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Drug repositioning of approved drugs offers advantages over de novo drug development for a rare type of cancer. To efficiently identify on-target drugs from clinically successful kinase inhibitors in cancer drug repositioning, drug screening and molecular profiling of cell lines are essential to exclude off-targets. We developed a pharmacoproteogenomic approach to identify on-target kinase inhibitors, combining molecular profiling of genomic features and kinase activity, and drug screening of patient-derived cell lines. This study examined eight patient-derived giant cell tumor of the bone (GCTB) cell lines, all of which harbored a signature mutation of H3-3A but otherwise without recurrent copy number variants and mutations. Kinase activity profiles of 100 tyrosine kinases with a three-dimensional substrate peptide array revealed that nine kinases were highly activated. Pharmacological screening of 60 clinically used kinase inhibitors found that nine drugs directed at 29 kinases strongly suppressed cell viability. We regarded ABL1, EGFR, and LCK as on-target kinases; among the two corresponding on-target kinase inhibitors, osimertinib and ponatinib emerged as on-target drugs whose target kinases were significantly activated. The remaining 26 kinases and seven kinase inhibitors were excluded as off-targets. Our pharmacoproteomic approach enabled the identification of on-target kinase inhibitors that are useful for drug repositioning., (© 2024. The Society for In Vitro Biology.)

Background: Proximal femoral fractures in geriatric patients are a major challenge in orthopedics, often leading to major functional impairment. Early surgical intervention is crucial for improving patient recovery and overall health outcomes. Thus, Japan's Ministry of Health, Labour and Welfare initiated a reimbursement policy in April 2022 to encourage early surgery for these fractures in patients aged ≥75 years. This study investigated the impact of this policy on early surgery rates in Japan and identified factors influencing the timing of surgical interventions., Methods: We retrospectively analyzed the data of patients who underwent surgery for proximal femoral fractures at our institution between April 2022 and March 2023. Patients were categorized into two groups based on the timing of surgery relative to the injury: ≤48 h and >48 h. Demographic and clinical data, including age, sex, fracture type, and various health- and admission-related factors, were assessed., Results: Of the 192 patients, 152 were included in the study. Among them, 38% underwent early surgery (≤48 h), and 15% of the patients arrived more than 48 h post-injury. Significant differences were found in admission routes and residence types between the groups. The ≤48 h group had shorter intervals from injury to admission and surgery than the >48 h group. Factors such as the admission process, day of the week, and C-reactive protein levels significantly influenced the timing of surgery., Conclusions: After introducing incentives for early surgery in Japan, 38% of patients with proximal femoral fractures underwent surgery within 48 h of injury. Factors contributing to patients not receiving early surgery included transport from another hospital, weekend hospitalization, and elevated CRP levels. These findings suggest that achieving surgery within 48 h of injury is challenging through hospital efforts alone, and the time criteria might be more appropriate if changed to "admission to surgery.", Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objectives: Emergency medical triage is crucial for prioritizing patient care in emergency situations, yet its effectiveness can vary significantly based on the experience and training of the personnel involved. This study aims to evaluate the efficacy of integrating Retrieval Augmented Generation (RAG) with Large Language Models (LLMs), specifically OpenAI's GPT models, to standardize triage procedures and reduce variability in emergency care., Methods: We created 100 simulated triage scenarios based on modified cases from the Japanese National Examination for Emergency Medical Technicians. These scenarios were processed by the RAG-enhanced LLMs, and the models were given patient vital signs, symptoms, and observations from emergency medical services (EMS) teams as inputs. The primary outcome was the accuracy of triage classifications, which was used to compare the performance of the RAG-enhanced LLMs with that of emergency medical technicians and emergency physicians. Secondary outcomes included the rates of under-triage and over-triage., Results: The Generative Pre-trained Transformer 3.5 (GPT-3.5) with RAG model achieved a correct triage rate of 70%, significantly outperforming Emergency Medical Technicians (EMTs) with 35% and 38% correct rates, and emergency physicians with 50% and 47% correct rates ( p  < 0.05). Additionally, this model demonstrated a substantial reduction in under-triage rates to 8%, compared with 33% for GPT-3.5 without RAG, and 39% for GPT-4 without RAG., Conclusions: The integration of RAG with LLMs shows promise in improving the accuracy and consistency of medical assessments in emergency settings. Further validation in diverse medical settings with broader datasets is necessary to confirm the effectiveness and adaptability of these technologies in live environments.

Introduction This research aimed to explore the relationship between spinal characteristics and the length of the abdominal aorta in adult spinal deformity (ASD) patients who underwent corrective spinal surgery. We hypothesized that adjusting spinal alignment might affect the abdominal aorta's length. Methods This study included thirteen patients with ASD (average age: 63.0 ± 8.9 years; four males and nine females) who received spinal correction surgery. We measured both pre-operative and post-operative spinal parameters, including thoracolumbar kyphosis (TLK), and calculated their differences (Δ). The length of the aorta (AoL) was determined using an automated process that measures the central luminal line from the celiac artery's bifurcation to the inferior mesenteric artery. This measurement was made using contrast-enhanced computed tomography for three-dimensional aortic reconstruction. We compared the pre-operative and post-operative AoLs and their differences (Δ). The study examined the correlation between changes in spinal parameters and changes in AoL. Results Post-operatively, there was an increase in aortic length (ΔAoL: 4.2 ± 4.9 mm). There was a negative correlation between the change in TLK and the change in AoL (R 2 = 0.45, p = 0.012, β = -0.21). No significant correlations were found with other spinal parameters. Conclusions The abdominal aorta can elongate by 4.8% after spinal corrective surgery in patients with ASD. The degree of elongation of the abdominal aorta is associated with spinal alignment correction., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ohyama et al.)