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Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors., Significance: The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer., (©2024 American Association for Cancer Research.)

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers., (© 2023. The Author(s).)

Critically ill patients with requirement of continuous renal replacement therapy (CRRT) represent a growing intensive care unit (ICU) population. Optimal CRRT delivery demands continuous communication between stakeholders, iterative adjustment of therapy, and quality assurance systems. This Quality Improvement (QI) study reports the development, implementation and outcomes of a quality assurance system to support the provision of CRRT in the ICU. This study was carried out at the University of Kentucky Medical Center between September 2016 and June 2019. We implemented a quality assurance system using a step-wise approach based on the (a) assembly of a multidisciplinary team, (b) standardization of the CRRT protocol, (c) creation of electronic CRRT flowsheets, (d) selection, monitoring and reporting of quality metrics of CRRT deliverables, and (e) enhancement of education. We examined 34-month data comprising 1185 adult patients on CRRT (~ 7420 patient-days of CRRT) and tracked selected QI outcomes/metrics of CRRT delivery. As a result of the QI interventions, we increased the number of multidisciplinary experts in the CRRT team and ensured a continuum of education to health care professionals. We maximized to 100% the use of continuous veno-venous hemodiafiltration and doubled the percentage of patients using regional citrate anticoagulation. The delivered CRRT effluent dose (~ 30 ml/kg/h) and the delivered/prescribed effluent dose ratio (~ 0.89) remained stable within the study period. The average filter life increased from 26 to 31 h (p = 0.020), reducing the mean utilization of filters per patient from 3.56 to 2.67 (p = 0.054) despite similar CRRT duration and mortality rates. The number of CRRT access alarms per treatment day was reduced by 43%. The improvement in filter utilization translated into ~ 20,000 USD gross savings in filter cost per 100-patient receiving CRRT. We satisfactorily developed and implemented a quality assurance system for the provision of CRRT in the ICU that enabled sustainable tracking of CRRT deliverables and reduced filter resource utilization at our institution.

Objectives: To compare the clinical performance of a universal adhesive in class V non-carious cervical lesions (NCCLs) using two surface treatment protocols (self-etch [SfE] vs selective-enamel-etch [SelE])., Material and Methods: Thirty-three adults, each with ≥2 NCCLs, received one resin composite restoration utilizing a SfE universal adhesive and another utilizing the adhesive and SelE with 37% phosphoric acid. Restorations were evaluated for sensitivity, retention, marginal discoloration, marginal adaptation, and clinical acceptability through 24 months using Cochran-Mantel-Haenszel tests for stratified, ordered categorical outcomes., Results: Sixty-six restorations (35 SfE, 31 SelE; 27 volunteers) were evaluated at 24 months. There were no significant differences between SfE and SelE for sensitivity, retention, marginal adaptation, or clinical acceptability. One SfE restoration was lost. Marginal adaptation was significantly worse at 24 months than baseline for SelE (P = 0.01), but not for SfE. Marginal discoloration was significantly worse for SfE (P = 0.02), but not for SelE. Sensitivity improved from baseline to 24 months for both groups (SelE P = 0.004, SfE P = 0.002)., Conclusions: Twenty-four-month data indicated significantly reduced sensitivity for both groups, worse marginal discoloration for SfE, and worse marginal adaptation for SelE. No changes in retention or clinical acceptability were observed in either group. All retained restorations were clinically acceptable at 24 months., Clinical Significance: Both self-etch and selective enamel etch techniques with a universal adhesive produced clinically acceptable results in resin composite restorations for NCCLs over 2 years., (© 2020 Wiley Periodicals LLC.)

Dental educators should consider alternative modalities of instruction when experiencing difficulties conveying feedback to students. The aim of this study was to determine if integrating iPad technology as a visual learning tool would enhance the exchange of assessment information and improve academic performance in Indiana University School of Dentistry's preclinical curriculum. In 2016, the first-year Tooth Morphology (TM) and second-year Fixed Prosthodontics (Fixed) courses implemented a project using iPad images that allowed instructors to annotate acceptable and deficient areas of students' tooth wax-ups and preparations. In the two courses, all students (TM n=106 and Fixed n=105) and instructors (TM n=21 and Fixed n=17) were given pre-intervention surveys to report their perceived effectiveness of verbal feedback and were given post-intervention surveys to rate their experiences with iPad image feedback. Response rates for students in the two courses on the pre surveys were TM 87.7% and Fixed 85.7% and on the post surveys were TM 26.4% and Fixed 76.2%. Response rates for instructors on the pre surveys were TM 52.4% and Fixed 82.4% and on the post surveys were TM 76.2% and Fixed 76.5%. The results showed that a majority of both groups preferred the combination of verbal and iPad image feedback: 53% of responding students in TM and 51% in Fixed, and 75% of instructors in TM and 77% in Fixed. In the TM course, responding instructors had a statistically significantly higher agreement than students that feedback with iPad images was superior to verbal feedback alone (p=0.008). Furthermore, a multi-year analysis of TM practical examination grades found statistically significant lower change scores for the first and second exams in 2014 and 2015 compared to the 2016 scores when the iPad intervention occurred. These results suggest that verbal feedback combined with iPad images resulted in an enhanced exchange of information and increased student grades, particularly in the first-year dental curriculum.

At Indiana University School of Dentistry, a New Clinical Faculty Training (NCFT) program was created with the primary goals of informing new part-time faculty members of clinical policies and assessment guidelines and thus developing qualified and satisfied faculty members. The aim of this study was to determine if participation in the training program improved the participants' satisfaction and competence in comparison to their colleagues who did not participate in the program. Two cohorts were compared: a control group of part-time faculty members who did not receive formal training when they were hired (n=21; response rate 58.3%); and the intervention group, who had participated in the NCFT program (n=12; response rate 80%). A survey of faculty members in the control group gathered information on their experiences when initially hired, and a pretest was administered to measure their knowledge of clinical policies. After the control group was given an overview of the program, their feedback was collected through post surveys, and a posttest identical to the pretest was given that found statistically significant increases on questions one (p=0.003) and four (p=0.025). In February 2014, 15 new faculty members participated in the pilot implementation of the NCFT program. Of those 15, 12 (the intervention group) completed follow-up surveys identical to the pre survey used with the control group. Statistically significant differences were found for the factors clinical teaching (p=0.005) and assessment training (p=0.008) with better responses for the NCFT group. These results suggest that participation in the program was associated with improved clinical teaching knowledge and job satisfaction.

A traditional summative grading structure, used at Indiana University School of Dentistry (IUSD) for more than 30 years, was identified by faculty as outdated for assessing students' clinical performance. In an effort to change the status quo, a feedback-driven assessment was implemented in 2012 to provide a constructive assessment tool acceptable to both faculty and students. Building on the successful non-graded clinical evaluation employed at Baylor College of Dentistry, IUSD implemented a streamlined electronic formative feedback model (FFM) to assess students' daily clinical performance. An important addition to this evaluation tool was the inclusion of routine student self-assessment opportunities. The aim of this study was to determine faculty and student response to the new assessment instrument. Following training sessions, anonymous satisfaction surveys were examined for the three user groups: clinical faculty (60% response rate), third-year (D3) students (72% response rate), and fourth-year (D4) students (57% response rate). In the results, 70% of the responding faculty members preferred the FFM over the summative model; however, 61.8% of the D4 respondents preferred the summative model, reporting insufficient assessment time and low faculty participation. The two groups of students had different responses to the self-assessment component: 70.2% of the D4 respondents appreciated clinical self-assessment compared to 46% of the D3 respondents. Overall, while some components of the FFM assessment were well received, a phased approach to implementation may have facilitated a transition more acceptable to both faculty and students. Improvements are being made in an attempt to increase overall satisfaction.