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Objective. To determine whether human patient simulation (HPS) is superior to case-based learning (CBL) in teaching diabetic ketoacidosis (DKA) and thyroid storm (TS) to pharmacy students. Design. In this cross-over, open-label, single center, randomized control trial, final-year undergraduate pharmacy students enrolled in an applied therapeutics course were randomized to HPS or CBL groups. Pretest, posttest, knowledge retention tests, and satisfaction survey were administered to students. Assessment. One hundred seventy-four students participated in this study. The effect sizes attributable to HPS were larger than CBL in both cases. HPS groups performed significantly better in posttest and knowledge retention test compared to CBL groups pertaining to TS case (p<0.05). Students expressed high levels of satisfaction with HPS sessions. Conclusion. HPS was superior to CBL in teaching DKA and TS to final-year undergraduate pharmacy students.

To determine whether human patient simulation (HPS) is superior to case-based learning (CBL) in teaching diabetic ketoacidosis (DKA) and thyroid storm (TS) to pharmacy students. In this cross-over, open-label, single center, randomized control trial, final-year undergraduate pharmacy students enrolled in an applied therapeutics course were randomized to HPS or CBL groups. Pretest, posttest, knowledge retention tests, and satisfaction survey were administered to students. One hundred seventy-four students participated in this study. The effect sizes attributable to HPS were larger than CBL in both cases. HPS groups performed significantly better in posttest and knowledge retention test compared to CBL groups pertaining to TS case (p<0.05). Students expressed high levels of satisfaction with HPS sessions. HPS was superior to CBL in teaching DKA and TS to final-year undergraduate pharmacy students.

The results revealed that compounding of Drugs (100%) followed by Pharmaceutical Calculations (98%), Sterile Compounding, Aseptic Technique and IV Admixture (98%) and Medication Error Deterrence (96%) were the most frequently cited topics required to be the part of an effective curriculum. [...] Dispensing (92%), Good Manufacturing Practice and Quality Control (95.7%), and Interpreting Medication Order and Prescriptions (94%) were also thought to be a required component of the curriculum.

Meropenem is commonly used against Pseudomonas aeruginosa. Traditionally, the time unbound antibiotic concentration exceeds the MIC (fT>MIC) is used to select carbapenem regimens. We aimed to: characterize the effects of different baseline resistance mechanisms on bacterial killing and resistance emergence; evaluate whether fT>MIC can predict these effects; and, develop a novel quantitative and systems pharmacology (QSP) model to describe effects of baseline resistance mechanisms on the time-course of bacterial response. Seven isogenic P. aeruginosa strains with a range of resistance mechanisms and MICs were used in 10-day hollow-fiber infection model studies. Meropenem pharmacokinetic profiles were simulated for various regimens (t1/2,meropenem=1.5h). All viable counts on drug-free, 3×MIC and 5×MIC meropenem-containing agar across all strains, five regimens and control (n=90 profiles) were simultaneously subjected to QSP modeling. Whole genome sequencing was completed for total population samples and emergent resistant colonies at 239h. Regimens achieving ≥98%fT>1xMIC suppressed resistance emergence of the mexR knockout strain. Even 100%fT>5xMIC failed to achieve this against the strain with OprD loss and the ampD and mexR double-knockout strain. Baseline resistance mechanisms affected bacterial outcomes, even for strains with the same MIC. Genomic analysis revealed that pre-existing resistant subpopulations drove resistance emergence. During meropenem exposure, mutations in mexR were selected in strains with baseline oprD mutations, and vice versa, confirming these as major mechanisms of resistance emergence. Secondary mutations occurred in lysS or argS, coding for lysyl and arginyl tRNA synthetases, respectively. The QSP model well characterized all bacterial outcomes of the seven strains simultaneously, which fT>MIC could not.

BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively. BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.

The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC. Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors. Resistance to anti-HER2 therapies in breast cancer remains a significant clinical challenge. Here, the authors demonstrate that EZH2 regulates response to HER2-targeting therapies in breast cancer, in part, by modulating the expression of PPP2R2B .

Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

The human genome contains instructions to transcribe more than 200,000 RNAs. However, many RNA transcripts are generated from the same gene, resulting in alternative isoforms that are highly similar and that remain difficult to quantify. To evaluate the ability to study RNA transcript expression, we profiled seven human cell lines with five different RNA-sequencing protocols, including short-read cDNA, Nanopore long-read direct RNA, amplification-free direct cDNA and PCR-amplified cDNA sequencing, and PacBio IsoSeq, with multiple spike-in controls, and additional transcriptome-wide N 6 -methyladenosine profiling data. We describe differences in read length, coverage, throughput and transcript expression, reporting that long-read RNA sequencing more robustly identifies major isoforms. We illustrate the value of the SG-NEx data to identify alternative isoforms, novel transcripts, fusion transcripts and N 6 -methyladenosine RNA modifications. Together, the SG-NEx data provide a comprehensive resource enabling the development and benchmarking of computational methods for profiling complex transcriptional events at isoform-level resolution. This analysis provides a collection of sequencing datasets generated from long-read and short-read RNA sequencing, serving as a valuable resource for transcriptome profiling.