Citations

AbstractINTRODUCTIONPhosphorylated ubiquitin (p‐S65‐Ub) is generated during PINK1‐PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p‐S65‐Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.METHODSTo identify novel mitophagy regulators, we performed a genome‐wide association study using p‐S65‐Ub level as a quantitative trait in 1012 autopsy‐confirmed Lewy body disease (LBD) samples.RESULTSWe identified a significant genome‐wide association with p‐S65‐Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p‐S65‐Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.DISCUSSIONOur findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network.

OBJECTIVE Surgery is typically indicated for mechanical pain in metastatic spine disease or severe neurological compromise, but how radicular pain responds to oncological treatment is not well described. The primary aim of this study was to describe how radicular pain responds to oncological treatment, while secondary aims included pain outcomes between patients with mechanical and tumoral pain and motor improvement in patients with weakness due to nerve root compression. METHODS Patients treated with surgery and/or radiotherapy for spinal metastases were identified from an international multicenter prospective cohort. The primary outcome was the numeric rating scale (NRS) score for pain at 3 months posttreatment. Motor recovery from radicular compression in patients with myotomic weakness and low-grade epidural compression was also analyzed. RESULTS Of 284 patients, 129 (45%) had radicular pain ± axial pain and 155 (55%) had axial pain alone. The two groups did not significantly differ in age, comorbidities, tumor characteristics, or treatment. Two hundred two patients (71%) underwent surgery ± radiotherapy, whereas 82 (29%) had radiotherapy alone. The NRS score of patients with radicular pain improved from 6.7 to 3.4 at 3 months, a statistically significantly higher magnitude than in patients with isolated axial pain (p = 0.021). The NRS score at 3 months was similar for both groups (p = 0.876). Patients with radicular pain experienced a larger improvement with surgery compared with radiotherapy alone (p = 0.007) but had higher pretreatment pain (mean NRS score 7.0 vs 5.6, p = 0.013). Twenty-three patients identified with radicular/myotomic weakness (mean American Spinal Injury Association score 96.3 ± 3.2) at baseline improved 2.1 ± 3.8 points at 3 months. CONCLUSIONS The magnitude of pain improvement for patients with radicular pain following surgery and radiotherapy for metastatic spine disease is higher than for patients with axial pain alone. Surgery is associated with a larger improvement in radicular pain than radiotherapy alone. These results will allow clinicians to tailor treatment options for patients with metastatic spine disease.

OBJECTIVE The aim of this study was to determine independent risk factors for vertebral compression fracture (VCF) following stereotactic body radiation therapy (SBRT) in metastatic spine disease. METHODS Patients treated with SBRT for spinal metastasis at a single tertiary care center between 2008 and 2019 were retrospectively identified. Patients with CT scans obtained within 1 year of SBRT completion were included. Variables collected included demographics, Spine Instability Neoplastic Score (SINS), primary tumor pathology, Weinstein-Boriani-Biagini (WBB) classification, chemoradiation treatment details, and bone quality as assessed by Hounsfield units (HUs) on CT. HUs were measured for the medullary bone of the metastatic level, the tumor, and the vertebral bodies cephalad and caudal to the metastasis. Multivariable logistic regression was used to identify predictors of post-SBRT pathological fracture. RESULTS A total of 292 patients (mean age 66 years) with 392 unique lesions were included. The most common pathologies were prostate (n = 193), kidney/renal cell (n = 46), and lung (n = 33). The most common tumor levels were thoracic (n = 206 lesions) and lumbar (n = 128 lesions). SBRT was generally delivered in 1–3 fractions with doses ranging from 16 to 24 Gy in 1 fraction and 24–36 Gy in 3 fractions. Of the 392 lesions, 73 suffered VCF: 21 (29%) with < 25% height loss, 15 (21%) with 25%–40% height loss, and 37 (51%) with > 40% height loss. On univariate analysis, patients with VCF had lower average HUs (156 ± 52 vs 202 ± 89, p < 0.001), more WBB sectors involved (3 ± 2 vs 3 ± 1, p < 0.001), higher SINSs (8 ± 3 vs 6 ± 2, p < 0.001), were more commonly female (33% vs 22%, p = 0.05), and more commonly had nonprostate pathology (67% vs 47%, p = 0.003). VCF rates were similar between moderate (< 20 Gy in 1 fraction, < 30 Gy in 3 or 5 fractions) and high-dose (> 20 Gy in 1 fraction, > 30 Gy in 3 or 5 fractions) radiation schema (15% VCF vs 16% no VCF, respectively; p = 0.99). On multivariable logistic regression, independently significant predictors of VCF were HUs ≤ 229 (OR 6, p < 0.001), affected levels ≥ 3 WBB segments (OR 3, p < 0.001), and an SINS ≥ 8 (OR 2, p = 0.02). CONCLUSIONS Low pre-radiation HUs, involvement of more WBB sectors, and a higher SINS were independent predictors of VCF following SBRT for metastatic spine disease.

Artificial intelligence (AI)-based object detection in radiology can assist in clinical diagnosis and treatment planning. This article examines the AI-based object detection models currently used in many imaging modalities, including X-ray Magnetic Resonance Imaging (MRI), Computed Tomography (CT), and Ultrasound (US). The key models from the convolutional neural network (CNN) as well as the contemporary transformer and hybrid models are analyzed based on their ability to detect pathological features, such as tumors, lesions, and tissue abnormalities. In addition, this review offers a closer look at the strengths and weaknesses of these models in terms of accuracy, robustness, and speed in real clinical settings. The common issues related to these models, including limited data, annotation quality, and interpretability of AI decisions, are discussed in detail. Moreover, the need for strong applicable models across different populations and imaging modalities are addressed. The importance of privacy and ethics in general data use as well as safety and regulations for healthcare data are emphasized. The future potential of these models lies in their accessibility in low resource settings, usability in shared learning spaces while maintaining privacy, and improvement in diagnostic accuracy through multimodal learning. This review also highlights the importance of interdisciplinary collaboration among artificial intelligence researchers, radiologists, and policymakers. Such cooperation is essential to address current challenges and to fully realize the potential of AI-based object detection in radiology.

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions.

AbstractINTRODUCTIONWe compare the stability of phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 at different storage temperatures.METHODSTen ethylenediaminetetraacetic acid–plasma sample aliquots stored at frozen, refrigerated, and ambient temperatures were tested at various timepoints up to 30 days. The mean percent change from baseline was calculated.RESULTSAβ42 and Aβ40 concentrations decreased by >15% after 6 hours at ambient temperature and after 24 hours refrigerated, while p‐tau217 remained stable over 72 hours with < 10% deviation from baseline at either storage temperature. The Aβ42/40 ratio remained relatively constant as each analyte concentration decreased concurrently, while the p‐tau217/Aβ42 ratio deviated from baseline over time. All biomarkers were stable up to 30 days frozen.DISCUSSIONDifferences in the stability of Aβ42 and p‐tau217 may lead to altered p‐tau217/Aβ42 ratio results if samples are not handled properly during the pre‐analytical testing phase. Ideally, samples should be frozen promptly and sent to the laboratory frozen.Highlights Plasma phosphorylated tau (p‐tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p‐tau217/Aβ42 stability was assessed. P‐tau217 was stable, but Aβ42 and Aβ40 started decreasing by 6 hours at ambient temperature. The analyte stability differences led to falsely increased p‐tau217/Aβ42 ratios. Increases > 15% were seen in p‐tau217/Aβ42 after 6 hours at ambient temperature or 24 hours at 4°C.

Over the past decade, stress echocardiography has evolved from a test for assessing epicardial artery stenosis to a comprehensive functional test, targeting multiple cardiovascular parameters. The new approach includes several structured steps: (a) evaluating regional wall motion abnormalities to detect epicardial artery stenosis or vasospasm; (b) assessing pulmonary congestion and diastolic function via B-lines with lung ultrasound; (c) gauging preload and contractile reserve with volumetric echocardiography; (d) measuring coronary microvascular reserve using Doppler-based coronary flow velocity in the middistal left anterior descending artery; and (e) determining cardiac sympathetic reserve by tracking heart rate reserve on an ECG. This evolution was supported extensively by the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI), which played a key role in five areas: (1) developing the initial, curiosity-driven project; (2) disseminating protocols and results at national and international conferences, supporting logistic infrastructure and publication expenses; (3) establishing a digital platform (customized Redcap) for data entry and storage; (4) facilitating patient recruitment across 19 Italian centers; and (5) offering formal endorsement through six presidencies, adding credibility and reach beyond any single institution. The protocol quickly advanced from concept to high-impact publications, earning inclusion in 2024 specialty guidelines. Initially Italian-led, the study now includes 50 centers across 20 countries (e.g. USA and China). Beyond the 50 peer-reviewed papers published in 2016–2024, this study offers a novel, sustainable approach to cardiac stress testing, providing more information at lower costs, with zero radiation and minimal environmental impact. SIECVI’s endorsement was instrumental in amplifying the study’s rigor and outreach.