John B. MacMillan

Antifungal activity of bifunctional sphingolipids. intramolecular synergism within long-chain α,ω-bis-aminoalcohols

Abstract The in vitro antifungal activity of a series of α,ω-bifunctionalized aminoalcohols against Candida glabrata was measured. The dimeric bi-functionalized lipids exhibited activity about ∼10-fold higher higher than d -sphingosine, which is a larger factor than expected from the simple additive effects of vicinal aminoalcohols groups.

ICU Bedside Nurses' Involvement in Palliative Care Communication: A Multicenter Survey.

CONTEXTnSuccessful and sustained integration of palliative care into the intensive care unit (ICU) requires the active engagement of bedside nurses.nnnOBJECTIVESnTo describe the perspectives of ICU bedside nurses on their involvement in palliative care communication.nnnMETHODSnA survey was designed, based on prior work, to assess nurses perspectives on palliative care communication, including the importance and frequency of their involvement, confidence, and barriers. The 46-item survey was distributed via e-mail in 2013 to bedside nurses working in ICUs across the five academic medical centers of the University of California, U.S.nnnRESULTSnThe survey was sent to 1791 nurses; 598 (33%) responded. Most participants (88%) reported that their engagement in discussions of prognosis, goals of care, and palliative care was very important to the quality of patient care. Axa0minority reported often discussing palliative care consultations with physicians (31%) or families (33%); 45% reported rarely or never participating in family meeting discussions. Participating nurses most frequently cited the following barriers to their involvement in palliative care communication: need for more training (66%), physicians not asking their perspective (60%), and the emotional toll of discussions (43%).nnnCONCLUSIONnICU bedside nurses see their involvement in discussions of prognosis, goals of care, and palliative care as a key element of overall quality of patient care. Based on the barriers participants identified regarding their engagement, interventions are needed to ensure that nurses have the education, opportunities, and support to actively participate in these discussions.

Palliative Care Professional Development for Critical Care Nurses: A Multicenter Program

&NA; C E 1.0 Hour This article has been designated for CE contact hour(s). See more CE information at the end of this article. This article is followed by an AJCC Patient Care Page on page 372. Background Integrating palliative care into intensive care units (ICUs) requires involvement of bedside nurses, who report inadequate education in palliative care. Objective To implement and evaluate a palliative care professional development program for ICU bedside nurses. Methods From May 2013 to January 2015, palliative care advanced practice nurses and nurse educators in 5 academic medical centers completed a 3‐day train‐the‐trainer program followed by 2 years of mentoring to implement the initiative. The program consisted of 8‐hour communication workshops for bedside nurses and structured rounds in ICUs, where nurse leaders coached bedside nurses in identifying and addressing palliative care needs. Primary outcomes were nurses ratings of their palliative care communication skills in surveys, and nurses identification of palliative care needs during coaching rounds. Results Each center held at least 6 workshops, training 428 bedside nurses. Nurses rated their skill level higher after the workshop for 15 tasks (eg, responding to family distress, ensuring families understand information in family meetings, all P < .01 vs preworkshop). Coaching rounds in each ICU took a mean of 3 hours per month. For 82% of 1110 patients discussed in rounds, bedside nurses identified palliative care needs and created plans to address them. Conclusions Communication skills training workshops increased nurses ratings of their palliative care communication skills. Coaching rounds supported nurses in identifying and addressing palliative care needs. (American Journal of Critical Care. 2017;26:361‐371)

Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

&NA; Modulators of insulin secretion could be used to treat diabetes and as tools to investigate &bgr; cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin‐linked luciferase that is cosecreted with insulin in MIN6 &bgr; cells to perform a high‐throughput screen of natural products for chronic effects on glucose‐stimulated insulin secretion. In this study, using multiple phenotypic analyses, we found that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion by at least three potential mechanisms: disruption of Wnt signaling, interference of &bgr; cell gene expression, and partial suppression of Ca2+ influx. Chronic treatment with CMA2 largely ablated glucose‐stimulated insulin secretion even after washout, but it did not inhibit glucose‐stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel opener diazoxide, we uncovered defects in depolarization‐induced Ca2+ influx that may contribute to the suppressed secretory response. Glucose‐responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. By querying the FUSION bioinformatic database, we revealed that the phenotypic effects of CMA2 cluster with a number of Wnt‐GSK3 pathway‐related genes. Furthermore, CMA2 consistently decreased GSK3&bgr; phosphorylation and suppressed activation of a &bgr;‐catenin activity reporter. CMA2 and a related compound, mithramycin, are known to have DNA interaction properties, possibly abrogating transcription factor binding to critical &bgr; cell gene promoters. We observed that CMA2 but not mithramycin suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2‐induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt &bgr; cell function through both noncytotoxic and cytotoxic mechanisms. Future therapeutic applications of CMA2 and similar aureolic acid analogues should consider their potential effects on pancreatic islet function. &NA; Drugs that target insulin secretion are useful to understand &bgr; cell function and the pathogenesis of diabetes. Kalwat et al. investigate an aureolic acid that inhibits insulin secretion and reveal that it disrupts Wnt signaling, interferes with gene expression, and suppresses Ca2+ influx in &bgr; cells.

Abstract IA12: Developing precision medicine-based new lung cancer therapeutics

We have used a “chemistry first” approach to discover druggable acquired vulnerabilities that have been acquired in the pathogenesis of non-small cell lung cancer (NSCLC). We screened chemical libraries (~200,000 compounds) for chemical toxins that killed subsets of NSCLC but not normal human lung epithelial cells (HBECs). We first screened a panel of 12 NSCLC lines that represented a variety of known oncogenotypes and identified chemicals with large Z scores and appropriate properties, including re-supply, chemistry, and reproducible drug response phenotypes, and from this narrowed down a list of 202 chemicals and 18 drugs with known targeting (we called our “Precision Oncology Probe” set, POPS). These and a panel of 30 clinically available drugs, targeted therapies, and drug combinations, already in use or in trials for NSCLC treatment, were then tested on a panel of 96 NSCLC lines for their drug response phenotypes in 12-point dose response curves. This information was analyzed using scanning ranked KS (Kolmogorov–Smirnov) and elastic net biostatistics approaches to identify molecular biomarkers (mutations, mRNA expression, copy number variation, protein expression, and metabolomics) that could predict for sensitivity or resistance to a particular chemical toxin or treatment regimen. From this we have discovered that our approach identifies already known molecular biomarker drug sensitivities (e.g., EGFR mutations and EGFR TK inhibitors); many clinically available chemotherapy agents have molecular biomarkers predicting preclinical model drug responses; the POP set of chemical toxins provides novel drug-response phenotype patterns in the large NSCLC panel different from those found with clinically available agents including a therapeutic window; many of the POP toxins only hit a small % (~5%) of the NSCLC panel but the POP set as a whole provides “coverage” of the entire NSCLC panel; there are simple, one- or two-component molecular biomarkers (mutations, mRNA expression) that predict responses to the different chemical toxins in the NSCLC panel; and that the molecular biomarkers provide some information on the targets and pathways involved in response to the chemical toxins. Thus, we have identified a group of chemical toxins with selectivity for subsets of NSCLC and associated tumor molecular biomarkers to facilitate their development for precision medicine and also, in some cases, information on the targets and pathways interdicted by these chemical compounds. In addition, we have discovered NSCLC predictive biomarkers for clinically available agents. University of Texas SPORE in Lung Cancer (P50CA70907), NCI CTD2N (U01 CA176284), and CPRIT Grants. Citation Format: John D. Minna, Elizabeth McMillan, Luc Girard, Michael Peyton, Kenneth Huffman, Dhruba Deb, Paul Yenerall, Amit Das, Longshan Li, Maithili Dalvi, Boning Gao, Yang Xie, Yonghao Yu, Suzie Hight, Rachel Vaden, Caroline Diep, Michael Roth, Bruce Posner, John MacMillan, Ralph Deberardinis, David Wheeler, John V. Heymach, Ignacio I. Wistuba, Adi Gazdar, Michael White. Developing precision medicine-based new lung cancer therapeutics [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA12.