TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers.

The grammar in this abstract is generally correct, but there's a minor issue with sentence structure in one part. Here's a slightly revised version with improved grammar and flow:ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1-positive non-small cell lung cancer, but resistance remains a challenge. We investigated the activity of various TKIs against wildtype and mutant ROS1, focusing on the emerging L2086F resistance mutation. Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib. The ROS1 L2086F mutant kinase showed resistance to type I TKIs, while type II TKIs retained activity. Gilteritinib inhibited both wildtype and L2086F mutant ROS1 but was ineffective against the G2032R mutation. Structural analyses revealed distinct binding poses for cabozantinib and gilteritinib, explaining their efficacy against L2086F. Clinical cases demonstrated cabozantinib's effectiveness in patients with TKI-resistant, ROS1 L2086F mutant NSCLCs. This study provides the first comprehensive report of ROS1 L2086F in the context of later-generation TKIs, including macrocyclic inhibitors. While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.

Removal of infected bone in-growth pelvic fixation implants and microcomputed tomography analysis of osseous integration: illustrative case.

BACKGROUND: A novel pelvic fixation screw fusion device (iFuse Bedrock Granite implant) was designed to promote bony fusion through self-harvesting fenestrations throughout the outer screw shank. Bone on-growth and in-growth using this design have been demonstrated in a sheep model, but data from human subjects have not been reported. A 66-year-old medically complex female with 2 prior spine fusions developed spondylodiscitis cephalad to a prior fusion, requiring the removal of instrumentation, which included screw fusion devices. OBSERVATIONS: Within this case report, the authors present a novel bone-preserving technique for the removal of well-fixed screw fusion devices. One screw backed out with a driver, and the other 3 had to be trephined out. One screw sheared off the T30 torque driver, implying a removal torque greater than 270 inch-lbs (30.5 Nm). In addition, the removed implants were analyzed using microcomputed tomography (micro-CT) and demonstrated bone on-growth, in-growth, and through-growth in all 4 screws. LESSONS: Micro-CT clearly demonstrated osseous integration of the screw fusion devices and provided significant support for the use of these implants for lumbopelvic fixation. The authors' hope is that the novel bone-preserving technique will help other surgeons when faced with the difficult removal of well-fixed screw fusion devices. https://thejns.org/doi/10.3171/CASE24274.

Automated magnetic resonance imaging-based grading of the lumbar intervertebral disc and facet joints.

Background: Degeneration of both intervertebral discs (IVDs) and facet joints in the lumbar spine has been associated with low back pain, but whether and how IVD/joint degeneration contributes to pain remains an open question. Joint degeneration can be identified by pairing T1 and T2 magnetic resonance imaging (MRI) with analysis techniques such as Pfirrmann grades (IVD degeneration) and Fujiwara scores (facet degeneration). However, these grades are subjective, prompting the need to develop an automated technique to enhance inter-rater reliability. This study introduces an automated convolutional neural network (CNN) technique trained on clinical MRI images of IVD and facet joints obtained from public-access Lumbar Spine MRI Dataset. The primary goal of the automated system is to classify health of lumbar discs and facet joints according to Pfirrmann and Fujiwara grading systems and to enhance inter-rater reliability associated with these grading systems. Methods: Performance of the CNN on both the Pfirrmann and Fujiwara scales was measured by comparing the percent agreement, Pearson's correlation and Fleiss kappa value for results from the classifier to the grades assigned by an expert grader. Results: The CNN demonstrates comparable performance to human graders for both Pfirrmann and Fujiwara grading systems, but with larger errors in Fujiwara grading. The CNN improves the reliability of the Pfirrmann system, aligning with previous findings for IVD assessment. Conclusion: The study highlights the potential of using deep learning in classifying the IVD and facet joint health, and due to the high variability in the Fujiwara scoring system, highlights the need for improved imaging and scoring techniques to evaluate facet joint health. All codes required to use the automatic grading routines described herein are available in the Data Repository for University of Minnesota (DRUM).

The impact of the COVID-19 public health response on service demand and patient perceptions in a tertiary Australian gynaecology oncology unit.

INTRODUCTION: The public health response (PHR) to the COVID-19 pandemic significantly disrupted healthcare services worldwide. Our hospital, a major tertiary centre, is a unique two-state service across Queensland and New South Wales (NSW). OBJECTIVE: The primary objective is to describe changes in service demand and delivery in our hospital resulting from the COVID-19 PHR. The secondary objective is to investigate patient perceptions of this impact. MATERIALS AND METHODS: We performed a retrospective interrupted time series analysis and a population-based survey to examine patient perceptions of the impact of the COVID-19 PHR. The study periods were demarcated by the initiation of the COVID-19 PHR on 1 March 2020 with the 'pre' and 'during' COVID-19 periods defined as the 12 months before and after this date respectively. RESULTS: More patients were seen during the COVID-19 PHR period. The number or stage of cancer diagnoses was not different (P > 0.05). There was evidence (P = 0.03) of an increase in overall occasions of service and fewer failed attendances (P = 0.005). Fewer surgeries were performed on NSW patients (P = 0.005). The survey response rate was 19.3% (n = 185) with 48% stating that COVID-19 had negatively affected their emotional wellbeing. More participants from NSW than Queensland identified border closures as the most significant impact of the COVID-19 PHR. DISCUSSION: The COVID-19 PHR resulted in an unexpected increase in unit service demand and delivery. The necessary implementation of telephone appointments, while less preferred by patients, sustained service requirements. Cross-border tertiary healthcare services should consider the significant impact of border restrictions on patient wellbeing.

Association Between Antibiotic Duration and Recurrence of Urinary Tract Infection in the Neonatal Critical Care Unit.

OBJECTIVES: Urinary tract infection (UTI) is the most common bacterial infection in infants. Current practice guidelines suggest a treatment duration of 7 to 14 days. Suboptimal therapy may increase the risk for recurrent UTIs leading to renal scarring and possibly chronic kidney disease. The primary objective is to evaluate the duration of therapy for UTIs and its association with the incidence of recurrent UTIs in a neonatal intensive care unit (NICU). The secondary objectives are to identify the risk factors and the most common organisms for recurrent UTIs. METHODS: Patients were identified via the diagnosis codes for UTIs and were included if admitted to the NICU and if they received antibiotics prior to hospital discharge. Patients were divided into 2 groups: antibiotic treatment for 7 days or fewer and antibiotic treatment for greater than 7 days. RESULTS: Eighty-six infants were included in the study. Twenty-six patients received antibiotics for 7 days or fewer, and 60 for more than 7 days. In the study, the median birth weight was 977 g and the median gestational age was 27.6 weeks. There was no significant difference in the rate of recurrent UTIs between the 2 groups (p = 0.66). However, in the subgroup analysis, the incidence was higher for patients receiving antibiotic therapy for fewer than 7 days versus 7 days (p = 0.03). CONCLUSION: There was no difference in recurrence of UTI between treatment groups (≤7 days versus >7 days), and recurrence was seen in a higher percentage of patients with a urinary tract anomaly.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Sacropelvic Fixation with Porous Fusion/Fixation Screws: A Technical Note and Retrospective Review.

OBJECTIVE: The goal of this study was to analyze our initial experience using a novel porous fusion/fixation screw (PFFS) for pelvic fixation and determine our rate of screw malposition requiring intraoperative repositioning. METHODS: We reviewed 83 consecutive patients who underwent sacropelvic fixation with PFFS at our institution from June 1, 2022 to June 30, 2023 using intraoperative computed tomography-based computer-assisted navigation via an open posterior approach. Following PFFS insertion, intraoperative computed tomography scans were obtained to assess screw positioning. Demographic data were collected, and operative reports and patient images were reviewed to determine what implants were used and if any PFFS required repositioning. RESULTS: Seventy-four patients (26M:48F) were included, and 57 (77.0%) had a prior sacroiliac joint or lumbar spine surgery. A stacked screw configuration was used in 62/74 cases (83.8%). A total of 235 PFFS were used and six (2.6%) were malpositioned. Of 88 cephalic screws placed in stacked configuration, 4 were malpositioned (4.5%) and 1/123 caudal screws were malpositioned (0.8%). One of 24 sacral-alar-iliac screws placed in a stand-alone configuration was malpositioned (4.2%). Malpositions included 4 medial, 1 lateral, and 1 inferior, and all were revised intraoperatively without major sequela. CONCLUSIONS: Although PFFSs are larger than traditional sacropelvic fixation screws, stacked sacral-alar-iliac instrumentation can be done safely with computer-assisted navigation. We found a low malposition rate in our initial series of patients, the majority being the cephalad screw in a stacked configuration. This isn't surprising, as these are placed after the caudal screws, which reduces the available corridor size and increases the placement difficulty.

How can healthcare organisations increase doctors' research engagement? A scoping review.

PURPOSE: Clinician engagement in research has positive impacts for healthcare, but is often difficult for healthcare organisations to support in light of limited resources. This scoping review aimed to describe the literature on health service-administered strategies for increasing research engagement by medical practitioners. DESIGN/METHODOLOGY/APPROACH: Medline, EMBASE and Web of Science databases were searched from 2000 to 2021 and two independent reviewers screened each record for inclusion. Inclusion criteria were that studies sampled medically qualified clinicians; reported empirical data; investigated effectiveness of an intervention in improving research engagement and addressed interventions implemented by an individual health service/hospital. FINDINGS: Of the 11,084 unique records, 257 studies were included. Most (78.2%) studies were conducted in the USA, and were targeted at residents (63.0%). Outcomes were measured in a variety of ways, most commonly publication-related outcomes (77.4%), though many studies used more than one outcome measure (70.4%). Pre-post (38.8%) and post-only (28.7%) study designs were the most common, while those using a contemporaneous control group were uncommon (11.5%). The most commonly reported interventions included Resident Research Programs (RRPs), protected time, mentorship and education programs. Many articles did not report key information needed for data extraction (e.g. sample size). ORIGINALITY/VALUE: This scoping review demonstrated that, despite a large volume of research, issues like poor reporting, infrequent use of robust study designs and heterogeneous outcome measures limited application. The most compelling available evidence pointed to RRPs, protected time and mentorship as effective interventions. Further high-quality evidence is needed to guide healthcare organisations on increasing medical research engagement.

A Novel Surgical Indication for Scheuermann's Kyphosis.

Scheuermann kyphosis can be treated surgically to restore proper sagittal alignment. Thoracic curves >70° are typically indicated for surgical intervention. However, patients who have reached their natural limit of compensatory lumbar hyperlordosis are at risk of accelerated degeneration. This can be determined by comparing lumbar lordosis on standing neutral radiographs and supine extension radiographs. Minimal additional lordosis in extension compared with neutral, abutment of the spinous processes, or greater lumbar lordosis standing than with attempted extension suggest the patient is maximally compensated. We present a case of an adolescent boy with Scheuermann kyphosis who had reached the limit of his hyperlordosis compensation reserve. He subsequently underwent a T4 to L2 posterior spinal fusion with T7 to T11 Ponte Smith-Petersen grade two osteotomies. He tolerated the procedure well with no intraoperative complications or neuromonitoring changes. The patient has continued to do well and progressed to normal activity at 5-month follow-up.

Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

Spine surgeon versus AI algorithm full-length radiographic measurements: a validation study of complex adult spinal deformity patients.

INTRODUCTION: Spinal measurements play an integral role in surgical planning for a variety of spine procedures. Full-length imaging eliminates distortions that can occur with stitched images. However, these images take radiologists significantly longer to read than conventional radiographs. Artificial intelligence (AI) image analysis software that can make such measurements quickly and reliably would be advantageous to surgeons, radiologists, and the entire health system. MATERIALS AND METHODS: Institutional Review Board approval was obtained for this study. Preoperative full-length standing anterior-posterior and lateral radiographs of patients that were previously measured by fellowship-trained spine surgeons at our institution were obtained. The measurements included lumbar lordosis (LL), greatest coronal Cobb angle (GCC), pelvic incidence (PI), coronal balance (CB), and T1-pelvic angle (T1PA). Inter-rater intra-class correlation (ICC) values were calculated based on an overlapping sample of 10 patients measured by surgeons. Full-length standing radiographs of an additional 100 patients were provided for AI software training. The AI algorithm then measured the radiographs and ICC values were calculated. RESULTS: ICC values for inter-rater reliability between surgeons were excellent and calculated to 0.97 for LL (95% CI 0.88-0.99), 0.78 (0.33-0.94) for GCC, 0.86 (0.55-0.96) for PI, 0.99 for CB (0.93-0.99), and 0.95 for T1PA (0.82-0.99). The algorithm computed the five selected parameters with ICC values between 0.70 and 0.94, indicating excellent reliability. Exemplary for the comparison of AI and surgeons, the ICC for LL was 0.88 (95% CI 0.83-0.92) and 0.93 for CB (0.90-0.95). GCC, PI, and T1PA could be determined with ICC values of 0.81 (0.69-0.87), 0.70 (0.60-0.78), and 0.94 (0.91-0.96) respectively. CONCLUSIONS: The AI algorithm presented here demonstrates excellent reliability for most of the parameters and good reliability for PI, with ICC values corresponding to measurements conducted by experienced surgeons. In future, it may facilitate the analysis of large data sets and aid physicians in diagnostics, pre-operative planning, and post-operative quality control.

TKI Type Switching Overcomes ROS1 L2086F in ROS1 Fusion-Positive Cancers.

Purpose: Despite the robust efficacy of ROS1 tyrosine kinase inhibitors (TKIs) in ROS1-positive non-small cell lung cancer, TKI resistance continues to hamper durability of the therapeutic response. The resistance liabilities of next-generation ROS1 TKI are sparsely characterized. Design: We compared the activity of type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to the type II TKIs (cabozantinib and merestinib), and to the type I FLT3 inhibitor, gilteritinib, in CD74-ROS1 wildtype and F2004C, L2026M, G2032R, or L2086 mutant Ba/F3 cells. The findings from the Ba/F3 cell model were confirmed using NIH3T3 colony formation assays and in vivo tumor growth. CRISPR/Cas9 gene editing was used to generate isogenic wildtype and L2086F mutant TPM3-ROS1 expressing patient-derived cell lines. These lines were used to further evaluate TKI activity using cell viability and immunoblotting methods. Molecular modeling studies enabled the characterization of structural determinants of TKI sensitivity in wildtype and mutant ROS1 kinase domains. We also report clinical cases of ROS1 TKI resistance that were treated with cabozantinib. Results: ROS1 L2086F mutant kinase is resistant to type I TKI including crizotinib, entrectinib, lorlatinib, repotrectinib, taletrectinib, while the type II TKI cabozantinib and merestinib retain activity. Additionally, we found that gilteritinib, a type I FLT3 inhibitor, inhibited wildtype and L2086F mutant ROS1, however ROS1 G2032R solvent front mutation imposed resistance. The specific binding poses adopted by cabozantinib in the DFG-out kinase conformation and gilteritinib in the DFG-in kinase, provide rationale for their activity in the ROS1 mutants. Clinical cases demonstrated response to cabozantinib in tumors developing TKI resistance due to the ROS1 L2086F mutation. Conclusion: Cabozantinib and gilteritinib effectively inhibit ROS1 L2086F. Clinical activity of cabozantinib is confirmed in patients with TKI-resistant, ROS1 L2086F mutant NSCLC. Gilteritinib may offer an alternative with distinct off-target toxicities, however further studies are required. Since cabozantinib and gilteritinib are multi-kinase inhibitors, there is a persistent unmet need for more selective and better-tolerated TKI to overcome ROS1 L2086F kinase-intrinsic resistance. Translational relevance: ROS1 L2086F is an emerging recurrent resistance mutation to type I ROS1 TKIs, including later generation TKIs. Here, we show corroborating preclinical and clinical evidence for the activity of the quinolone-based type II TKI, cabozantinib, in ROS1 L2086F resistance setting. In addition, we show activity of the pyrazine carboxamide-based type I TKI, gilteritinib, in ROS1 L2086F resistance, suggesting that gilteritinib could be another option for ROS1 L2086F TKI-resistant patients. This study represents the first comprehensive report of ROS1 L2086F in the context of later-generation TKIs, including the macrocyclic inhibitors.

Academic career progression in AANS/CNS Spine Section award recipients.

OBJECTIVE: The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Spine Section awards highlight outstanding abstracts submitted to the AANS/CNS Section on Disorders of the Spine and Peripheral Nerves by trainees interested in spine surgery, although the academic trajectory of awardees has not been studied. The aim of this study was to assess the academic career progression of prior recipients of the Journalistic and Academic Neurosurgical Excellence (JANE), Mayfield, and Kuntz research awards. METHODS: Prior JANE, Mayfield, and Kuntz award recipients were identified using awardee records accrued between 1984 and February 2022. Awardee sex, country of residence, specialty, subspecialty focus, and current academic appointment status (if applicable) were searched online. Awardee h-indices and number of peer-reviewed publications were assessed via Google Scholar profiles (or Scopus if unavailable) and PubMed, respectively. Receipt of federal research funding as principal investigator (PI) was determined using the websites of the National Institutes of Health, the National Science Foundation, and the Department of Defense Congressionally Directed Medical Research Programs. The abstract-to-publication rate was assessed. RESULTS: A total of 7 JANE awards, 57 Mayfield awards, and 149 Kuntz awards were identified. Of the JANE awardees, all recipients were male. Of the 4 unique JANE awardees who completed training, 2 (50.0%) held academic appointments at the time of the study. All of the JANE abstracts were published in peer-reviewed journals. The mean h-index of all JANE awardees was 28 and the mean number of publications was 126. None of the awardees have received federal research funding. Of the Mayfield awards, 98.2% were awarded to males. Of the 43 unique Mayfield awardees who completed training, 20 (46.5%) held faculty appointments at academic medical centers. All of the Mayfield abstracts since 2011 were published in peer-reviewed journals. The mean h-index of all Mayfield awardees was 26 and the mean number of publications was 82. Five Mayfield awardees received National Institutes of Health funding as PI, and 7 awardees received Department of Defense funding as PI. Of the Kuntz awards, 95.3% were awarded to males. Most awards were given to current residents and fellows (46.3%). Of the 55 unique Kuntz awardees who completed training, 31 (56.4%) held faculty appointments at academic medical centers. The abstract-to-publication rate of the total Kuntz abstracts was 70.5%. The mean h-index of all Kuntz awardees was 15 and the mean number of publications was 58. Five Kuntz awardees (3.4%) received federal research funding as PI. CONCLUSIONS: Many recipients of the JANE, Mayfield, and Kuntz Joint Spine Section awards have successfully translated award abstracts into peer-reviewed publications. Furthermore, approximately one-third of the awardees are active in academic neurosurgery, with some having secured federal research funding.

Does A Hinged Operating Table Facilitate Sagittal Correction in Transforaminal Lumbar Interbody Fusion With Smith-Peterson Osteotomy? A Radiographic Analysis.

BACKGROUND: Osteotomies allow the restoration of appropriate sagittal alignment; however, closure of osteotomies can be challenging. Typical closure involves compressing pedicle screw heads across the rods, potentially causing screw loosening and failure. Motorized hinged operating tables are often used to assist with controlled closure of osteotomies without manual compression, but there is no published research quantifying the amount of correction provided solely by changes in the table angle. QUESTION/PURPOSE: What is the incremental amount of correction achieved by change in the table angle versus instrumented manipulation during osteotomy closure in transforaminal lumbar interbody fusion (TLIF) with Smith-Petersen osteotomy? METHODS: Sixty-one patients undergoing Smith-Peterson osteotomy and bilateral TLIF using a motorized hinged table from October 2019 to March 2022 were prospectively enrolled. Two patients did not undergo surgery, two did not have table extension, and seven did not have data collected intraoperatively because of disruptions in research protocols owing to the coronavirus-19 pandemic. Fifty patients (24 male, 26 female) who underwent a total of 73 osteotomies were included in the final analysis. The mean ± standard deviation age was 61 ±11 years, and the mean BMI was 31 ± 6 kg/m2. Patients were positioned prone on the table and flexed to 10° for decompression, Smith-Petersen osteotomy, and TLIF. The table was then extended in 5° increments, and radiographs were taken until 10° of extension was achieved or the osteotomy was fully closed. Changes in segmental lordosis across the operative site for each 5° increment were measured to the nearest degree by two reviewers. Intraclass correlation coefficients for segmental lordosis measurements at each table angle change were calculated as 0.97 to 0.98, with all p values < 0.001, indicating excellent agreement. RESULTS: Table change from 10° to 5° yielded a mean segmental lordosis change of 1.9° ± 1.5° (73 osteotomies), 5° to 0° yielded a change of 1.3° ± 0.9° (73 osteotomies), 0° to -5° yielded a change of 1.3° ± 1.0° (69 osteotomies), and -5° to -10° yielded a change of 1.1° ± 1.3° (61 osteotomies). Rod placement and compression yielded a mean 1.8° ± 2.0° of additional segmental lordosis. CONCLUSION: Using a motorized hinged table facilitated an average of 5.6° of total segmental lordosis correction during controlled Smith-Peterson osteotomy closure without the need for cantilevering forces across spinal instrumentation. Surgeons can use this technique to reduce the compression forces needed to close osteotomies, which could eliminate a potential source of complications.Level of Evidence Level II, therapeutic study.

Population Health Projects: An Innovative Teaching Strategy for Baccalaureate Nursing Education.

The American Association of Colleges of Nursing (AACN) Core Competencies for Professional Nursing Education (2021) include a Population Health domain. Future nurses well-versed in the social determinants of health are poised to be leaders, creating change to improve the lives of vulnerable populations. The Population Health Project (PHP) is an innovative learning experience, immersing student nurses in authentic interactions that impact the communities they partner with. Baccalaureate nursing students, during their Population Health course, work in groups to produce innovative, community-focused PHPs, successfully incorporating the AACN competencies. Students identify issues impacting the wellbeing of their assigned population; these issues become the focus of their PHP. They engage with community stakeholders, including their patients, policy makers, and community partners to develop evidence-based and sustainable projects. PHPs focus on reducing health disparities and address priorities important to communities, including concepts of diversity, inclusion, and equity. Examples of long-term impacts of PHPs include: legislative change - a new law mandating pharmacies provide prescription labels in a language the patient can understand; innovative policies - initiating efforts to create a hospice for unhoused patients; and new service provision programs - teaming with a fire department to co-develop a home-visiting program to reduce non-emergent 911 calls.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Management of High-Grade Dysplastic Spondylolisthesis.

The Meyerding classification grades the degree of slippage in the sagittal plane on lateral standing neutral imaging: 0% to 25% Grade I, 25% to 50% Grade II, 50% to 75% Grade III, 75% to 100% Grade IV, and greater than 100% Grade V (Spondyloptosis). Grades I and II are considered low-grade and Grades III-V are considered high-grade. There are several etiologies of spondylolisthesis. A classification system of the most common causes: Type I - Dysplastic, Type II - Isthmic (including subtypes: A - Lytic, B - Elongation, and C - Acute fracture), Type III - Degenerative, Type IV - Traumatic, Type V - Pathologic, and Type VI - Iatrogenic. Dysplastic spondylolisthesis is a type of spondylolisthesis that occurs at L5-S1 when dysplastic lumbosacral anatomy is present, and is associated with high-grade slip and spina bifida occulta.

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors.

ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI-sensitive oncogenic variants in cell-based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.