Perception of the Scholarly Work Project by DNP/DNAP Graduates: A Preliminary Survey.

The purpose of this descriptive pilot survey was to understand the experiences of students completing scholarly work projects for practice doctorate programs. With this work, we hoped to fill the literature gap and to inform curriculum. A descriptive survey was used to answer the question: How do graduates of entry level and completion degree Doctor of Nursing Practice (DNP) and Doctor of Nurse Anesthesia Practice (DNAP) programs perceive the scholarly work requirements? The Chi-square test of independence was used to compare whether there was a statistically significant association between the responses to the survey question and the demographic variable. Only 46 DNP/DNAP graduates (4%) completed the survey. The survey results indicated that students in completion programs believed that their scholarly work empowered them to conduct future scholarly work as compared with the entry-topractice cohorts. Variables addressing each aspect of scholarly work project were described by the participants. This preliminary work provides a glimpse into the experience of scholarly work projects for the practice doctorate. To provide greater depth and understanding of this important aspect of doctoral education, a larger sampling of graduates is needed. A collaborative study might be beneficial.

Opioid-Free Anesthesia and Certified Registered Nurse Anesthetists: Barriers to Implementation.

While knowledge surrounding opioid-free anesthesia (OFA) has increased in current literature, there is an absence of research specific to nurse anesthesia practice. This study aimed to identify the number of surveyed Certified Registered Nurse Anesthetists (CRNAs) who incorporated OFA into practice and uncovered barriers to its implementation. This quantitative survey solicited data from 2,883 CRNAs across the United States. Of the participants, 81% administered OFA, and 88% felt that OFA techniques are beneficial in anesthesia practice. The results of the survey revealed that gender may be a barrier to the implementation of OFA. Female respondents were less likely to administer OFA often due to the facility culture. The level of education also influenced how CRNAs perceived their facility's culture as a barrier. Perceived access to a variety of multimodal anesthetics was also problematic. While most of those surveyed had administered OFA and acknowledged its benefit, barriers to wider implementation still exist.

Addressing Barriers to Implementing Problem-Based Learning.

Problem-based learning (PBL) allows students to address knowledge deficits by providing them with a clinical case so that they explore all aspects of patient care. The advantages of PBL for students include improving critical thinking skills, increased clinical reasoning, and exposure to self-directed learning. Although PBL is commonly used in medical education, it seems to be seldom used in nurse anesthesia education. An evidence-based review was conducted to identify barriers to implementing PBL and methods to address these barriers. Common barriers to PBL implementation were categorized as faculty resistance, student concerns, and resource limitations. Interventions to help address these barriers were presented to aid nurse anesthesia educators in incorporating PBL into the curriculum.

Scholarly Work for Practice Doctorate Nurse Anesthesia Programs: Current State and Guidance.

The Standards for Accreditation of Nurse Anesthesia Programs: Practice Doctorate was adopted by the Council on Accreditation of Nurse Anesthesia Educational Programs (COA) in January 2015. Balancing academic and clinical preparation for doctoral students, preparation for the National Certification Examination, and requirements for scholarly work represents a major challenge for students, faculty, and programs. With most nurse anesthesia programs having transitioned to the practice doctorate, the COA was in a pivotal position to examine the current state of scholarly work and to produce a white paper to guide programs' development of criteria for scholarly work. To inform the guidance contained in the white paper, nurse anesthesia educators provided input via a survey, a focus group at the 2019 Assembly of Didactic and Clinical Educators meeting, and an active discussion and question-and-answer session during the Assembly. A call for comments was also sent to stakeholders for review and comment on the draft white paper. The guidance set forth in the white paper in no way supersedes institutional and/or other accreditor requirements. The aim of this guidance is to aid nurse anesthesia programs in successfully managing scholarly project curriculum. This article provides an overview of the project.

A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.

Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAßGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments.

Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks.

Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated ß-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated ß-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells.

Predicting success in nurse anesthesia programs: an evidence-based review of admission criteria.

Nurse anesthesia programs strive to minimize attrition due to academic reasons and maximize student success. The authors examined the evidence for evaluating applicants to nurse anesthesia programs that may help predict success in the program and on the National Certification Examination for Nurse Anesthetists. A search strategy guided gathering of evidence from peer-reviewed journals. Evidence from non-anesthesia graduate nursing programs was included because of the suspected lack of evidence specifically examining nurse anesthesia programs. Eight sources involved solely graduate nurse anesthesia programs, 9 involved graduate nursing programs without stu-graduate nursing programs with student registered Nurdent registered nurse anesthetists, and 2 pertained to nurse anesthetists. Most of the evidence sources were descriptive studies. The evidence overall supports current commonly used admissions criteria such as undergraduate grade point averages. The requirement for applicants to take the Graduate Record Examination should be examined closely. Programs should also consider the length of time the applicant has been out of a formal educational setting. Based on these findings, programs may cautiously explore revising the admission policy. Further investigations are proposed to explore the predictive value of various admission criteria.

Predicting academic progression for student registered nurse anesthetists.

In order to foster academic progression and improve retention in nurse anesthesia programs, admission selection criteria require attention. With the escalating cost of graduate education coupled with the current economic crisis, efforts by educational leaders to minimize attrition remain pivotal. Selecting potential candidates who are most likely to succeed, aligned with data-driven evidence, offers the greatest potential for academic success for student registered nurse anesthetists. The purpose of this quantitative correlational study was to determine if a relationship existed between admission criteria (grade point average [GPA], science grade point average [SGPA], Graduate Record Examination scores, and critical care experience) and academic progression (current academic status and GPA). Key findings revealed that statistically significant relationships exist between the admission selection criteria and academic progression. Findings also indicated that a combination of the independent variables, specifically the GPA and SGPA, predict academic progression. Further research that includes examination of cognitive and noncognitive admission criteria may offer greater evidence predicting academic performance by student registered nurse anesthetists.

Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma.

BACKGROUND: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. RESULTS: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro-inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. CONCLUSIONS: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner.

TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression.

Replicative senescence forms a major barrier to tumor progression. Cancer cells bypass this by using one of the two known telomere maintenance mechanisms: telomerase or the recombination-based alternative lengthening of telomeres (ALT) mechanism. The molecular details of ALT are currently poorly understood. We have previously shown that telomerase is actively repressed through complex networks of kinase, gene expression, and chromatin regulation. In this study, we aimed to gain further understanding of the role of kinases in the regulation of telomerase expression in ALT cells. Using a whole human kinome small interfering RNA (siRNA) screen, we highlighted 106 kinases whose expression is linked to human telomerase reverse transcriptase (hTERT) promoter activity. Network modeling of transcriptional regulation implicated c-Myc as a key regulator of the 106 kinase hits. Given our previous observations of lower c-Myc activity in ALT cells, we further explored its potential to regulate telomerase expression in ALT. We found increased c-Myc binding at the hTERT promoter in telomerase-positive compared with ALT cells, although no expression differences in c-Myc, Mad, or Max were observed between ALT and telomerase-positive cells that could explain decreased c-Myc activity in ALT. Instead, we found increased expression of the c-Myc competitive inhibitor TCEAL7 in ALT cells and tumors and that alteration of TCEAL7 expression levels in ALT and telomerase-positive cells affects hTERT expression. Lower c-Myc activity in ALT may therefore be obtained through TCEAL7 regulation. Thus, TCEAL7 may present an interesting novel target for cancer therapy, which warrants further investigation.

Dynamic telomerase gene suppression via network effects of GSK3 inhibition.

BACKGROUND: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. METHODOLOGY/PRINCIPAL FINDINGS: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3'-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFkappaB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. CONCLUSIONS/SIGNIFICANCE: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting.

The hTERT and hTERC telomerase gene promoters are activated by the second exon of the adenoviral protein, E1A, identifying the transcriptional corepressor CtBP as a potential repressor of both genes.

Telomerase plays a role in the unlimited replicative capacity of the majority of cancer cells and provides a potential anticancer target. The regulation of telomerase is complex but transcriptional control of its two essential components, hTERC (RNA component) and hTERT (reverse transcriptase component), is of major importance. To investigate this further, we have used the adenoviral protein, E1A, as a tool to probe potential pathways involved in the control of telomerase transcription. The second exon of the adenoviral protein E1A activates both telomerase gene promoters in transient transfections. The corepressor, C terminal binding protein, is one of only two proteins known to bind to this region, and we propose that E1A activates both promoters by sequestering CtBP, thereby relieving repression. Activation by exon 2 of E1A involves the SP1 sites in both promoters, and consistent with this, SP1 and CtBP interact in coimmunoprecipitation studies. Modulation of the chromatin environment has been implicated in the regulation of hTERT transcription and appears to involve the SP1 sites. CtBP can be found within a histone-modifying complex and it is possible that a CtBP complex, associating with the SP1 sites, represses transcription from the telomerase promoters by modifying chromatin structure.

Gastrokine 1 is abundantly and specifically expressed in superficial gastric epithelium, down-regulated in gastric carcinoma, and shows high evolutionary conservation.

Through previous large-scale gene expression profiling we identified a transcript that was abundant in normal stomach and down-regulated in gastric cancer. Genes expressed at similar levels included gastrin, MUC5 and pS2, which are important in gastric function. We aimed to characterise this candidate, gastrokine 1 (GKN1), at mRNA, DNA, protein and tissue levels. The gene was studied in human, mouse, rat and cow, and was highly conserved across these species. The mRNA transcripts averaged 750 bp in length. The human, mouse and rat genes all contained six exons spanning 6 kb, and were located on chromosomes 2, 6 and 4 respectively. The full-length translation products were 183-185 amino acids long, reducing to the mature protein of 18 kDa following signal peptide cleavage; these predictions were confirmed by Western blotting. Tagged gastrokine 1 yielded granular cytoplasmic staining with perinuclear accentuation, representing the Golgi apparatus, in keeping with secretion or expression on the extracellular surface. Gene expression in tissues was profiled extensively by Northern blotting, in situ hybridisation and immunohistochemistry. Gastrokine 1 was highly expressed in normal stomach, where it was located in the superficial/foveolar gastric epithelium, but was absent from gastric carcinomas. Outwith the stomach, gastrokine 1 was found only in epithelia showing gastric metaplasia eg Barrett's oesophagus, the ulcer-associated cell lineage and ovarian mucinous neoplasms. In conclusion, we have characterised gastrokine 1, previously known as CA11, AMP-18 or foveolin. Its abundance in, and specificity for, native or metaplastic gastric epithelium, down-regulation in gastric carcinoma and evolutionary conservation suggest that this gene is physiologically important in the stomach. The function of gastrokine 1 is unknown but a role in mucosal protection is postulated.

Percutaneous myocardial laser revascularization in patients with refractory angina pectoris.

This study aimed to determine the safety and efficacy of percutaneous myocardial laser revascularization (PMLR). Seventy-three patients with stable angina pectoris (class III or IV) who were unsuitable for conventional revascularization and had evidence of reversible ischemia by thallium-201 scintigraphy, ejection fraction of > or =25%, and myocardial wall thickness > or =8 mm were randomized to optimal medical therapy alone (n = 37) or PMLR with optimal medical therapy (n = 36). Patients were followed up at 3, 6, and 12 months. The primary end point was exercise time. Secondary end points included angina scores, left ventricular ejection fraction, quality of life, changes in medical therapy, and hospitalizations. All 36 patients randomized to PMLR underwent the procedure successfully with no periprocedure deaths. One patient developed sustained ventricular tachycardia that required electrical cardioversion, and 1 patient developed cardiac tamponade that required surgical drainage. At 12 months, exercise times improved by 109 seconds in the PMLR group but decreased by 62 seconds in the control group (p <0.01). Angina scores improved by 2 classes in 36% of PMLR-treated patients at 12 months compared with 0% of the control patients (p <0.01). We conclude that PMLR is a relatively safe procedure that provides patients with symptomatic angina relief and improvement in exercise capacity and quality of life.