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PARP1-targeted fluorescence molecular endoscopy as novel tool for early detection of esophageal dysplasia and adenocarcinoma.
No full textBACKGROUND: Esophageal cancer is one of the 10 most common cancers worldwide and its incidence is dramatically increasing. Despite some improvements, the current surveillance protocol with white light endoscopy and random untargeted biopsies collection (Seattle protocol) fails to diagnose dysplastic and cancerous lesions in up to 50% of patients. Therefore, new endoscopic imaging technologies in combination with tumor-specific molecular probes are needed to improve early detection. Herein, we investigated the use of the fluorescent Poly (ADP-ribose) Polymerase 1 (PARP1)-inhibitor PARPi-FL for early detection of dysplastic lesions in patient-derived organoids and transgenic mouse models, which closely mimic the transformation from non-malignant Barrett's Esophagus (BE) to invasive esophageal adenocarcinoma (EAC).
METHODS: We determined PARP1 expression via immunohistochemistry (IHC) in human biospecimens and mouse tissues. We also assessed PARPi-FL uptake in patient- and mouse-derived organoids. Following intravenous injection of 75 nmol PARPi-FL/mouse in L2-IL1B (n = 4) and L2-IL1B/IL8Tg mice (n = 12), we conducted fluorescence molecular endoscopy (FME) and/or imaged whole excised stomachs to assess PARPi-FL accumulation in dysplastic lesions. L2-IL1B/IL8Tg mice (n = 3) and wild-type (WT) mice (n = 2) without PARPi-FL injection served as controls. The imaging results were validated by confocal microscopy and IHC of excised tissues.
RESULTS: IHC on patient and murine tissue revealed similar patterns of increasing PARP1 expression in presence of dysplasia and cancer. In human and murine organoids, PARPi-FL localized to PARP1-expressing epithelial cell nuclei after 10 min of incubation. Injection of PARPi-FL in transgenic mouse models of BE resulted in the successful detection of lesions via FME, with a mean target-to-background ratio > 2 independently from the disease stage. The localization of PARPi-FL in the lesions was confirmed by imaging of the excised stomachs and confocal microscopy. Without PARPi-FL injection, identification of lesions via FME in transgenic mice was not possible.
CONCLUSION: PARPi-FL imaging is a promising approach for clinically needed improved detection of dysplastic and malignant EAC lesions in patients with BE. Since PARPi-FL is currently evaluated in a phase 2 clinical trial for oral cancer detection after topical application, clinical translation for early detection of dysplasia and EAC in BE patients via FME screening appears feasible
Efficient Contextformer: Spatio-Channel Window Attention for Fast Context Modeling in Learned Image Compression
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Is the Habitual Dietary Intake of Foods of Plant or Animal Origin Associated with Circulating Hemostatic Factors?—Results of the Population-Based KORA-Fit Study
No full textSynthetic Communities of Gut Microbes for Basic Research and Translational Approaches in Animal Health and Nutrition
No full textParametrische Projektionsbasierte Modellreduktion für Crashsimulationen
No full textIn this work, parametric projection-based model order reduction is developed for crash systems. Local reduced-order bases models are transferred to crash to enable parametric problems. A hyper-reduction strategy for path-dependent materials is proposed to achieve computational speedup. Systems combining reduced and unreduced parts are successfully simulated using the proposed reduced models. Finally, hyper-reduced projection-based reduced-order models using autoencoders are introduced.Diese Arbeit stellt parametrische projektionsbasierte reduzierte Modelle für Crashsysteme vor. Die Methode der lokalen reduzierten Basen wird auf parametrische Crashsysteme übertragen. Eine Hyperreduktionsstrategie für geschichtsabhängige Materialen wird eingeführt, um Rechenzeitverkürzungen zu erzielen. Systeme, die reduzierte und unreduzierte Komponenten kombinieren, werden erfolgreich berechnet. Abschließend werden hyperreduzierte Modelle auf der Basis von Autoencodern vorgestellt
A methodology for automatically evaluating outdoor thermal comfort based on publicly available CityGML data
No full textSpectral computed tomography angiography using a gadolinium-based contrast agent for imaging of pathologies of the aorta.
No full textOBJECTIVES: Especially patients with aortic aneurysms and multiple computed tomography angiographies (CTA) might show medical conditions which oppose the use of iodine-based contrast agents. CTA using monoenergetic reconstructions from dual layer CT and gadolinium (Gd-)based contrast agents might be a feasible alternative in these patients. Therefore, the purpose of this study was to evaluate the feasibility of clinical spectral CTA with a Gd-based contrast agent in patients with aortic aneurysms.
METHODS: Twenty-one consecutive scans in 15 patients with and without endovascular aneurysm repair showing contraindications for iodine-based contrast agents were examined using clinical routine doses (0.2 mmol/kg) of Gd-based contrast agent with spectral CT. Monoenergetic reconstructions of the spectral data set were computed.
RESULTS: There was a significant increase in the intravascular attenuation of the aorta between pre- and post-contrast images for the MonoE40 images in the thoracic and the abdominal aorta (p < 0.001 for both). Additionally, the ratio between pre- and post-contrast images was significantly higher in the MonoE40 images as compared to the conventional images with a factor of 6.5 ± 4.5 vs. 2.4 ± 0.5 in the thoracic aorta (p = 0.003) and 4.1 ± 1.8 vs. 1.9 ± 0.5 in the abdominal aorta (p < 0.001).
CONCLUSIONS: To conclude, our study showed that Gd-CTA is a valid and reliable alternative for diagnostic imaging of the aorta for clinical applications. Monoenergetic reconstructions of computed tomography angiographies using gadolinium based contrast agents may be a useful alternative in patients with aortic aneurysms and contraindications for iodine based contrast agents
Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.
No full textOBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age.
METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS).
RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time.
INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732
