Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic.

Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.

Valued characteristics of community pharmacy residency applicants.

OBJECTIVES: To determine the attributes of postgraduate year 1 (PGY1) community pharmacy residency applicants and candidates that are most appealing to community residency program directors (CRPDs). DESIGN: A 22-question online survey, designed to collect residency demographics, desirable characteristics for consideration for interview invitation (applicants), and characteristics that should be displayed during an interview (candidates). SETTING: American Society of Health-System Pharmacists (ASHP)-recognized community pharmacy residency programs (CPRPs). PARTICIPANTS: The CRPDs of 109 ASHP-recognized CPRPs throughout the United States. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Minimum applicant requirements; rank order of valued characteristics at application and interview stage of hiring process. RESULTS: The response rate was 71/109 (65.1%). Applicant work experience in chain pharmacy (90.1%) and independent pharmacy (77.5%) was most highly valued by CRPDs, with 85.9% preferring applicants with a minimum of 1 year or more of community pharmacy experience. A large majority of CPRPs (91.4%) indicated a preference for applicants who have been an officer of a student organization. Among CPRPs that required minimum grade point averages (GPAs), a mean GPA of 2.88 ± 0.34 was reported (range 2.0 to 3.5; mode 3.0). Pharmacy work experience (68.1%) and letters of recommendation (59.4%) were most frequently cited as top factors in the decision-making process for selecting candidates to interview. At the interview stage, CRPDs rated interest and knowledge about the residency (62.3%), time management and prioritization (50.7%), and self-awareness and commitment to improvement (43.5%) as the most important skills for candidates to demonstrate. CONCLUSION: Community pharmacy work experience, organizational leadership experience, and positive letters of recommendation appear to be the most valued attributes of a community pharmacy residency applicant. Applicants should consider aligning themselves with these characteristics to successfully match to a community pharmacy residency.

Protein disulfide isomerase capture during thrombus formation in vivo depends on the presence of ß3 integrins.

Extracellular protein disulfide isomerase (PDI) is required for platelet thrombus formation and fibrin generation after arteriolar wall injury in live mice. PDI is secreted from platelets and endothelial cells on cellular activation, but the mechanism of capture of secreted PDI within the injured vasculature is unknown. We establish that, like the endothelial ß3 integrin α(V)ß(3), the platelet integrin α(IIb)ß(3) binds PDI. PDI also binds to recombinant ß3. Using intravital microscopy, we demonstrate that PDI accumulation at the site of laser-induced arteriolar wall injury is markedly reduced in ß3-null (ß3(-/-)) mice, and neither a platelet thrombus nor fibrin is generated at the vessel injury site. The absence of fibrin after vascular injury in ß3(-/-) mice is because of the absence of extracellular PDI. To evaluate the relative importance of endothelial α(V)ß(3) versus platelet α(IIb)ß(3) or α(V)ß(3), we performed reciprocal bone marrow transplants on wild-type and ß3(-/-) mice. PDI accumulation and platelet thrombus formation were markedly decreased after vessel injury in wild-type mice transplanted with ß3(-/-) bone marrow or in ß3(-/-) mice transplanted with wild-type bone marrow. These results indicate that both endothelial and platelet ß3 integrins contribute to extracellular PDI binding at the vascular injury site.

Remimazolam: A Novel Option for Procedural Sedation in High Risk Patients.

PURPOSE: The purpose of this drug review was to explore the safety and efficacy of the newly approved benzodiazepine, remimazolam, in order to evaluate its place in therapy. SUMMARY: Remimazolam has a faster onset of action and recovery time than midazolam when given as single IV doses. Additionally, it has no known CYP450 interactions that would contribute to drug-drug interactions. Patients with severe hepatic impairment may require dose titration as well as the elderly who should be closely monitored. Although remimazolam vials should be protected from light and must be reconstituted immediately before use, the reconstituted vial may be stored for later use at room temperature for up to 8 hours. Remimazolam is more expensive than current options used in practice, as such individual institutional formulary and provider preference will require review to see if its advantages are worth the additional cost and to determine its place in therapy. CONCLUSION: Remimazolam is a novel option when choosing a benzodiazepine for procedural sedation that has pharmacokinetic and pharmacodynamic advantages when compared to other commonly prescribed sedatives. Remimazolam has proved superior to midazolam when analyzing drug-drug interactions, onset, and time to alertness. Remimazolam also has a shorter elimination half-life and decreased volume of distribution when compared to midazolam.

The AACP Academic Affairs Committee's Final 2022 Curricular Outcomes and Entrustable Professional Activities (COEPA) for Pharmacy Graduates to Replace 2013 CAPE and 2016 EPAs.

The American Association of Colleges of Pharmacy (AACP) Academic Affairs Committee was charged with revising both the 2013 Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes (EOs) and the 2016 Entrustable Professional Activities (EPAs). The Committee changed the document name from the CAPE outcomes to COEPA, (Curricular Outcomes and Entrustable Professional Activities) since the EOs and EPAs would now be housed together. A draft of the COEPA EOs and EPAs was released at the AACP July 2022 Annual meeting. After receiving additional stakeholder feedback during and after the meeting, the Committee made additional revisions. The final COEPA document was submitted to and approved by the AACP Board of Directors in November 2022. This COEPA document contains the final version of the 2022 EOs and EPAs. The revised EOs have been reduced to 3 domains and 12 subdomains (from 4 domains and 15 subdomains previously in CAPE 2013) and the revised EPAs have been reduced from 15 to 13 activities.

The AACP Academic Affairs Committee's Guidance for Use of the Curricular Outcomes and Entrustable Professional Activities (COEPA) for Pharmacy Graduates.

The 2021-2023 American Association of Colleges of Pharmacy Academic Affairs Committee (AAC) was charged with and completed the revision of the 2013 Center for the Advancement of Pharmacy Education Outcomes and the 2016 Entrustable Professional Activity (EPA) statements for new pharmacy graduates. This work resulted in a new combined document, the Curricular Outcomes and Entrustable Professional Activities (COEPA) that was unanimously approved by the American Association of Colleges of Pharmacy Board of Directors and was published in the Journal. The AAC was also charged with providing stakeholders with guidance about how to use the new COEPA document. To achieve this charge, the AAC created example objectives for all 12 Educational Outcomes (EOs) and example tasks for all 13 EPAs. Although programs are asked to retain the EO domains, subdomains, one-word descriptors, and descriptions, unless they are adding more EOs or increasing the taxonomy level of a description, colleges and schools of pharmacy can expand or edit the example objectives and example tasks to meet local needs, as these are not designed to be prescriptive. This guidance document is published separately from the COEPA EOs and EPAs to reinforce the message that the example objectives and tasks are modifiable.

Revising the Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes and Entrustable Professional Activities (EPAs): The Report of the 2021-2022 Academic Affairs Standing Committee.

EXECUTIVE SUMMARY. The 2021-22 Academic Affairs Committee was charged to 1) Update the Center for the Advancement of Pharmacy Education (CAPE) Outcomes and Entrustable Professional Activity (EPA) statements for new pharmacy graduates; 2) Nominate at least one person for an elected AACP or Council Office; and 3) Consider ways that AACP can improve its financial health. This report primarily focuses on the process undertaken by the committee to revise the CAPE Educational Outcomes and EPAs. Proposed changes to the current outcomes are discussed and the reasoning behind these revisions are described. AACP members will have the opportunity to provide feedback prior to the final document being approved and published later this year.

Finalizing the Work Related to the Curriculum Outcomes and Example Objectives and Entrustable Professional Activities (COEPA) Document: The Report of the 2022-2023 Academic Affairs Standing Committee.

The 2022-2023 Academic Affairs Committee (AAC) was charged to (1) complete the Center for the Advancement of Pharmacy Education Outcomes and Entrustable Professional Activities (EPAs) revisions (now renamed as COEPA - Curriculum Outcomes and Entrustable Professional Activities) after receiving feedback at the 2022 American Association of Colleges of Pharmacy (AACP) Annual Meeting; (2) offer guidance on how the revised COEPA education outcomes and EPA statements should be used by member institutions, faculty, preceptor, and students; (3) guide input into the ongoing revision of the Accreditation Council for Pharmacy Education (ACPE) standards for the Doctor of Pharmacy program. The published report of the 2021-2022 AAC outlines the work of the Committee through the spring of 2022.1 This 2022-2023 AAC report focuses on the work related to finalizing the COEPA educational outcomes, EPAs, preamble, and glossary and formally receiving approval from the AACP Board of Directors.2 This report also describes the creation of a COEPA guidance document, including educational outcomes example learning objectives, and EPA example tasks for the Academy, however, the actual guidance document will be published separately. Finally, this current report outlines the feedback the AAC sought, received, synthesized, summarized, and prioritized from key interested and affected parties about the ACPE 2016 standards revisions for the ACPE 2025 draft standards.3 The Committee offers revisions for 1 AACP policy statement pertaining to diversity, equity, inclusion, accessibility, justice, and anti-racism. One new policy statement is also offered that urges ACPE to create accreditation standards for pharmacy education that support diversity, equity, inclusion, accessibility, justice, and anti-racism, despite presence of laws, executive orders, and policies that oppose these concepts.

Remote Work in Pharmacy Academia and Implications for the New Normal.

Objective. To determine the extent to which pharmacy faculty engaged in remote work during the first two years of the COVID-19 pandemic and, secondarily, to characterize pharmacy faculty and administrator perceptions of remote work.Methods. A 28-question online survey was sent to 6548 members of the American Association of Colleges of Pharmacy (AACP). Questions centered on the extent of remote work and perceptions of its impact on productivity, effectiveness, and work-life balance. Focus groups were held to provide additional insight, and data were analyzed statistically.Results. In total, 6322 AACP members met inclusion criteria, of whom 1293 responded to the survey (21% response rate). At least one faculty member responded from 139 schools (99% response rate), and at least one administrator responded from 126 schools (89% response rate). During the pandemic, 97% of faculty were permitted to work remotely, 94% of whom did so at least some of the time. Most faculty indicated no change or an improvement in productivity (85%) and effectiveness (80%). Similarly, most administrators indicated no change or an increase in their unit's productivity (81%) and effectiveness (85%). More than half of respondents indicated better work-life balance while working remotely.Conclusion. Nearly all respondents were permitted to work remotely at least some of the time during the pandemic. Considering that most faculty and administrators believe productivity and effectiveness were not compromised and that there appear to be benefits to work-life balance, schools of pharmacy in the United States should consider permitting faculty to work remotely some of the time as we navigate the pandemic and thereafter.

The Illusion of Urgency.

Faculty frequently have many tasks that need to be completed on a daily basis. Prioritizing these tasks effectively can be challenging, especially considering the relative urgency and importance of each. Decision matrices such as the Eisenhower Matrix and the Time Management Matrix can assist individuals in categorizing tasks in order to value what is truly career building versus a distraction. It is imperative for faculty to develop strategies to address common distractors, such as email, meetings, and requests from others. Identifying tasks that are truly urgent over those that only appear to be urgent may help faculty increase their productivity and efficiency.

Enhancing Pharmacy Faculty Well-Being and Productivity While Reducing Burnout.

Objective To explore methods that pharmacy programs can use to redefine their work environment to reduce stress, improve well-being, and increase faculty productivity.Findings To demonstrate a culture of support, organizations should consider a five-fold approach to enhancing and maintaining faculty well-being, including optimizing faculty and staff support, establishing a faculty development and mentoring program, permitting flexibility in work schedules, improving productivity of meetings, and managing communication tools. Individuals can also take measures to improve their well-being, including controlling email, giving attention to faculty citizenship, implementing stress reduction and coping techniques, and maintaining boundaries between work and home.Summary This article discusses approaches that have been shown to reduce burnout and provides strategies organizations and individuals can implement to improve productivity and faculty well-being. While certain areas, such as faculty wellness and productivity, have been well-studied in the pharmacy and health professions literature, significant gaps were identified in other areas, including alternate work arrangements. In some cases, data from the business sector can be extrapolated to pharmacy education; however, inferences from effective corporate strategies may not be transferable to the culture and expectations of academia. While there is significant overlap between institutional and individual strategies, a culture of communication, collaboration, support, and citizenship is foundational. There is no single strategy that will work for everyone, and flexibility is important to develop an individualized approach.

Zafirlukast is a broad-spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times.

BACKGROUND AND PURPOSE: Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet responses, aggregation, adhesion and thrombus formation. Recently, the therapeutic potential of TI inhibition has been recognised and drug-development technologies were used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin, is known to be nephrotoxic, which prohibits its systemic therapeutic usage. EXPERIMENTAL APPROACH: We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. A total of 3,641 compounds were screened for inhibitory effects on the redox activity of ERp5, protein disulphide isomerase (PDI), ERp57, ERp72 and thioredoxin in an insulin turbidity assay. Of the lead compounds identified, zafirlukast was selected for further investigation. KEY RESULTS: When applied to platelets, zafirlukast diminished platelet responses in vitro. Zafirlukast was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since TIs are known to modulate adhesion receptor function, we explored the effects of zafirlukast on cell migration. This was inhibited independently of cysteinyl LT receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface. CONCLUSION AND IMPLICATIONS: We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide-ranging effects on platelet function, thrombosis and integrin-mediated cell migration. Zafirlukast is antithrombotic but does not cause bleeding.

Strategies, Ideas, and Lessons Learned While Engaging in SoTL Without Formal Training.

Most pharmacy faculty members are more confident in their foundation as research scientists or clinical pharmacists than with the scholarship of teaching and learning (SoTL). However, many wish to enter this rewarding field of scholarship in order to test pedagogical innovations, measure teaching effectiveness, and share success with the Academy. This commentary provides general advice for those who wish to explore SoTL but lack formal education and training in this area. Four opportunities are highlighted: educational research, small activities and projects, course redesign, and longitudinal assessment and evaluation.

Pharmacy Education Crosses the Rubicon.

The pandemic caused by the novel coronavirus identified in 2019 (COVID-19) has resulted in seismic changes throughout society. Accordingly, academia has been forced to adapt. Changes across all aspects of teaching and instruction have occurred. Students have departed campuses and prospects of their return remain unclear. The Academy, which is generally reluctant to change, has been forced to make rapid adjustments. Among other issues, pharmacy schools and colleges have been forced to mitigate changes to experiential education. Tremendous resources and energy have been invested to actuate the changes that have occurred. In many ways, the disruptions forced upon pharmacy education may usher in a new normal. The likelihood for even a partial return to the customary way of doing things appears increasingly unlikely.

Leadership Lessons and Career Advice From the Musical Hamilton.

The musical Hamilton, written by Lin-Manuel Miranda, creatively depicts the life and career of founding father Alexander Hamilton. While Hamilton is the primary focus, highlights of the career and personal journeys of other leaders, such as George Washington, Thomas Jefferson, and Aaron Burr, are interjected throughout the production. Often the musical numbers in Hamilton focus on aspects of leadership and career development that Hamilton and his contemporaries were learning or needed to learn. These lessons are applicable to the challenges that faculty members in academic pharmacy face today at different stages of a career. These include the importance of maximizing opportunities, listening, self-reflection, compromise, patience, empathy, prioritizing, tending relationships, making difficult decisions, knowing when to say goodbye, and managing a legacy.

Placement and Integration of Pathophysiology, Anatomy, and Physiology Within the Doctor of Pharmacy Curriculum.

Objective. To examine the placement of pathophysiology, anatomy, and physiology within the curricula of US pharmacy schools and colleges for variations in program length, prerequisites, institution type, geographic region, and establishment date.Methods. The websites of 146 pharmacy programs were examined for information related to pathophysiology, anatomy, and physiology courses and instruction. Eight programs listed uninterpretable or incomplete website data and were excluded, producing a final sample size of 138 programs. Data were analyzed to determine differences in curricular placement, credit hours, and integration.Results. The majority (65.3%) of pathophysiology courses were incorporated into the curriculum by integration, while some (14.5%) had both stand-alone and integrated pathophysiology courses. The remaining programs (20.2%) had stand-alone pathophysiology courses only. Of those with stand-alone pathophysiology courses, the mean number of credit hours was 5. Most programs (76.1%) required anatomy and/or physiology as a prerequisite or as part of the professional program, with significantly more public programs than private programs requiring it as a prerequisite (77.9% vs 48.6%).Conclusion. Pathophysiology is taught in diverse formats throughout US pharmacy schools, with the only consensus among programs being that it belongs in the professional curriculum. While the majority of programs teach pathophysiology as an integrated course, stand-alone courses are also common. There is also great diversity in the type of instruction used in anatomy and physiology courses. While every program requires students to complete anatomy and physiology courses, these are commonly taught as part of the professional curriculum or are prerequisites. Overall, there are few significant differences in the instruction of these subjects among US pharmacy schools.

Protein Disulfide Isomerases Regulate IgE-Mediated Mast Cell Responses and Their Inhibition Confers Protective Effects During Food Allergy.

The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.

Current Status and Best Practices of Shared Governance in US Pharmacy Programs.

Objective. To characterize shared governance in US schools and colleges of pharmacy and recommend best practices to promote faculty engagement and satisfaction. Findings. The literature review revealed only one study on governance in a pharmacy school and some data from an AACP Faculty Survey. Of the 926 faculty members who responded to the survey, the majority were satisfied or very satisfied with faculty governance (64%) and the level of input into faculty governance (63%) at their school. Faculty members in administrative positions and those at public institutions were more satisfied with governance. The forum resulted in the development of five themes: establish a clear vision of governance in all areas; ensure that faculty members are aware of their roles and responsibilities within the governance structure; ensure faculty members are able to join committees of interest; recognize and reward faculty contributions to governance; and involve all full-time faculty members in governance, regardless of their tenure status. Summary. Establishing shared governance within a school or college of pharmacy impacts overall faculty satisfaction and potentially faculty retention.

Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks.

The radiomimetic enediyne C-1027 induces almost exclusively DNA double-strand breaks (DSB) and is extremely cytotoxic. Unique among radiomimetics, ataxia-telangiectasia mutated (ATM) is dispensable for cellular responses to C-1027-induced DNA damage. This study explores the biological activity of three recently bioengineered C-1027 analogues: 7''-desmethyl-C-1027 (desmethyl), 20'-deschloro-C-1027 (deschloro), and 22'-deshydroxy-C-1027 (deshydroxy). Each compound maintains the characteristic ability of radiomimetics to cleave DNA in cell-free systems, varying in activity from 2-fold (deschloro) to 55-fold (desmethyl) less than C-1027. The induction of cellular DNA breaks based on pulsed field gel electrophoresis, comet analysis, and gammaH2AX activation was in the same rank order as cell-free DNA break induction, although the amount of breaks induced by desmethyl is greatly reduced compared with the other analogues. Despite the disparity in inducing DNA DSBs, all of the analogues produced G2-M cell cycle arrest and activated DNA DSB damage response proteins, such as p53-Ser15 and Chk2-Thr68, at concentrations in concordance with their ability to inhibit cell growth. Interestingly, of the three analogues, only the desmethyl-induced DNA damage response was similar to C-1027, as it did not cause hypersensitive cell growth inhibition in the absence of ATM nor require the kinase to phosphorylate p53 or Chk2. These findings show that simple modifications of the chromophore of C-1027 can result in varied induction of, and cellular response to, DNA DSBs.

The Effect of Banning Computers on Examination Performance in a First-Year Pathophysiology Class.

Objective. To assess the effects of a computer-free classroom on first-year Doctor of Pharmacy (PharmD) students' performance in a pathophysiology course. Methods. In the 2018 course offering, the instructor enforced an electronics-free classroom where students could not access computers to take notes during lectures. Data were compared to a previous iteration of the course in which students could use computers for notetaking if they desired. Four in-class examinations were given by the instructor and performance between the two student classes were compared. Results. The average examination grade increased 3% in the electronics-free classroom. Overall, final course grades were similar for students receiving A's and B's, but there was a notable increase in C's and a corresponding decrease in course failures. Course evaluations remained consistent and a slight majority of student comments were supportive of the computer-free environment. Conclusion. Student performance on examinations and in the course improved within the electronics-free classroom, especially for students at the lower end of the grading scale. This work provides important insights for faculty and administrators as they weigh whether to create a computer-free learning environment.