy of Audiology meeting, Nashville TN, April 2018.

Abstract

This classroom teaching poster outlines an interprofessional classroom activity involving audiology and pharmacy graduate students.   Audiology students presented on the relationship between loop diuretics and ototoxicity, and participating pharmacy students were surveyed regarding their perceptions of this activity.   This poster outlines components of the classroom activity, perceptions of students participating in the activity, and illustrates how this activity can help academic programs close curriculum gaps and fulfill requirements established by academic guidelines and accreditation bodies. Rationale/Purpose: Interprofessional collaboration between students in various healthcare fields has become increasingly prevalent in academic institutions in recent years.   In many instances, collaboration between students focuses on analyzing case studies involving multiple disciplines or exploring various roles played by members of the interdisciplinary healthcare team.   While these interprofessional activities provide students with an understanding of other allied healthcare professions, there are opportunities for audiology students to interact with students in professions in a teaching capacity.The purpose of this poster is to outline and evaluate the efficacy of an interprofessional classroom teaching activity facilitated by Au. D students in the School of Pharmacy at Pacific University.   For the past five years, Au. D. students presented a lecture and coordinated an interactive learning activity as part of a renal-focused course in the Pharm. D. program.   The lecture focuses on ototoxicity of loop diuretics, but aspects of cochlear physiology, causes of hearing loss, and an overview of audiology scope of practice are also incorporated.   Following the activity, pharmacy students were surveyed and asked to evaluate various components of this classroom activity and to provide feedback regarding the efficacy of this activity in providing a better understanding of the auditory system and ototoxicity of diuretics.   A pre and post-activity quiz were also administered to measure learning outcomes. This poster outlines components of the classroom activity, perceptions of students participating in the activity, and illustrates how this activity can help academic programs fulfill curriculum requirements established by oversight guidelines and accreditation bodies. Methods: This poster focuses on the structure of an interprofessional teaching activity and perceptions of participating students. A group of Au. D. students prepared a lecture and an interactive activity focused on loop diuretics and ototoxicity. Components of the lecture and design of the interactive activity component will be outlined. Following the completion of the activity, a voluntary survey was made available to pharmacy students who participated in the activity. The survey was designed to capture details regarding student perceptions and learning outcomes achieved by students participating in this activity. Results and Conclusions: At present time, survey data is still being collected and analyzed. Once data analysis is complete, feedback provided by students will be used not only to serve as a potential measure of the efficacy of this unique interprofessional activity, but will also be used to further develop this and other interprofessional activities facilitated by students at Pacific University and beyond. Data could serve as a means to measure peer-to-peer teaching efficacy, which could in turn be incorporated into not only other areas of audiology curricula, but also interprofessional educational activities outside of audiology. Audiology graduate students teaching pharmacy graduate students about the ototoxicity of loop diuretics is a novel approach in interprofessional education. Not only do the audiology students involved gain experience designing and giving a professional presentation to non-audiology students, but pharmacy students gain a better understanding of the profession of audiology. In turn, both groups of students achieve curriculum requirements set forth by accreditation bodies.

Poster

Batra N, Krig S, Sam A, Macias K, Vinall RL et al.  Differential expression and localization of the E3 ubiquitin ligase Nrdp1 in African American versus Caucasian American prostate cancer cells.  Presented at  the American Association for Cancer Research (AACR) Annual Meeting, Chicago IL, April 2018.

Abstract

Despite a recent decrease in overall incidence of prostate cancer (CaP), CaP incidence continues to be much higher among men of African origin living in the United States (223.9 men per 100,000) compared to those of European origin (139.9 men per 100,000). Also, the CaP age-specific mortality rates are 2.4 times greater among African-American (AA) compared with European American (EA) men. The causes for these differences are multifactorial, but include genetic effects that contribute to CaP-associated health disparity. We previously showed that the androgen receptor (AR) can suppress levels of the receptor tyrosine kinase ErbB3, a molecule that is known to drive CaP progression, by stimulating the E3 ubiquitin ligase Nrdp1 (also called RNF41 or FLRF). The goals of the current study were to determine whether differential expression and/or localization of Nrdp1

contribute to CaP-associated health disparities, and to further elucidate the mechanisms by which regulation of Nrdp1 levels and localization occurs. Immunohistochemistry (IHC) in prostate tissue determined that nuclear Nrdp1 levels are significantly lower in AA CaP patients (n=19) versus CA CaP patients (n=121) with localized disease (p=0.008). A similar association was observed in CaP cell lines; immunofluorescence (IF) analyses demonstrated MDAPCa2b and E006 (cell lines derived from AA CaP patients) express significantly lower levels of nuclear Nrdp1 compared to LNCaP, CWR22Rv1, C4-2, and C4-2B (cell lines derived from CA CaP patients). Western blot and qPCR determined that Nrdp1 levels are lower in AA versus CA CaP cells (MDAPCa2b express ~2-fold less Nrdp1 protein and mRNA levels compared to LNCaP), and that androgen withdrawal has a bigger impact on Nrdp1 expression levels in AA CaP cells (2-fold decrease in MDAPCa2b compared to ~1.2-fold decrease in LNCaP). Proteasomal regulation of Nrdp1 also occurs; treatment with MG132 resulted in accumulation of Nrdp1 in both AA and CA CaP cell lines. Interestingly, altering androgen and/or AR levels also affected Nrdp1 localization (IF analyses) as well as the ability of Nrdp1 to mediate CaP cell apoptosis (flow cytometry). In summary, we demonstrate that Nrdp1 is differentially expressed in AA versus CA CaP patients as well as in AA versus CA CaP-patient derived cell lines, and that androgen withdrawal has a bigger impact on Nrdp1 expression in AA CaP cell lines. We also demonstrate that androgen/AR is involved in determining Nrdp1 localization, and that Nrdp1 can mediate CaP cell apoptosis in the presence of AR. The combined data, and the knowledge that Nrdp1 regulates ErbB3 levels, suggest that differential expression of Nrdp1 in AA versus CA CaP may contribute to CaP-associated health disparities and may occur as a result of dysregulation of the regulation of Nrdp1 by androgen/AR.

 

Podium and Poster

True H, Trinh J, Love Q, Badejo A, Rao D, Malhotra A. Raloxifene Compromises Mitochondria, Induces ROS Stress and the Unfolded Protein Response, and Synergizes Gemcitabine's Cytotoxicity in Pancreatic Cancer Cells. Accepted for Presentation at Annual ASPET Meeting, San Diego CA, April 2018.

Abstract: Pancreatic adenocarcinoma (PCa) is a deadly disease associated with high mortality and a very poor 5-year survival rate of only 6-8%. There is a lack of knowledge about how mutations in the human homolog of the Kirsten Rat Sarcoma viral oncogene (KRAS), which occur in 90% of the patient population, lead to its development. This knowledge gap, coupled with substantial chemoresistance, has led to a scarcity in effective therapy to combat PCa. To reduce the bench-to-bedside time for the development of drugs for use in PCa, we repurposed FDA-approved drugs, screening for their cytotoxic potential in KRAS-mutant human PCa cell cultures. Our data show that the FDA-approved raloxifene, a selective estrogen receptor modulator used in the treatment of osteoporosis caused apoptosis of multiple PCa cell lines (MIA PaCa-2, PANC-1, BxPC-3). IC50 for raloxifene was 1.81 + 0.38 μM (MIA PaCa-2), 58.16 + 5.37 μM (PANC-1), and 4.20 + 2.16 μM (BxPC-3). This compared well with the IC50 for gemcitabine, the gold-standard drug used for treating PCa since 1997, values for which were 4.75 + 1.67 μM (MIA PaCa-2), 58.60 + 14.78 μM (PANC-1), and 6.10 + 1.70 μM (BxPC-3) because in each PCa cell line, raloxifene had a lower IC50 than gemcitabine. Further, combination index (CI) analysis using a 1:1 raloxifene-gemcitabine combination showed evidence for synergism with CI values <1 for a broad range of dose concentrations within the three cell lines, and specifically at 50% of cells affected. To investigate the mechanism of cytotoxicity, we examined mitochondrial function and found that in MIA PaCa-2 cells, raloxifene treatment induces reactive oxidative species (ROS) production and decreases mitochondrial membrane potential. Pre-treatment of MIA PaCa-2 cells with the NADPH oxidase inhibitor diphenylene iodonium (DPI) reduced ROS production for each raloxifene concentration used, suggesting that the mitochondria were the source of the ROS. To further investigate the mechanism, we examined the effect of raloxifene treatment on the enzymes involved in the ROS pathway. Our data show that while raloxifene induced the expression of glutathione synthetase, glutathione s-transferase, it had no effect on superoxide dismutase 1 or 2 or glutathione peroxiredoxin. However, catalase expression was decreased in MIA PaCa-2 cells, suggesting that raloxifene induced oxidative stress in these cells, making them susceptible and responsive to further apoptotic stimuli like treatment with gemcitabine. Finally, our data also show that raloxifene induces the unfolded protein response and endoplasmic reticulum stress in PCa cells as evident by an increase in endoplasmic reticulum oxidoreductase 1 (ERO1- α) and cleavage of Activating transcription factor 6 (ATF6), confirming that it helps overcome the chemoresistance of PCa cells.

Poster

Mohamed I, Thomas S, Searles C. miR-155: a negative modulator of Acute Oscillatory Shear Stress (OSS)-induced Vascular Inflammation and Dysfunction. Accepted for presentation at ATVB/PVD Scientific Meeting, San Francisco CA, May 2018. 

Abstract

Introduction: Shear-sensitive micro-RNAs play an integral role in dictating vascular wall pro-inflammatory response and development of atherosclerosis. Previously, our group and others have identified an inverse relationship between micro-RNA-155 (miR-155) expression and inflammation in atheroprone areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and in-vitro.

Hypothesis: we hypothesized that miR-155 negatively regulates acute OSS-induced vascular inflammation and dysfunction, via modulation of the MAPK-ETS-1 pathway.

Methods: 12-week old C57B/6J wild type (WT) and miR-155 knockout mice (KO) were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of OSS, for 3-7 days. Downstream acute OSS segments were compared to upstream unidirectional shear stress (USS) segments of thoracic aorta using RT-PCR, western blot and two-way ANOVA followed by Tukey’s multiple comparison analyses.

Results: In WT mice, acute OSS induced vascular inflammation evidenced by upregulation of MCP-1 and VCAM-1 expression in OSS segments compared with USS. This was associated with loss of vascular barrier function as evaluated by extravasation of Evans-blue dye assay along with increased MMP-9 and MMP-3 expression. However, vascular miR-155 levels were also higher in OSS segments compared with USS (n=6-12, P<0.05). Nevertheless, miR-155 KO mice showed enhanced expression and activation of ERK and p-38 MAPKs and downstream ETS-1, VCAM-1 and MMP-9 expression in OSS segments compared with USS versus WT controls (n=3-4, P<0.05). Tail vein injections of miR-155 overexpressing lentivirus particles in WT mice after AAC resulted in further upregulation of miR-155 and abolished OSS-induced upregulation of p-38 and downstream ETS-1, VCAM-1 and MMP-9 expression in OSS segments compared with USS versus scramble controls (n=5-6, P<0.05).

Conclusions: Despite the early upregulation of shear-sensitive miR-155, our data suggest that miR-155 serves as a negative feedback regulator to acute OSS-induced vascular inflammation via inhibition of p-38 and ETS-1. Further studies are in progress to evaluate the effect of exogenous miR-155 on OSS-induced oxidative stress and vascular function, which can serve as basis for developing novel miRNA-based therapeutic modalities.

Poster

Fitzpatrick LR, Talbott G et al. al. Ex vivo effects of ROR-gamma T inhibitors on pro-inflammatory cytokine secretion from colonic strips of mice with DSS-induced colitis.  Accepted for presentation at Digestive Disease Week Annual Meeting, Washington DC, June 2018.

Abstract:  ROR gamma t (RORγt) inhibitors (e.g., GSK 805, VPR 254) have shown efficacy in murine models of colitis. To determine an optimal compound(s) for further in vivo testing, we utilized an ex vivo colonic strip model from mice with DSS-induced colitis. This colitis has been proposed by some investigators to involve IL-17, IL-21 and CCL20, which are under transcriptional control by RORγt. Therefore, we hypothesized that secretion of these cytokines by colonic strips would be attenuated by RORγt inhibitors. Methods: Five RORγt inhibitors were obtained from Visionary Pharmaceuticals (San Diego, CA). Dextran Sulfate Sodium (DSS) was given to male C57BL/6 mice (n = 16) in the drinking water (2% concentration), for a six-day period, to induce colitis. Control mice (n = 8) received water. The ex vivo effects of the RORγt inhibitors (0.05 to 5 μM concentration range) were tested in our 24 hour colonic culture system [Fitzpatrick et al., Inflammopharmacology, 2014]. We utilized ≈ 4 mm colonic strips (n = 4 to 10 per RORγt inhibitor group) from mice with DSS-induced colitis. Some colonic strips were stimulated with IL-1β (10 ng/ml) plus IL-23 (10 ng/ml) to induce enhanced cytokine secretion. The secretion of IL-17, IL-21 and CCL20 were determined in the cell culture media by ELISA. Results: Mice that were administered DSS showed clear evidence of colitis (enhanced disease activity indices and reduced colon lengths). Ex vivo treatment with VPR 254, VPR 425 and GSK 805 were most effective for inhibiting basal IL-17 secretion from colonic strips of mice with colitis. VPR 425 and GSK 805 most effectively attenuated basal (non-stimulated) secretion of IL-21 and CCL20. For dual cytokine stimulated IL-17 secretion, some IL-17 values (pg/ml) were: 112±35 (Vehicle), 87 ± 21 (VPR 254, 5μM), 64 ± 9 (VPR 425, 5 μM) and 45 ± 9 (GSK 805, 5 μM). The calculated IC50 value of VPR 425 for inhibiting stimulated IL-17 secretion was 0.13 μM, while for GSK 805 it is < 0.05 μM. Three compounds (VPR 254, VPR 425 and GSK 805) significantly attenuated (at certain concentrations) dual cytokine stimulated IL-21 secretion from colonic strips of mice with DSS-induced colitis. Overall, the most effective compounds were VPR 425 and GSK 805. Four compounds (VPR 426, VPR 254, VPR 425 and GSK 805) attenuated (to some degree) stimulated CCL20 chemokine secretion from colonic strips of mice with DSS-induced colitis. Chemokine secretion was reduced to the basal level by ex vivo treatment with VPR 425 (0.5 and 5 μM concentrations). Summary: Ex vivo treatment with structurally diverse RORγt inhibitors inhibited basal and stimulated pro-inflammatory cytokine secretion from colonic strips of mice with DSS-induced colitis. Conclusion: These data further contribute to the identification of optimal RORγt inhibitors, which can be used for follow-up in vivo testing in murine models of colitis.

Podium

Basson MC, Wang Q, Chaturvedi LS, Vomhof-DeKrey E. Schlafen 12 Promotes Human Intestinal Epithelial Differentiation via Serpin B12 Modulation of the Deubiquitylation of Transcription Factors Such as CDX2. Accepted for presentation at Digestive Disease Week Annual Meeting, Washington DC, June 2018.

Human enterocytic differentiation is altered during development, fasting, adaptation, and bariatric surgery, but its intracellular control remains unclear. We have previously reported that Schlafen 12 (SLFN12), which decreases in human mucosa after prolonged fasting, regulates Caco-2 sucrase-isomaltase expression in a manner dependent on its binding to Serpin B12 (SERPB12). SLFN12 is chiefly a cytosolic protein, and the rodent Slfn3 still acts even when bound to a nuclear exclusion sequence. We now sought to determine how this cytosolic protein that has no homology to any known signaling protein can influence gene transcription in the nucleus. Both SLFN12 and SERPB12 overexpression increased sucrase-isomaltase promoter activity, mRNA, and protein, while reducing SERPB12 expression prevented the SLFN12 effect. Sucrase-isomaltase induction by both SLFN12 and SERPB12 was attenuated by reducing either of the deubuitylases UCHL5 or USP14, and completely blocked by reducing both. SERPB12 coprecipitated USP14 but not UCHL5 and purified SERPB12 protein stimulated the activity of purified USP14 but not of UCHL5. SLFN12 and SERPB12 increased protein levels of the sucrase-isomaltase-promoter-binding transcription factor Cdx2 without altering Cdx2 mRNA. This was prevented by reducing UCHL5 and USP14. Moreover, reducing Cdx2 with siRNA prevented the induction of sucrase-isomaltase promoter activity by SLFN12. We next validated this SLFN-SERPB12-USP14-Cdx2-sucrase pathway beyond Caco-2 cells. Both SLFN12 and SERPB12 overexpression also stimulated sucrase-isomaltase expression in nonmalignant HIEC6 cells, and siRNA reduction of SERPB12 reduced mucosal ileal sucrase-isomaltase expression in mice, along with expression of two other enterocytic differentiation markers, villin-1 and Glut1. These results suggest that SLFN12 regulates human enterocytic differentiation by a pathway involving SERPB12 and the deubiquitylases, modulating deubiquitylation and cytosolic proteasomal degradation of transcription factors like Cdx2 to regulate gene transcription. This pathway may be targeted to manipulate human enterocytic differentiation in mucosal atrophy, short gut, or obesity. 

Poster

Title: Student Perceptions of the PCOA- A Multi-institutional Sample. Accepted for presentation at the Annual AACP Meeting, Boston MA, July 2018.

Authors:   Daugherty KK, Welch A, Gortney J, Castleberry A, Le U et al.

Background:  Questions regarding use of the PCOA to identify at risk students and serve as a high stakes exam have been debated in the literature, but no data exists regarding students’ perceptions of the exam.  The purpose of our study was to assess students’ perceptions of the PCOA exam.

Method:  A 21-question, electronic survey was developed and beta-tested by faculty representing geographically diverse S/COPs. APPE students from 5 S/COPs completed this survey regarding their PCOA exam study habits, feedback, and results use.

Results: 131 students complete the study with the majority being female. A majority of students indicated that they did not study for the PCOA (65%) or use results of PCOA to prepare for APPE (93%) or NAPLEX (81%) nor did they review results with an advisor (78%).  Most students were neutral or disagreed with the statement that doing well on this test was important to them (65%) but most agreed they gave good effort on the test (61%). Students agreed that the following incentives would influence their motivation on the PCOA: if it affected progression (70%), APPE placement (65%), or required remediation (69%). 

Conclusion:  This study revealed that a majority of students do not study for the PCOA exam and do not discuss their results with faculty advisors in order to improve their area(s) of weakness for APPEs. It is unclear if student perceptions are the result of a lack of understanding of the PCOA’s goals, student time, exam result interpretation and mentoring, or tangible incentives for strong performance. 

Podium

Chaturvedi LS, Vyas, D. Second generation proteasome inhibitor Carfilzomib (CFZ) Inhibits proliferation and induces apoptosis in human triple-negative breast MDA-MB-231 cancer cells.  Accepted for Presentation at ACS-2018 Meeting, Boston MA, August 2018.

Carfilzomib (CFZ) is a selective irreversible second generation proteasome inhibitor is used for the treatment of relapsed and refractory multiple myeloma as anticancer therapy. However, it role and molecular mechanism has not been elucidated in human triple negative breast cancer. Herein, we investigated its antiproliferative and apoptotic effects alone or in combination with Doxorubicin (DOX) on human triple negative (TNBC) MDA-MB-231 breast cancer cells. In these cells, CFZ inhibited proliferation, induced cell cycle alterations and increased apoptosis in a dose and time dependent manner. Its action was compared to Doxorubicin (DOX), a first line chemotherapeutic agent used for TNBC and other cancers. DOX also inhibited proliferation, induced cell cycle alterations and increased apoptosis but was less potent than CFZ. A combination of both CFZ and DOX did not further reduce growth but significantly enhanced apoptosis in comparison to CFZ or DOX alone. The immunoblot analysis of cell cycle protein expression revealed that CFZ increased cyclin-B1 but reduced cyclin-D1 significantly without affecting cyclin-A and cyclin-E1 expression levels. On the other hand, DOX robustly increased cyclin-E1, modestly cyclin-A without affecting cyclin-B1 and cyclin-D1 expression levels. A combination of both CFZ and DOX significantly enhanced expression of cyclin B1 and cyclin-E1 while reducing expression of cyclin-D1. Low doses of either CFZ or DOX alone enhanced the phosphorylation of the DNA double strand break marker gamma-H2AX while higher dose of either drug proved to be less effective on the phosphorylation of gamma-H2AX. Thus our data suggests that irreversible proteasome inhibitor CFZ induces apoptosis, modulates cell cycle proteins, and induces phosphorylation of gamma-H2AX in human triple-negative breast MDA-MB-231 cancer cells. These findings suggest a potential use of CFZ against tumors harboring drug-resistant phenotypes.

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