Fostering cultural sensitivity amongst students of pharmacy through an interprofessional book club activity.

BACKGROUND AND PURPOSE: To describe a large-scale, cultural sensitivity-focused interprofessional book club activity that is required in the first-professional year of an accelerated pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: An interprofessional book club activity, focusing on the need for cultural sensitivity in health care, is conducted annually for students in the acupuncture, pharmacy, physical therapy, physician assistant, and sonography programs. Each year over 400 students are required to attend and are assigned to interprofessional groups to discuss guided questions pertaining to the book written by Anne Fadiman, The Spirit Catches You and You Fall Down: A Hmong Child, Her American Doctors, and the Collision of Two Cultures. Pharmacy students complete multiple assignments before and after the activity. Students are administered a post-survey to collect student feedback and self-assessment data. The book club has been run in both synchronous and asynchronous formats. FINDINGS: Student survey responses have consistently revealed that the majority of students agreed or strongly agreed that they were better prepared for culturally-diverse patient interactions, the activity allowed for interprofessional learning, and the activity should continue for future students. SUMMARY: A book club activity is an effective strategy for delivering content related to cultural sensitivity in an interprofessional format. This activity model can be used to support interactions with multiple professions in different schools within the same university or with multiple professions located at different universities/institutions.

Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent.

In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.

Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-ß receptor type I inhibitor.

Transforming growth factor-ß (TGFß) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFß receptor I (TGFßRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFßRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFß-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFß-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects. Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFß-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFß pathway inhibitors.

Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7.

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.

Comprehensive perinatal safety initiative to reduce adverse obstetric events.

A comprehensive perinatal safety initiative (PSI) was incrementally introduced from August 2007 to July 2009 at a large tertiary medical center to reduce adverse obstetrical outcomes. The PSI introduced: (1) evidence-based protocols, (2) formalized team training with emphasis on communication, (3) standardization of electronic fetal monitoring with required documentation of competence, (4) a high-risk obstetrical emergency simulation program, and (5) dissemination of an integrated educational program among all healthcare providers. Eleven adverse outcome measures were followed prospectively via modification of the Adverse Outcome Index (MAOI). Additionally, individual components were evaluated. The logistic regression model found that within the first year, the MAOI decreased significantly to 0.8% from 2% (p<.0004) and was maintained throughout the 2-year period. Significant decreases over time for rates of return to the operating room (p<.018) and birth trauma (p<.0022) were also found. Finally, significant improvements were found in staff perceptions of safety (p<.0001), in patient perceptions of whether staff worked together (p<.028), in the management (p<.002), and documentation (p<.0001) of abnormal fetal heart rate tracings, and the documentation of obstetric hemorrhage (p<.019). This study demonstrates that a comprehensive PSI can significantly reduce adverse obstetric outcomes, thereby improving patient safety and enhancing staff and patient experiences.

Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.