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Primary bone cancer (PBC) comprises several subtypes each underpinned by distinctive genetic drivers. This driver diversity produces novel morphological features and clinical behaviour that serendipitously makes PBC an excellent metastasis model. Here, we report that some transfer RNA-derived small RNAs termed tRNA fragments (tRFs) perform as a constitutive tumour suppressor mechanism by blunting a potential pro-metastatic protein-RNA interaction. This mechanism is reduced in PBC progression with a gradual loss of tRNAGlyTCC cleavage into 5' end tRF-GlyTCC when comparing low-grade, intermediate-grade and high-grade patient tumours. We detected recurrent activation of miR-140 leading to upregulated RUNX2 expression in high-grade patient tumours. Both tRF-GlyTCC and RUNX2 share a sequence motif in their 3' ends that matches the YBX1 recognition site known to stabilise pro-metastatic mRNAs. Investigating some aspects of this interaction network, gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, respectively, showed that ectopic tRF-GlyTCC reduced RUNX2 expression and dispersed 3D micromass architecture in vitro. iCLIP sequencing revealed YBX1 physical binding to the 3' UTR of RUNX2. The interaction between YBX1, tRF-GlyTCC and RUNX2 led to the development of the RUNX2 inhibitor CADD522 as a PBC treatment. CADD522 assessment in vitro revealed significant effects on PBC cell behaviour. In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic.
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Foot ulcers are a frequent and costly problem in people with diabetes mellitus and can lead to amputations. Prevention of these ulcers is therefore of paramount importance. Claw/hammer toe deformities are commonly seen in people with diabetes. These deformities increase the risk of ulcer development specifically at the (tip of) the toe. Percutaneous needle tenotomy of the tendon of the m. flexor digitorum longus (tendon tenotomy) can be used to reduce the severity of claw/hammer toe deformity with the goal to prevent ulcer recurrence. The main objective of this randomized controlled trial is to assess the efficacy of flexor tenotomy to prevent recurrence of toe ulcers in people with diabetes and a history of toe (pre-)ulcers. Additionally, we aim to assess interphalangeal joints (IPJ) and metatarsophalangeal joint (MTPJ) angles in a weight-bearing and non-weight-bearing position, barefoot plantar pressure during walking, cost-effectiveness and quality of life before and after the intervention and compare intervention and control study groups. Sixty-six subjects with diabetes and claw/hammer toe deformity and a recent history of (pre-)ulceration on the tip of the toe will be included and randomized between flexor tenotomy of claw/hammer toes (intervention) versus standard of care including orthosis and shoe offloading (controls) in a mono-center randomized controlled trial. Clinicaltrialsgov registration: NCT05228340.
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Purpose: Conventional computed tomography (CT) images are severely affected by metal artifacts in patients with intracranial coils. Monoenergetic images have been suggested to reduce metal artifacts.The aim of this study was to assess metal artifacts in virtual monoenergetic images (VMIs) reconstructed from spectral brain CT. Methods: Thirty-two consecutive patients with intracranial coils examined by spectral non contrast brain CT (NCCT) at our center between November 2017 and April 2019 were included. Attenuation and standard deviations were measured in regions of interest (ROIs) at predefined areas in artifact-free and artifact-affected areas. Measurements were performed in conventional polyenergetic images (CIs) and the corresponding data for VMIs were retrieved through spectral diagrams for the each ROI. Subjective analysis was performed by visual grading of CIs and specific VMIs by two neuroradiologists, independently. Results: In artefact-affected image areas distal from the metal objects, the attenuation values decreased with higher energy level VMIs. The same effect was not seen for artefact-affected image areas close to the metal.Subjective rating of the artefact severity was significantly better in VMIs at 50 keV for one of the two reviewers compared to the CIs. Overall image quality and tissue differentiation scores were significantly higher for both reviewers in VMIs at 60 and 70 keV compared to CIs. Conclusion: Our quantitative and qualitative image analysis shown that there is a small significant reduction of intracranial coils artifacts severity by all monoenergetic reconstructions from 50 to 200 keV with preserved or increased overall subjective image quality compared to conventional images.
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Background: Aim of this study was to investigate immune cells and subsets in different stages of human coronary artery disease with a novel multiplex immunohistochemistry (mIHC) technique. Methods: Human left anterior descending coronary artery specimens were analyzed: eccentric intimal thickening (N = 11), pathological intimal thickening (N = 10), fibroatheroma (N = 9), and fibrous plaque (N = 9). Eccentric intimal thickening was considered normal, and pathological intimal thickening, fibroatheroma, and fibrous plaque were considered diseased coronary arteries. Two mIHC panels, consisting of six and five primary antibodies, autofluoresence, and DAPI, were used to detect adaptive and innate immune cells. Via semi-automated analysis, (sub)types of immune cells in whole plaques and specific plaque regions were quantified. Results: Increased numbers of CD3+ T cells (P < 0.001), CD20+ B cells (P = 0.013), CD68+ macrophages (P = 0.003), CD15+ neutrophils (P = 0.017), and CD31+ endothelial cells (P = 0.024) were identified in intimas of diseased coronary arteries compared to normal. Subset analyses of T cells and macrophages showed that diseased coronary arteries contained an abundance of CD3+CD8- non-cytotoxic T cells and CD68+CD206- non-M2-like macrophages. Proportions of CD3+CD45RO+ memory T cells were similar to normal coronary arteries. Among pathological intimal thickening, fibroatheroma, and fibrous plaque, all immune cell numbers and subsets were similar. Conclusions: The type of immune response does not differ substantially between different stages of plaque development and may provide context for mechanistic research into immune cell function in atherosclerosis. We provide the first comprehensive map of immune cell subtypes across plaque types in coronary arteries demonstrating the potential of mIHC for vascular research.
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Background: The aim of this study is to quantify the short-term motion of the gastrointestinal tract (GI-tract) and its impact on dosimetric parameters in stereotactic body radiation therapy (SBRT) for pancreatic cancer. Methods: The analyzed patients were eleven pancreatic cancer patients treated with SBRT or proton beam therapy. To ensure a fair analysis, the simulation SBRT plan was generated on the planning CT in all patients with the dose prescription of 40â¯Gy in 5 fractions. The GI-tract motion (stomach, duodenum, small and large intestine) was evaluated using three CT images scanned at spontaneous expiration. After fiducial-based rigid image registration, the contours in each CT image were generated and transferred to the planning CT, then the organ motion was evaluated. Planning at risk volumes (PRV) of each GI-tract were generated by adding 5â¯mm margins, and the volume receiving at least 33â¯Gy (V33)â¯<â¯0.5â¯cm3 was evaluated as the dose constraint. Results: The median interval between the first and last CT scans was 736â¯s (interquartile range, IQR:624-986). To compensate for the GI-tract motion based on the planning CT, the necessary median margin was 8.0â¯mm (IQR: 8.0-10.0) for the duodenum and 14.0â¯mm (12.0-16.0) for the small intestine. Compared to the planned V33 with the worst case, the median V33 in the PRV of the duodenum significantly increased from 0.20â¯cm3 (IQR: 0.02-0.26) to 0.33â¯cm3 (0.10-0.59) at Wilcoxon signed-rank test (pâ¯=â¯0.031). Conclusion: The short-term motions of the GI-tract lead to high dose differences.
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Rationale and objectives: Selecting region of interest (ROI) for left atrial appendage (LAA) filling defects assessment can be time consuming and prone to subjectivity. This study aimed to develop and validate a novel artificial intelligence (AI), deep learning (DL) based framework for automatic filling defects assessment on CT images for clinical and subclinical atrial fibrillation (AF) patients. Materials and methods: A total of 443,053 CT images were used for DL model development and testing. Images were analyzed by the AI framework and expert cardiologists/radiologists. The LAA segmentation performance was evaluated using Dice coefficient. The agreement between manual and automatic LAA ROI selections was evaluated using intraclass correlation coefficient (ICC) analysis. Receiver operating characteristic (ROC) curve analysis was used to assess filling defects based on the computed LAA to ascending aorta Hounsfield unit (HU) ratios. Results: A total of 210 patients (Group 1: subclinical AF, n = 105; Group 2: clinical AF with stroke, n = 35; Group 3: AF for catheter ablation, n = 70) were enrolled. The LAA volume segmentation achieved 0.931-0.945 Dice scores. The LAA ROI selection demonstrated excellent agreement (ICC ≥0.895, p < 0.001) with manual selection on the test sets. The automatic framework achieved an excellent AUC score of 0.979 in filling defects assessment. The ROC-derived optimal HU ratio threshold for filling defects detection was 0.561. Conclusion: The novel AI-based framework could accurately segment the LAA region and select ROIs while effectively avoiding trabeculae for filling defects assessment, achieving close-to-expert performance. This technique may help preemptively detect the potential thromboembolic risk for AF patients.
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This article describes a dataset of synthetic images representing biological scenery as captured by a Fourier Lightfield Microscope (FLMic). It includes 22,416 images related to eight scenes composed of 3D models of objects typical for biological samples, such as red blood cells and bacteria, and categorized into Cells and Filaments groups. For each scene, two types of image data structures are provided: 51 × 51 Elemental Images (EIs) representing Densely Sampled Light Fields (DSLF) and 201 images composing Z-Scans of the scenes. Auxiliary data also includes information about camera intrinsic and extrinsic calibration parameters, object descriptions, and MATLAB scripts for camera pose compensation. The images have been generated using Blender. The dataset can be used to develop and assess methods for volumetric reconstruction from Light Field (LF) images captured by a FLMic.
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Objective: With the deepening of magnetic biomedical effects and electromagnetic technology, some medical instruments based on static magnetic field (SMF) have been used in orthopedic-related diseases treatment. Studies have shown SMF could combat osteoporosis by regulating the differentiation of mesenchymal stem cells (MSCs), osteoblast and osteoclast. With the development of nanotechnology, iron oxide nanoparticles (IONPs) have been reported to regulate the process of bone anabolism. As for SMF combined with IONPs, studies indicated osteogenic differentiation of MSCs were promoted by the combination of SMF and IONPs. However, there are few reports on the effects of SMF combined with IONPs on osteoclast. Herein, the purpose of this study was to investigate the effects of high static magnetic field (HiSMF) combined with IONPs on unloading-induced bone loss in vivo and osteoclastic formation in vitro, and elucidated the potential molecular mechanisms. Methods: In vivo, C57BL/6 âJ male mice were unloaded via tail suspension or housed normally. The hindlimb of mice were fixed and exposed to 1-2 âT SMF for 1 âh every day, 10 âmg/kg of Ferumoxytol or saline were injected by tail vein once a week, last for 4 weeks. Bone microstructure, mechanical properties, and osteoclastogenesis were examined respectively. In vitro, the RAW264.7 âcells were used to assess the effects of 1-2 âT SMF combined with IONPs in osteoclastogenesis. The iron content was detected by atomic absorption spectrometry and Prussian blue staining. DCFH-DA and MitoSOX™ fluorescence staining were used to assess oxidative stress levels. NF-κB and MAPK signaling pathways were examined by western blot assay. Results: In vivo, the results showed 1-2 âT SMF and IONPs prevented the damage to bone microstructure and improved the mechanical properties, diminished the number of osteoclasts in unloaded mice, 1-2 âT SMF combined with IONPs was found more effective. The iron content in the liver and spleen was reduced by the combination of 1-2 âT SMF and IONPs, enhancing iron levels in the femur. In vitro, osteoclast formation was inhibited by 1-2 âT SMF and IONPs treatment, and 1-2 âT SMF combined with IONPs had a more pronounced effect. Moreover, iron uptake of IONPs in osteoclast was reduced to 1-2 âT SMF exposure. Oxidative stress levels were decreased in osteoclast differentiation under 1-2 âT SMF combined with IONPs treatment. Molecularly, the expression of NF-κB and MAPK signaling pathways were inhibited under 1-2 âT SMF combined with IONPs in osteoclastogenesis. Conclusions: Synthetically, our research illustrated 1-2 âT SMF combined with IONPs prevented unloading-induced bone loss by regulating iron metabolism in osteoclastogenesis.Translational potential of this article: As a non-invasive alternative therapy, some medical instruments based on SMF have been used for orthopedic-related diseases treatment for their portability, cheapness and safety. Ferumoxytol (Feraheme™), the first FDA-approved IONP drug for the treatment of iron deficiency anemia, has been also adapted in translational research for osteoporosis. Based on the above-mentioned two points, we found the synergistic effects of SMF and Ferumoxytol for treatment of experimental osteoporosis. These results show translational potentials for clinical application.
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Objective: The Woven EndoBridge (WEB) device (MicroVention, Tustin, CA) has extended the treatment of cerebral aneurysms. Despite the fact that the WEB device has shown promising clinical results, little is known about the caused intra-aneurysmal flow alterations. Here we present our clinical experience with the WEB, including examining various syngo iFlow (Siemens AG, Erlangen, Germany) parameters to predict aneurysm occlusion. Methods: We reviewed the data from patients with unruptured cerebral aneurysms treated with a WEB device between 2016 and 2020. Aneurysm occlusion and complications were assessed. Furthermore, different quantitative criteria were evaluated using syngo iFlow after digital subtraction angiography. Results: A total of 26 patients hosting 26 cerebral aneurysms met the inclusion criteria. Follow-up was available for 21 patients, with a mean of 7.3 ± 6.3 months. A total of 71.4% (n = 15) of the aneurysms included were located in the anterior and 28.6% (n = 6) in the posterior circulation. Adequate aneurysm occlusion was achieved in 85.7% (n = 18). The iFlow parameters for reduced aneurysm outflow (ID-R) differed significantly from the parameters for reduced inflow (PI-R and PI-D) (P < 0.001). The parameters did not differ significantly between adequately and insufficiently occluded aneurysms. Only a trend towards a lower ID-R of insufficiently occluded aneurysms was observed (P = 0.063), indicating a potential predictive value for insufficient aneurysmal outflow. There was no treatment-related morbidity or mortality. Conclusions: The applied syngo iFlow parameters confirmed that flow changes induced by the WEB device significantly affect outflow compared to inflow and have potential predictive value for adequate aneurysm occlusion.
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Objective: Knee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1-34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1-34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1-34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms. Methods: In vivo study, eight-week-old male mice including wild-type (WT) (n â= â54) and OPG-/- (n â= â54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n â= â18), the DMM group (WT-DMM; n â= â18), and the PTH (1-34)-treated group (WT-DMM â+ âPTH (1-34); n â= â18). Similarly, the OPG-/- mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1-34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1-34) in vitro. Results: Compared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1-34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1-34) treatment. Among the OPG-/- mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1-34) treatment. Compared with the WT-DMM mice, the OPG-/--DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG-/--DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1-34). In vitro study, PTH (1-34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6). Conclusion: Both wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG-/- mice. PTH (1-34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA. The translational potential of this article: Systemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.
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Objective: To demonstrate that deep learning (DL) methods can produce robust prediction of gene expression profile (GEP) in uveal melanoma (UM) based on digital cytopathology images. Design: Evaluation of a diagnostic test or technology. Subjects Participants and Controls: Deidentified smeared cytology slides stained with hematoxylin and eosin obtained from a fine needle aspirated from UM. Methods: Digital whole-slide images were generated by fine-needle aspiration biopsies of UM tumors that underwent GEP testing. A multistage DL system was developed with automatic region-of-interest (ROI) extraction from digital cytopathology images, an attention-based neural network, ROI feature aggregation, and slide-level data augmentation. Main Outcome Measures: The ability of our DL system in predicting GEP on a slide (patient) level. Data were partitioned at the patient level (73% training; 27% testing). Results: In total, our study included 89 whole-slide images from 82 patients and 121 388 unique ROIs. The testing set included 24 slides from 24 patients (12 class 1 tumors; 12 class 2 tumors; 1 slide per patient). Our DL system for GEP prediction achieved an area under the receiver operating characteristic curve of 0.944, an accuracy of 91.7%, a sensitivity of 91.7%, and a specificity of 91.7% on a slide-level analysis. The incorporation of slide-level feature aggregation and data augmentation produced a more predictive DL model (P = 0.0031). Conclusions: Our current work established a complete pipeline for GEP prediction in UM tumors: from automatic ROI extraction from digital cytopathology whole-slide images to slide-level predictions. Our DL system demonstrated robust performance and, if validated prospectively, could serve as an image-based alternative to GEP testing.
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Purpose: To assess the potential of radiomic features in comparison to dual-energy CT (DECT) material decomposition to objectively stratify abdominal lymph node metastases. Materials and methods: In this retrospective study, we included 81 patients (m, 57; median age, 65 (interquartile range, 58.7-73.3) years) with either lymph node metastases (n = 36) or benign lymph nodes (n = 45) who underwent contrast-enhanced abdominal DECT between 06/2015-07/2019. All malignant lymph nodes were classified as unequivocal according to RECIST criteria and confirmed by histopathology, PET-CT or follow-up imaging. Three investigators segmented lymph nodes to extract DECT and radiomics features. Intra-class correlation analysis was applied to stratify a robust feature subset with further feature reduction by Pearson correlation analysis and LASSO. Independent training and testing datasets were applied on four different machine learning models. We calculated the performance metrics and permutation-based feature importance values to increase interpretability of the models. DeLong test was used to compare the top performing models. Results: Distance matrices and t-SNE plots revealed clearer clusters using a combination of DECT and radiomic features compared to DECT features only. Feature reduction by LASSO excluded all DECT features of the combined feature cohort. The top performing radiomic features model (AUC = 1.000; F1 = 1.000; precision = 1.000; Random Forest) was significantly superior to the top performing DECT features model (AUC = 0.942; F1 = 0.762; precision = 0.800; Stochastic Gradient Boosting) (DeLong < 0.001). Conclusion: Imaging biomarkers have the potential to stratify unequivocal lymph node metastases. Radiomics models were superior to DECT material decomposition and may serve as a support tool to facilitate stratification of abdominal lymph node metastases.
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Background and purpose: Predicting tumour response would be useful for selecting patients with locally advanced rectal cancer (LARC) for organ preservation strategies. We aimed to develop and validate a prediction model for T downstaging (ypT0-2) in LARC patients after neoadjuvant chemoradiotherapy and to identify those who may benefit from consolidation chemotherapy. Materials and methods: cT3-4 LARC patients at three tertiary medical centers from January 2012 to January 2019 were retrospectively included, while a prospective cohort was recruited from June 2021 to March 2022. Eight filter (principal component analysis, least absolute shrinkage and selection operator, partial least-squares discriminant analysis, random forest)-classifier (support vector machine, logistic regression) models were established to select radiomic features. A nomogram combining radiomics and significant clinical features was developed and validated by calibration curve and decision curve analysis. Interaction test was conducted to investigate the consolidation chemotherapy benefits. Results: A total of 634 patients were included (426 in training cohort, 174 in testing cohort and 34 in prospective cohort). A radiomic prediction model using partial least-squares discriminant analysis and a support vector machine showed the best performance (AUC: 0.832 [training]; 0.763 [testing]). A nomogram combining radiomics and clinical features showed significantly better prognostic performance (AUC: 0.842 [training]; 0.809 [testing]) than the radiomic model. The model was also tested in the prospective cohort with AUC 0.727. High-probability group (score > 81.82) may have potential benefits from ≥ 4 cycles consolidation chemotherapy (OR: 4.173, 95 % CI: 0.953-18.276, p = 0.058, pinteraction = 0.021). Conclusion: We identified and validated a model based on multicenter pre-treatment radiomics to predict ypT0-2 in cT3-4 LARC patients, which may facilitate individualised treatment decision-making for organ-preservation strategies and consolidation chemotherapy.
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Purpose: Clinical OCT angiography (OCTA) of the retinal microvasculature offers a quantitative correlate to systemic disease burden and treatment efficacy in sickle cell disease (SCD). The purpose of this study was to use the higher resolution of adaptive optics scanning light ophthalmoscopy (AOSLO) to elucidate OCTA features of parafoveal microvascular compromise identified in SCD patients. Design: Case series of 11 SCD patients and 1 unaffected control. Participants: A total of 11 eyes of 11 SCD patients (mean age, 33 years; range, 23-44; 8 female, 3 male) and 1 eye of a 34-year-old unaffected control. Methods: Ten sequential 3 × 3 mm parafoveal OCTA full vascular slab scans were obtained per eye using a commercial spectral domain OCT system (Avanti RTVue-XR; Optovue). These were used to identify areas of compromised perfusion near the foveal avascular zone (FAZ), designated as regions of interest (ROIs). Immediately thereafter, AOSLO imaging was performed on these ROIs to examine the cellular details of abnormal perfusion. Each participant was imaged at a single cross-sectional time point. Additionally, 2 of the SCD patients were imaged prospectively 2 months after initial imaging to study compromised capillary segments across time and with treatment. Main Outcome Measures: Detection and characterization of parafoveal perfusion abnormalities identified using OCTA and resolved using AOSLO imaging. Results: We found evidence of abnormal blood flow on OCTA and AOSLO imaging among all 11 SCD patients with diverse systemic and ocular histories. Adaptive optics scanning light ophthalmoscopy imaging revealed a spectrum of phenomena, including capillaries with intermittent blood flow, blood cell stasis, and sites of thrombus formation. Adaptive optics scanning light ophthalmoscopy imaging was able to resolve single sickled red blood cells, rouleaux formations, and blood cell-vessel wall interactions. OCT angiography and AOSLO imaging were sensitive enough to document improved retinal perfusion in an SCD patient 2 months after initiation of oral hydroxyurea therapy. Conclusions: Adaptive optics scanning light ophthalmoscopy imaging was able to reveal the cellular details of perfusion abnormalities detected using clinical OCTA. The synergy between these clinical and laboratory imaging modalities presents a promising avenue in the management of SCD through the development of noninvasive ocular biomarkers to prognosticate progression and measure the response to systemic treatment.
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Objective: To prospectively evaluate the image quality and diagnostic performance of a compact flat-panel detector (FD) scanner for thoracic diseases compared to a clinical CT scanner. Materials and methods: The institutional review board approved this single-center prospective study, and all participants provided informed consent. From December 2020 to May 2021, 30 patients (mean age, 67.1 ± 8.3 years) underwent two same-day low-dose chest CT scans using clinical state-of-art and compact FDCT scanners. Image quality was assessed visually and quantitatively. Two readers evaluated the diagnostic performance for nodules, parenchymal opacifications, bronchiectasis, linear opacities, and pleural abnormalities in 40 paired CT scans. The other 20 paired CT scans were used to examine the agreement of semi-quantitative CT scoring regarding bronchiectasis, bronchiolitis, nodules, airspace consolidations, and cavities. Results: FDCT images had significantly lower visual image quality than clinical CT images (all p < 0.001). The two CT image sets showed no significant differences in signal-to-noise and contrast-to-noise ratios (56.8 ± 12.5 vs. 57.3 ± 15.2; p = 0.985 and 62.9 ± 11.7 vs. 60.7 ± 16.9; p = 0.615). The pooled sensitivity was comparable for nodules, parenchymal opacifications, linear opacities, and pleural abnormalities (p = 0.065-0.625), whereas the sensitivity was significantly lower in FDCT images than in clinical CT images for micronodules (p = 0.007) and bronchiectasis (p = 0.004). The specificity was mostly 1.0. Semi-quantitative CT scores were similar between the CT image sets (p > 0.05), and intraclass correlation coefficients were around 0.950 or higher, except for bronchiectasis (0.869). Conclusion: Compact FDCT images provided lower image quality but comparable diagnostic performance to clinical CT images for nodules, parenchymal opacifications, linear opacities, and pleural abnormalities.
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Purpose: Motion artifacts caused by breathing or involuntary motion of patients, which may lead to reduced image quality and a loss of diagnostic information, are a major problem in shoulder magnetic resonance imaging (MRI). The MultiVane (MV) technique decreases motion artifacts; however, it tends to prolong the acquisition time. As a parallel imaging technique, SENSitivity Encoding (SENSE) can be combined with the compressed sensing method to produce compressed SENSE (C-SENSE), resulting in a markedly reduced acquisition time. This study aimed to evaluate the use of C-SENSE MV for MRI of the shoulder joint. Methods: Thirty-one patients who were scheduled to undergo MRI of the shoulder were included. This prospective study was approved by our institution's medical ethics committee, and written informed consent was obtained from all 31 patients. Two sets of oblique coronal images derived from the standard protocol were acquired without (standard) or with C-SENSE MV: proton-density weighted imaging (PDWI), PDWI with C-SENSE MV, T2-weighted imaging (T2WI) with fat suppression (fs), and T2WI fs with C-SENSE MV. Two radiologists graded motion artifacts and the detectability of anatomical shoulder structures on a 4-point scale (3, no artifacts/excellent delineation; 0, severe artifacts/difficulty with delineation). The Wilcoxon signed-rank test was used to compare the data for the standard and C-SENSE MV images. Results: Motion artifacts were significantly reduced on the C-SENSE MV images (p < 0.001). Regarding the detectability of anatomical structures, the ratings for the C-SENSE MV sequences were significantly better (p < 0.001).In conclusion, in shoulder MRI the newly developed C-SENSE MV technique reduces motion artifacts and increases the detectability of anatomical structures compared with standard sequences.
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Purpose: To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathologic vascularization. Design: Experimental study in mouse, rat, and rabbit animal models. Participants: Ten-week-old Lister Hooded male rats, 8-week-old Brown Norway male rats, 9-day-old C57BL/6J mice, and 12-month-old New Zealand male rabbits. Methods: Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging after topical ALM201 application to rabbit eyes. A mouse choroidal sprouting assay, with aflibercept as positive control, was used to evaluate choroidal neovascularization (CNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed using a rat laser CNV model of neovascular age-related macular degeneration. Main Outcome Measures: Clinical scoring and histologic analysis of vascularized corneas, sprouting area, lesion size, and vessel leakiness in posterior segments. Results: Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (P = 0.0065) and vessel distance to suture (P = 0.021) compared with vehicle control (phosphate-buffered saline [PBS]). Infiltration of inflammatory cells into the corneal stroma also was reduced significantly compared with PBS (724.5 ± 122 cells/mm2 vs. 1837 ± 195.9 cells/mm2, respectively; P = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in anterior and posterior ocular segments 1 hour after topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared with PBS treatment (44.5 ± 14.31 pixels vs. 120.9 ± 33.37 pixels, respectively; P = 0.04) and was not inferior to aflibercept (65.63 ± 11.86 pixels; P = 0.7459). Furthermore, topical ALM201 significantly improved vessel leakiness (leakage scores: 2.1 ± 0.7 vs. 2.9 ± 0.1; P = 0.0274) and lesion size (144,729 ± 33,239 µm3 vs. 187,923 ± 28,575 µm3; P = 0.03) in the rat laser CNV model when compared with topical PBS vehicle. Conclusions: ALM201 is a promising novel molecule with anti-inflammatory and antivascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered therapeutic agent for treating inflammation and pathologic vascularization in the anterior and posterior segments of the eye.
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Transcriptome level expression data connected to the spatial organization of the cells and molecules would allow a comprehensive understanding of how gene expression is connected to the structure and function in the biological systems. The spatial transcriptomics platforms may soon provide such information. However, the current platforms still lack spatial resolution, capture only a fraction of the transcriptome heterogeneity, or lack the throughput for large scale studies. The strengths and weaknesses in current ST platforms and computational solutions need to be taken into account when planning spatial transcriptomics studies. The basis of the computational ST analysis is the solutions developed for single-cell RNA-sequencing data, with advancements taking into account the spatial connectedness of the transcriptomes. The scRNA-seq tools are modified for spatial transcriptomics or new solutions like deep learning-based joint analysis of expression, spatial, and image data are developed to extract biological information in the spatially resolved transcriptomes. The computational ST analysis can reveal remarkable biological insights into spatial patterns of gene expression, cell signaling, and cell type variations in connection with cell type-specific signaling and organization in complex tissues. This review covers the topics that help choosing the platform and computational solutions for spatial transcriptomics research. We focus on the currently available ST methods and platforms and their strengths and limitations. Of the computational solutions, we provide an overview of the analysis steps and tools used in the ST data analysis. The compatibility with the data types and the tools provided by the current ST analysis frameworks are summarized.
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Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.
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Background & Aims: In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging. Methods: To primary cocultures of astrocytes and neurons, low concentrations (1 and 5 µM) of NH4Cl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy. Results: Neuronal cultures treated with NH4Cl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both p <0.0001). BDL led to increased cerebral LP (p = 0.0003) and cytosolic ROS generation (p <0.0001), which was restored by OP (both p <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP. Conclusions: Our results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development. Lay summary: The impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.