Characterization of the generic mutant p53-rescue compounds in a broad range of assays.

Dozens of compounds that rescue tumor-associated mutant p53 have been reported. Xiao et al. perform 10 assays to evaluate effectiveness of the mutant p53-rescue compounds side-by-side but do not detect reliable rescue in any assay for the evaluated compounds, except for ATO and its analog PAT.

Validation of a Tool to Evaluate Nursing Students' Electronic Health Record Competency in Simulation.

AIM: The aim of the study was to establish reliability and validity of the Competency Assessment in Simulation of Electronic Health Records (CASE) tool. BACKGROUND: Effective teaching and learning practices, including valid and reliable assessment of students' electronic health record (EHR) competency, contribute to safe, high-quality, efficient nursing care. METHOD: The study used a mixed-methods design to test reliability and validity of the CASE tool. RESULTS: A nationally representative sample of faculty from universities representing 27 states provided scores for videos using the CASE tool. Forty-seven participants completed the first scoring survey; 22 of the 47 participants (47%) completed the second-round scoring. Intraclass correlation for the final score between the first and second responses shows the consistency of test-retest reliability (ICC = .78, p < .001). CONCLUSION: The CASE tool provided evidence of validity and reliability in evaluating EHR competency in simulation.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity.

Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure-activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-ß-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.

Arsenic trioxide extends survival of Li-Fraumeni syndrome mimicking mouse.

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

Interprofessional Collaborative Practice: Management of Chronic Disease and Mental Health Issues in Primary Care.

This case study describes the process of implementing and evaluating an interprofessional collaborative practice (IPCP) program for primary care and behavioral health integration focused on chronic disease management. The result was a strong IPCP program in a nurse-led federally qualified health center serving medically underserved populations. The IPCP program at the Larry Combest Community Health and Wellness Center at the Texas Tech University Health Sciences Center spanned >10 years of planning, development, and implementation, supported by demonstration, grants, and cooperative grants from the Health Resources and Services Administration. The program launched 3 projects: a patient navigation program, an IPCP program for chronic disease management, and a program for primary care and behavioral health integration. We established 3 evaluation domains to track the outcomes of the program: TeamSTEPPS education outcomes (Team Strategies and Tools to Enhance Performance and Patient Safety), process/service measures, and patient clinical and behavioral measures. TeamSTEPPS outcomes were evaluated before and after training on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree). Mean (SD) scores increased significantly in team structure (4.2 [0.9] vs 4.7 [0.5]; P < .001), situation monitoring (4.2 [0.8] vs 4.6 [0.5]; P = .002), and communication (4.1 [0.8] vs 4.5 [0.5]; P = .001). From 2014 to 2020, the rate of depression screening and follow-up improved from 16% to 91%, and the hypertension control rate improved from 50% to 62%. Lessons learned include recognizing partner contributions and the worth of each team member. Our program evolved with the help of networks, champions, and collaborative partners. Program outcomes show the positive impact of a team-based IPCP model on health outcomes among medically underserved populations.

Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations.

The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.

Quality Improvement Project to Reduce Opioid Use in Patients Undergoing Cesarean Birth.

After observing the effectiveness of Enhanced Recovery After Surgery (ERAS) protocols for gynecological surgery patients, an interdisciplinary team initiated a quality improvement project with an ERAS protocol to minimize opioid use of patients undergoing elective cesarean birth. Secondary outcomes during the three-month project included decreasing the patient's length of stay and inpatient care costs. We used the Lean Six Sigma methodology and measured aggregated patient outcomes of opioid use, length of hospital stay, and total cost. In addition, we incorporated the ERAS protocol into the electronic health record. Results showed a reduction use of morphine milligram equivalents of opioids, a slight decrease in length of hospital stay, and no change in the inpatient costs. The team recognized that implementation of an ERAS protocol is a best practice to reduce opioid use in patients undergoing a cesarean birth and decided to permanently include it in patient care processes.

A maternity care home model of enhanced prenatal care to reduce preterm birth rate and NICU use.

BACKGROUND: Centers for Medicare & Medicaid Services (CMS) funded 182 US health care sites to reduce preterm birth rates by enhancing prenatal care for at-risk women. As a funded site, the enhanced prenatal care maternity care home (MCH) model was implemented from 2013 to 2018 for 1042 Medicaid-eligible pregnant women. METHODS: This retrospective study evaluated the impact of enhanced services on preterm birth risk reduction. Certified community health workers provided enhanced services from enrollment through six weeks postpartum. Participants attending enhanced intake and third-trimester prenatal visits comprised the Active Group (N = 632). Participants missing third-trimester visits, but participating in enhanced intake and postpartum visits, comprised the Inactive Group (N = 128). Lost Group participants attended only intake visits (N = 282). Data were collected through CMS-developed intake, third-trimester, postpartum, and exit forms. Descriptive analysis, analysis of variance, and the chi-square tests analyzed the impact of risk factors, participant characteristics, and program participation on birth outcomes. RESULTS: Active Group compared with Inactive and Lost Group participants experienced significantly lower preterm birth rates (7.64% vs 22.48% and 15.82%, P < 0.001) and therefore a significantly lower NICU admission rate compared with Inactive and Lost Groups (2.82% vs 11.85% and 5.47%, P < 0.001). CONCLUSIONS: The MCH model of enhanced prenatal care reduced preterm birth and NICU admission rates for Active Group participants. The Black Active Group participant preterm birth rate was not significantly different than other Active Group rates, but was lower than Black Inactive and Lost Group rates.

Exploring the relationships between resilience, mindfulness, and experiential avoidance after the use of a mindfulness- and acceptance-based mobile app for posttraumatic stress disorder.

PURPOSE: This study used a mindfulness- and acceptance-based mobile app to examine the relationships between resilience, mindfulness, experiential avoidance, and posttraumatic stress disorder (PTSD) symptoms. DESIGN AND METHODS: A quasi-experimental pre-posttest, single-group study design was used. A total of 23 college student veterans used the app for 4 weeks. Outcomes of resilience, mindfulness, experiential avoidance, and PTSD were measured at three time-points (baseline, end of Week 2, and end of Week 4). FINDINGS: All outcomes significantly improved at postintervention. Improvements in resilience and PTSD significantly correlated with improvement in mindfulness. PRACTICE IMPLICATIONS: Mindfulness- and acceptance-based mobile apps can be safely used by individuals with PTSD as a complementary approach to enhance resilient coping with PTSD.

Three optimized assays for the evaluation of compounds that can rescue p53 mutants.

Identifying drugs targeting p53 remains a major focus of precision oncology, with over twenty compounds that can rescue p53 mutants reported. Here, we suggest three easily accessible assays to determine the thermostability, protein folding, and transcriptional activity of p53 mutants-the go-to criteria for evaluating a rescue compound that acts by increasing p53 thermostability. Because of the diversity of p53 mutants, a compound that meets the criteria of one assay does not necessarily meet the criteria of the other assays. For complete details on the use and execution of this protocol, please refer to Chen et al. (2021).

Academic Tenure: Perceptual Variations Among Tenured, Tenure-seeking and Non-tenure Faculty.

BACKGROUND: Tenure is a hallmark of higher education, but its value and relevance is questioned. PURPOSE: This study examined faculty perceptions of the value of tenured and non-tenured nursing faculty appointments. METHODS: A descriptive correlational design using an anonymous survey was sent to members of the American Association of College of Nursing. Participants (N = 542) from 44 states completed the survey. RESULTS: Significant differences in workload were found in teaching, administrative responsibilities, scholarship, and academic service. Compared to non-tenured faculty, tenured faculty had higher scores on Career Opportunities (p < 0.001), lower Life Balance scores (p = 0.001) and higher Academic Support scores (p = 0.014). Non-tenured faculty were less likely to agree than tenured faculty that tenure improves quality of education (χ2 = 86.48, p < 0.001) or is relevant to the modern university (χ2 = 75.20, p < 0.001). Narrative responses revealed six themes about tenure. Faculty on both tracks questioned the value of tenure. CONCLUSIONS: Faculties in schools of nursing nationwide need to re-evaluate the purpose of tenure and the tenure criteria in light of each institution's unique mission and expectations to determine how they are meeting the needs of both academic institution and nursing faculty. Although the idea of tenure is institutional, implementation is initiated at the school level. Our study revealed naivete about tenure among nursing faculty at the school level.

Predictors of student veterans progression and graduation in Veteran to Bachelor of Science in Nursing (VBSN) Programs: A multisite study.

BACKGROUND: Capitalizing on the veteran's extensive service experience, values, and norms, Health Resources Services Administration (HRSA) proposed Nurse Education, Practice, Quality and Retention - Veterans' Bachelor of Science (VBSN) Program grants (2016-2019). PURPOSE: The purpose was to identify predictors of student veterans' (SV) progression and graduation rates in VBSN programs. METHODS: A descriptive correlational retrospective design was used. Two hundred and eighty-two (282) SV records were examined. RESULTS: One hundred and forty (140) SVs graduated (49.6%) and 107 (37.9%) were still enrolled. Only program delivery mode (hybrid) was significantly associated with completion and confirmed by logistic regression modeling. An increased representation of SVs' gender, race/ethnicity was present; however, gender, age, race, ethnicity, and veteran status did not significantly predict progression nor graduation. CONCLUSIONS: Hybrid program delivery became the single predictor influencing VBSN progression and graduation. As non-traditional students in higher education with a history of social isolation and help-seeking stigma, this delivery mode may have assisted SV retention and persistence. With a registered nurse shortage and workforce calls for increased gender, race, and ethnic diversity, the findings suggest nursing education programs designed for veterans are a viable solution.

Building nurse resilience in the workplace.

AIMS: The aims of the study were 1) to replicate the research based on the pilot study; 2) to increase resilience in nurses working on all units at four hospitals and 3) to determine which interventions were preferred and most effective. BACKGROUND: Work stress mediates resilience and resilience moderates work stress. Resilience building activities in the literature are often time consuming, complex and done outside work hours. This study investigated use of portable, accessible and brief interventions by nurses to decrease stress and increase resilience during work hours. METHODS: This study used a cross sectional, longitudinal, repeated measures survey design. The study took place in October 2018 to January 2019. Toolkits included written instructions for completing the study protocol, and six activities. Nurses completed surveys at baseline, at 10 time points over a four- to six-week period, and at study conclusion. RESULTS: Connor-Davidson Resilience Scale-10 instrument scores showed resilience increased significantly at four weeks and the effect continued at three months (p < .02). Self-reported stress levels decreased over the study period and nurses self-selected to continue use of the interventions. CONCLUSION: The interventions used during work hours decreased self-reported stress and increased resilience. Nurse leaders may easily adopt these options to promote a less stressed workforce. Resilience can increase the ability of nurses to tolerate high stress in the workplace, which may decrease burnout and turnover. In the pandemic, resilience is even more important as hospitals struggle to retain nurses.

Fraud vulnerability quantitative assessment of Wuchang rice industrial chain in China based on AHP-EWM and ANN methods.

Vulnerability assessment has been used in the food fraud mitigation based on the subjective judgement of industry participants and simple calculation. To have a more objective result, an improved vulnerability quantitative assessment method was proposed. The overall fraud vulnerability was described by the vulnerability of fraud factors and the health and economic impact of fraud incidents. The fraud factors were related to opportunity, motivation and control measure. Analytic hierarchy process combined with entropy weighting method (AHP-EWM) and artificial neural networking (ANN) to improve judgment accuracy. In the application in Wuchang rice industrial chain, 51 fraud factors were used in the assessment and 10 experts, 36 farmers, 15 suppliers and 15 supervisors were interviewed. Results showed that Wuchang rice industrial chain was highly vulnerable to fraud. The opportunity for fraud was high, the motivation to commit it was moderate, and controls to prevent it needed reinforcing. Fraud vulnerability differed between farmers and suppliers. To reduce the fraud vulnerability, improved regulations and policies and stiffer penalties were strongly recommended.

Exploring Strategies to Build Resiliency in Nurses During Work Hours.

OBJECTIVE: This pilot study investigated increasing nurse resiliency utilizing a toolkit of stress-reducing interventions on medical-surgical units at 4 hospitals. BACKGROUND: Resiliency-building activities are time consuming and undertaken outside work hours. Although the activities show a positive impact on resilience, researchers investigated whether similar results could be achieved where nurses experience work stress. METHODS: This quasi-experimental pretest and posttest interventional study used a within-subjects design. Provided toolkits included written instructions to carry out the study. Nurses completed surveys at baseline, at 10 time points over a 6-week period, and at study conclusion. RESULTS: The Connor-Davidson Resilience Scale-10 scores increased significantly at follow-up (P < .02). Self-reported stress levels decreased over the 10 shifts with continued use of the interventions. CONCLUSION: Using stress-reducing interventions during work decreased stress and increased resiliency, thereby offering nurse leaders additional options to promote a healthy workforce at the bedside.