Publications by authors named "Sarah Keller"

113 Publications

A new therapeutic approach with tocilizumab in a 39-year-old patient with recurrent diabetic myonecrosis.

Mod Rheumatol Case Rep 2021 Sep 10. Epub 2021 Sep 10.

Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

We report the case of a 39-year-old female patient with acute painful swelling of the left thigh and symmetric muscle weakness in both upper legs. The patient had a history of long-standing, poorly controlled type 1 diabetes which required dialysis. Serum inflammatory markers were highly elevated. Magnetic resonance imaging (MRI) indicated necrotic or inflammatory colliquation. As antibiotic therapy did not lead to clinical improvement, a successful anti-inflammatory therapy with prednisolone was initiated. Three months later, the patient presented with a new onset of progressive and painful muscle swelling of the right thigh. MRI showed pronounced swelling of the right adductor muscles and inflammatory markers were massively elevated. In the absence of autoantibodies or any infectious agents and the recurrent symptomatology, relapsing diabetogenic myonecrosis was diagnosed. Initially, clinical improvement could only be achieved with high-dose glucocorticosteroids. Intravenous immunoglobulins did not show an effect, whereas serological and clinical remission was achieved after we administered tocilizumab intravenously. Diabetic myonecrosis is a rare complication of long-term, poorly controlled diabetes mellitus. Acute muscle pain and elevated inflammatory markers should prompt suspicion. Contralateral muscle involvement is also suggestive of the disease. The optimisation of diabetes treatment is crucial in order to prevent further disease complications.
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http://dx.doi.org/10.1093/mrcr/rxab016DOI Listing
September 2021

Recent developments of metal-based compounds against fungal pathogens.

Chem Soc Rev 2021 Jul 27. Epub 2021 Jul 27.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.

This review provides insight into the rapidly expanding field of metal-based antifungal agents. In recent decades, the antibacterial resistance crisis has caused reflection on many aspects of public health where weaknesses in our medicinal arsenal may potentially be present - including in the treatment of fungal infections, particularly in the immunocompromised and those with underlying health conditions where mortality rates can exceed 50%. Combination of organic moieties with known antifungal properties and metal ions can lead to increased bioavailability, uptake and efficacy. Development of such organometallic drugs may alleviate pressure on existing antifungal medications. Prodigious antimicrobial moieties such as azoles, Schiff bases, thiosemicarbazones and others reported herein lend themselves easily to the coordination of a host of metal ions, which can vastly improve the biocidal activity of the parent ligand, thereby extending the library of antifungal drugs available to medical professionals for treatment of an increasing incidence of fungal infections. Overall, this review shows the impressive but somewhat unexploited potential of metal-based compounds to treat fungal infections.
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http://dx.doi.org/10.1039/d0cs00945hDOI Listing
July 2021

Binding of Dipeptides to Fatty Acid Membranes Explains Their Colocalization in Protocells but Does Not Select for Them Relative to Unjoined Amino Acids.

J Phys Chem B 2021 07 20;125(29):7933-7939. Epub 2021 Jul 20.

Department of Chemistry, University of Washington, Seattle, Washington 98195 United States.

Dipeptides, which consist of two amino acids joined by a peptide bond, have been shown to have catalytic functions. This observation leads to fundamental questions relevant to the origin of life. How could peptides have become colocalized with the first protocells? Which structural features would have determined the association of amino acids and peptides with membranes? Could the association of dipeptides with protocell membranes have driven molecular evolution, favoring dipeptides over individual amino acids? Using pulsed-field gradient nuclear magnetic resonance, we find that several prebiotic amino acids and dipeptides bind to prebiotic membranes. For amino acids, the side chains and carboxylate contribute to the interaction. For dipeptides, the extent of binding is generally less than that of the constituent amino acids, implying that other mechanisms would be necessary to drive molecular evolution. Nevertheless, our results are consistent with a scheme in which the building blocks of the biological polymers colocalized with protocells prior to the emergence of RNA and proteins.
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http://dx.doi.org/10.1021/acs.jpcb.1c01485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323988PMC
July 2021

A Scoping Review of the Association of Social Disadvantage and Cerebrovascular Disease Confirmed by Neuroimaging and Neuropathology.

Int J Environ Res Public Health 2021 07 2;18(13). Epub 2021 Jul 2.

Center for Health Disparities Research, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.

Social disadvantage-a state of low-income, limited education, poor living conditions, or limited social support-mediates chronic health conditions, including cerebrovascular disease. Social disadvantage is a key component in several health impact frameworks, providing explanations for how individual-level factors interact with interpersonal and environmental factors to create health disparities. Understanding the association between social disadvantage and vascular neuropathology, brain lesions identified by neuroimaging and autopsy, could provide insight into how one's social context interacts with biological processes to produce disease. The goal of this scoping review was to evaluate the scientific literature on the relationship between social disadvantage and cerebrovascular disease, confirmed through assessment of vascular neuropathology. We reviewed 4049 titles and abstracts returned from our search and included records for full-text review that evaluated a measure of social disadvantage as an exposure variable and cerebrovascular disease, confirmed through assessment of vascular neuropathology, as an outcome measure. We extracted exposures and outcomes from 20 articles meeting the criteria after full-text review, and described the study findings and populations sampled. An improved understanding of the link between social factors and cerebrovascular disease will be an important step in moving the field closer to addressing the fundamental causes of disease and towards more equitable brain health.
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http://dx.doi.org/10.3390/ijerph18137071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297247PMC
July 2021

A Scoping Review of the Association of Social Disadvantage and Cerebrovascular Disease Confirmed by Neuroimaging and Neuropathology.

Int J Environ Res Public Health 2021 07 2;18(13). Epub 2021 Jul 2.

Center for Health Disparities Research, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.

Social disadvantage-a state of low-income, limited education, poor living conditions, or limited social support-mediates chronic health conditions, including cerebrovascular disease. Social disadvantage is a key component in several health impact frameworks, providing explanations for how individual-level factors interact with interpersonal and environmental factors to create health disparities. Understanding the association between social disadvantage and vascular neuropathology, brain lesions identified by neuroimaging and autopsy, could provide insight into how one's social context interacts with biological processes to produce disease. The goal of this scoping review was to evaluate the scientific literature on the relationship between social disadvantage and cerebrovascular disease, confirmed through assessment of vascular neuropathology. We reviewed 4049 titles and abstracts returned from our search and included records for full-text review that evaluated a measure of social disadvantage as an exposure variable and cerebrovascular disease, confirmed through assessment of vascular neuropathology, as an outcome measure. We extracted exposures and outcomes from 20 articles meeting the criteria after full-text review, and described the study findings and populations sampled. An improved understanding of the link between social factors and cerebrovascular disease will be an important step in moving the field closer to addressing the fundamental causes of disease and towards more equitable brain health.
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http://dx.doi.org/10.3390/ijerph18137071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297247PMC
July 2021

How Social Media Comments Inform the Promotion of Mask-Wearing and Other COVID-19 Prevention Strategies.

Int J Environ Res Public Health 2021 May 25;18(11). Epub 2021 May 25.

Department of Communication, College of Liberal Arts & Social Sciences, Montana State University Billings, Billings, MT 59101, USA.

Current COVID-19 messaging efforts by public health departments are primarily informational in nature and assume that audiences will make rational choices in compliance, contradicting extensive research indicating that individuals make lifestyle choices based on emotional, social, and impulsive factors. To complement the current model, audience barriers to prevention need to be better understood. A content analysis of news source comments in response to daily COVID-19 reports was conducted in Montana, one of the states expressing resistance to routine prevention efforts. A total of 615 Facebook comments drawn from Montana news sources were analyzed using the Persuasive Health Message Framework to identify perceived barriers and benefits of mask-wearing. A majority (63%) of comments expressed barriers, the most common of which were categorized as either misinformation about the virus or conspiracy theories. Benefits (46%) of mask-wearing were articulated as benefits to loved ones or people in one's community or saving hospital space. This paper analyzes the implications of low perceived threat accompanied by low perceived efficacy of mask-wearing to make recommendations for future prevention efforts.
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http://dx.doi.org/10.3390/ijerph18115624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197473PMC
May 2021

De Novo Radiomics Approach Using Image Augmentation and Features From T1 Mapping to Predict Gleason Scores in Prostate Cancer.

Invest Radiol 2021 Oct;56(10):661-668

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health.

Objectives: The aims of this study were to discriminate among prostate cancers (PCa's) with Gleason scores 6, 7, and ≥8 on biparametric magnetic resonance imaging (bpMRI) of the prostate using radiomics and to evaluate the added value of image augmentation and quantitative T1 mapping.

Materials And Methods: Eighty-five patients with subsequently histologically proven PCa underwent bpMRI at 3 T (T2-weighted imaging, diffusion-weighted imaging) with 66 patients undergoing additional T1 mapping at 3 T. The PCa lesions as well as the peripheral and transition zones were segmented pixel by pixel in multiple slices of the 3D MRI data sets (T2-weighted images, apparent diffusion coefficient, and T1 maps). To increase the size of the data set, images were augmented for contrast, brightness, noise, and perspective multiple times, effectively increasing the sample size 10-fold, and 322 different radiomics features were extracted before and after augmentation. Four different machine learning algorithms, including a random forest (RF), stochastic gradient boosting (SGB), support vector machine (SVM), and k-nearest neighbor, were trained with and without features from T1 maps to differentiate among 3 different Gleason groups (6, 7, and ≥8).

Results: Support vector machine showed the highest accuracy of 0.92 (95% confidence interval [CI], 0.62-1.00) for classifying the different Gleason scores, followed by RF (0.83; 95% CI, 0.52-0.98), SGB (0.75; 95% CI, 0.43-0.95), and k-nearest neighbor (0.50; 95% CI, 0.21-0.79). Image augmentation resulted in an average increase in accuracy between 0.08 (SGB) and 0.48 (SVM). Removing T1 mapping features led to a decline in accuracy for RF (-0.16) and SGB (-0.25) and a higher generalization error.

Conclusions: When data are limited, image augmentations and features from quantitative T1 mapping sequences might help to achieve higher accuracy and lower generalization error for classification among different Gleason groups in bpMRI by using radiomics.
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http://dx.doi.org/10.1097/RLI.0000000000000788DOI Listing
October 2021

Gender trends in authorships and publication impact in Academic Radiology-a 10-year perspective.

Eur Radiol 2021 May 19. Epub 2021 May 19.

Charité Universitaetsmedizin Berlin corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Objectives: To analyze the development of publication numbers of female authors in high-, medium-, and low-impact radiological journals.

Methods: In this bibliometric analysis, gender of the first (FA) and senior author (SA) was assigned to all original research articles and reviews, published in 10 high-, medium-, and low-impact radiological journals in 2007/8 and 2017/18. The adjusted event rate (AER) and adjusted odds ratio (AOR) were calculated using mixed logistic and multinomial logistic regression models to assess and compare female publications according to impact factor, journal, author position, and combination.

Results: The proportion of female FA and female SA in N = 6979 (2007/2008) and N = 7383 (2017/2018) articles increased to 29.1% and 16.1% in 2017/2018, respectively. While most female authorships were continuously observed in medium-impact journals, the strongest increase occurred for both female FA (AOR 2.0; p < .0001) and SA (AOR 2.1; p < .0001) in low-impact journals. Female SA published significantly more often in a low- (AOR 1.5) or medium- (AOR 1.8) than in a high-ranking journal. Among the high-ranking journals, female FA published most frequently in European Radiology (32.4%; 95% CI [29.3-35.8]; p < .0001), female SA in Investigative Radiology (15.9%; 95% CI [13.7-18.4]; p < .0001). Male same-sex authorships decreased (AOR 0.9), but remained at least twice as common as all-female or mixed authorships.

Conclusion: The increase in female authorship is reflected in all impact areas. Female FA and SA increased most in low-ranking journals but are most common in medium-ranking journals. Female SA remain rare, especially in high impact journals.

Key Points: • Compared to the proportion of female radiologists worldwide, female senior authors are underrepresented in all impact areas, in particular in high-impact journals. • Among the included high-ranking radiological journals, female first authors and senior authors were strongest represented in European Radiology and Investigative Radiology, while across all impact areas they mostly published in medium-ranking journals. • Female author combinations were more frequent in low- and medium- than in high-ranking journals, whereas male author combinations remained more common than female senior author collaborations in all impact areas.
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http://dx.doi.org/10.1007/s00330-021-07928-4DOI Listing
May 2021

Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model.

Contrast Media Mol Imaging 2021 27;2021:9999847. Epub 2021 Apr 27.

Department of Radiology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Charitéplatz 1, Berlin 10117, Germany.

Background: Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE-/- model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment.

Methods: Nine ApoE-/- mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE-/- animals without doxycycline treatment. Differences in mortality were also investigated between these groups.

Results: In a previous study, we found that approximately 25% of angiotensin II-infused ApoE-/- mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE-/- mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE-/- mice showed significantly lower contrast-to-noise (CNR) values (=0.017) in MRI compared to ApoE-/- mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (  = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment.

Conclusion: The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.
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http://dx.doi.org/10.1155/2021/9999847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099506PMC
April 2021

Time series analysis of the in-hospital diagnostic process in suspected pulmonary embolism evaluated by computed tomography: An explorative study.

Eur J Radiol 2021 Jul 8;140:109758. Epub 2021 May 8.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Purpose: This retrospective study aims to analyze the distribution of demand and the duration of the diagnostic workup of suspected pulmonary embolism (PE) using computed tomography pulmonary angiography (CTPA).

Methods: Time data from physical examination to report creation were identified for each CTPA in 2013 and 2018 at a tertiary hospital. Multivariable multinomial logistic and linear regression models were used to evaluate differences between 3 time intervals (I1: 6am-2pm, I2: 2pm-10pm, I3: 10pm-6am). A cosinor model was applied to analyze the amount of CTPA per hour.

Results: The relative demand for CTPA from the emergency room was lower in l1 compared to l2 and l3 (I1/I2: odds ratio (OR) 0.84, 95 % confidence interval (CI) 0.78-0.91; I1/I3: OR 0.80, 95 % CI 0.72-0.89; peak 4:23 pm). Requests for in-patients displayed a tendency towards I1 (I1/2: OR 1.15, 95 % CI 1.06-1.24; l1/l3: OR 1.19, 95 % CI 1.07-1.33; peak 1:54 pm). The time from CTPA request to study was shorter in I3 compared to I1 and I2 in 2013 (I1/I3: ratio 5.23, 95 % CI 3.38-8.10; I2/I3: ratio 3.50, 95 % CI 2.24-5.45) and 2018 (I1/I3: ratio 2.27, 95 % CI 1.60-3.22; I2/I3: ratio 2.11, 95 % CI 1.50-2.97). This applied similarly to fatal cases (I1/I3: ratio 2.91, 95 % CI 1.78-4.75; I2/I3: ratio 2.45, 95 % CI1.52-3.95).

Conclusions: The temporal distribution of demand for CTPA depends on the sector of patient care and the processing time differs substantially during the day. Time series analysis can reveal such coherences and may help to optimize workflows in radiology departments.
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http://dx.doi.org/10.1016/j.ejrad.2021.109758DOI Listing
July 2021

Deep-Learning-Based Diagnosis of Bedside Chest X-ray in Intensive Care and Emergency Medicine.

Invest Radiol 2021 Aug;56(8):525-534

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Radiology, Berlin, Germany.

Objectives: Validation of deep learning models should separately consider bedside chest radiographs (CXRs) as they are the most challenging to interpret, while at the same time the resulting diagnoses are important for managing critically ill patients. Therefore, we aimed to develop and evaluate deep learning models for the identification of clinically relevant abnormalities in bedside CXRs, using reference standards established by computed tomography (CT) and multiple radiologists.

Materials And Methods: In this retrospective study, a dataset consisting of 18,361 bedside CXRs of patients treated at a level 1 medical center between January 2009 and March 2019 was used. All included CXRs occurred within 24 hours before or after a chest CT. A deep learning algorithm was developed to identify 8 findings on bedside CXRs (cardiac congestion, pleural effusion, air-space opacification, pneumothorax, central venous catheter, thoracic drain, gastric tube, and tracheal tube/cannula). For the training dataset, 17,275 combined labels were extracted from the CXR and CT reports by a deep learning natural language processing (NLP) tool. In case of a disagreement between CXR and CT, human-in-the-loop annotations were used. The test dataset consisted of 583 images, evaluated by 4 radiologists. Performance was assessed by area under the receiver operating characteristic curve analysis, sensitivity, specificity, and positive predictive value.

Results: Areas under the receiver operating characteristic curve for cardiac congestion, pleural effusion, air-space opacification, pneumothorax, central venous catheter, thoracic drain, gastric tube, and tracheal tube/cannula were 0.90 (95% confidence interval [CI], 0.87-0.93; 3 radiologists on the receiver operating characteristic [ROC] curve), 0.95 (95% CI, 0.93-0.96; 3 radiologists on the ROC curve), 0.85 (95% CI, 0.82-0.89; 1 radiologist on the ROC curve), 0.92 (95% CI, 0.89-0.95; 1 radiologist on the ROC curve), 0.99 (95% CI, 0.98-0.99), 0.99 (95% CI, 0.98-0.99), 0.98 (95% CI, 0.97-0.99), and 0.99 (95% CI, 0.98-1.00), respectively.

Conclusions: A deep learning model used specifically for bedside CXRs showed similar performance to expert radiologists. It could therefore be used to detect clinically relevant findings during after-hours and help emergency and intensive care physicians to focus on patient care.
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http://dx.doi.org/10.1097/RLI.0000000000000771DOI Listing
August 2021

Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights.

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Charité-Universitaetsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.
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http://dx.doi.org/10.3390/ijms22052685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962044PMC
March 2021

Hepatic Radiofrequency Ablation: Monitoring of Ablation-Induced Macrophage Recruitment in the Periablational Rim Using SPION-Enhanced Macrophage-Specific Magnetic Resonance Imaging.

Invest Radiol 2021 Sep;56(9):591-598

Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Objectives: Macrophages accumulating in the periablational rim play a pivotal role in initiating and sustaining the perifocal inflammatory reaction, which has been shown to be at least 1 of the mechanisms responsible for the systemic pro-oncogenic effects of focal hepatic radiofrequency ablation (RFA). Herein, we tested the hypothesis to use superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI) for noninvasive quantification of iron-loaded macrophages in the periablational rim of VX2 tumor-bearing rabbits.

Materials And Methods: Twelve VX2 tumor-bearing rabbits underwent MRI immediately after and up to 3 weeks after focal hepatic RFA. For noninvasive quantification of macrophage accumulation in the periablational rim, animals were scanned before and 24 hours after SPION injection. T2*-weighted images were analyzed and correlated with histopathological and immunohistochemical findings. Furthermore, correlations with quantitative measurements (ICP-MS [inductively coupled plasma-mass spectrometry] and LA-ICP-MS [laser ablation-ICP-MS]) were performed.

Results: SPION-enhanced T2*-weighted MRI scans displayed a progressive increase in the areas of signal intensity (SI) loss within the periablational rim peaking 3 weeks after RFA. Accordingly, quantitative analysis of SI changes demonstrated a significant decline in the relative SI ratio reflecting a growing accumulation of iron-loaded macrophages in the rim. Histological analyses confirmed a progressive accumulation of iron-loaded macrophages in the periablational rim. The ICP-MS and LA-ICP-MS confirmed a progressive increase of iron concentration in the periablational rim.

Conclusions: SPION-enhanced MRI enables noninvasive monitoring and quantification of ablation-induced macrophage recruitment in the periablational rim. Given the close interplay between ablation-induced perifocal inflammation and potential unwanted tumorigenic effects of RFA, SPION-enhanced MRI may serve as a valuable tool to guide and modulate adjuvant therapies after hepatic RFA.
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http://dx.doi.org/10.1097/RLI.0000000000000777DOI Listing
September 2021

Elastin-specific MRI of extracellular matrix-remodelling following hepatic radiofrequency-ablation in a VX2 liver tumor model.

Sci Rep 2021 Mar 25;11(1):6814. Epub 2021 Mar 25.

Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 °C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 ± 6.0; gadobutrol: 3.5 ± 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y = 1.2x - 1.8, R = 0.89, p < 0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y = 0.04x + 1.2, R = 0.95, p < 0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim.
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http://dx.doi.org/10.1038/s41598-021-86417-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994448PMC
March 2021

Bilateral rhabdomyolysis of the arms after an extensive horse ride.

Rheumatology (Oxford) 2021 Mar 16. Epub 2021 Mar 16.

Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117.

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http://dx.doi.org/10.1093/rheumatology/keab244DOI Listing
March 2021

A Clinical Practice Guideline for the Use of Ankle-Foot Orthoses and Functional Electrical Stimulation Post-Stroke.

J Neurol Phys Ther 2021 04;45(2):112-196

Department of Physical Therapy, Jefferson College of Rehabilitation Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania and Ossur, Foothill Ranch, California (T.E.J.); Department of Physical Therapy, College of Health Sciences, Midwestern University, Downers Grove, Illinois (S.K.); Kessler Institute for Rehabilitation, Chester, New Jersey (C.D.-W.); and Boston University College of Health and Rehabilitation Sciences: Sargent, Boston, Massachusetts (L.B.).

Background: Level of ambulation following stroke is a long-term predictor of participation and disability. Decreased lower extremity motor control can impact ambulation and overall mobility. The purpose of this clinical practice guideline (CPG) is to provide evidence to guide clinical decision-making for the use of either ankle-foot orthosis (AFO) or functional electrical stimulation (FES) as an intervention to improve body function and structure, activity, and participation as defined by the International Classification of Functioning, Disability and Health (ICF) for individuals with poststroke hemiplegia with decreased lower extremity motor control.

Methods: A review of literature published through November 2019 was performed across 7 databases for all studies involving stroke and AFO or FES. Data extracted included time post-stroke, participant characteristics, device types, outcomes assessed, and intervention parameters. Outcomes were examined upon initial application and after training. Recommendations were determined on the basis of the strength of the evidence and the potential benefits, harm, risks, or costs of providing AFO or FES.

Results/discussion: One-hundred twenty-two meta-analyses, systematic reviews, randomized controlled trials, and cohort studies were included. Strong evidence exists that AFO and FES can each increase gait speed, mobility, and dynamic balance. Moderate evidence exists that AFO and FES increase quality of life, walking endurance, and muscle activation, and weak evidence exists for improving gait kinematics. AFO or FES should not be used to decrease plantarflexor spasticity. Studies that directly compare AFO and FES do not indicate overall superiority of one over the other. But evidence suggests that AFO may lead to more compensatory effects while FES may lead to more therapeutic effects. Due to the potential for gains at any phase post-stroke, the most appropriate device for an individual may change, and reassessments should be completed to ensure the device is meeting the individual's needs.

Limitations: This CPG cannot address the effects of one type of AFO over another for the majority of outcomes, as studies used a variety of AFO types and rarely differentiated effects. The recommendations also do not address the severity of hemiparesis, and most studies included participants with varied baseline ambulation ability.

Summary: This CPG suggests that AFO and FES both lead to improvements post-stroke. Future studies should examine timing of provision, device types, intervention duration and delivery, longer term follow-up, responders versus nonresponders, and individuals with greater impairments.

Disclaimer: These recommendations are intended as a guide for clinicians to optimize rehabilitation outcomes for people with poststroke hemiplegia who have decreased lower extremity motor control that impacts ambulation and overall mobility.A Video Abstract is available as supplemental digital content from the authors (available at: http://links.lww.com/JNPT/A335).
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http://dx.doi.org/10.1097/NPT.0000000000000347DOI Listing
April 2021

Time series analysis of the demand for COVID-19 related chest imaging during the first wave of the SARS-CoV-2 pandemic: An explorative study.

PLoS One 2021 3;16(3):e0247686. Epub 2021 Mar 3.

Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: The aim of this study was to investigate possible patterns of demand for chest imaging during the first wave of the SARS-CoV-2 pandemic and derive a decision aid for the allocation of resources in future pandemic challenges.

Materials And Methods: Time data of requests for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) lung disease were analyzed between February 27th and May 27th 2020. A multinomial logistic regression model was used to evaluate differences in the number of requests between 3 time intervals (I1: 6am - 2pm, I2: 2pm - 10pm, I3: 10pm - 6am). A cosinor model was applied to investigate the demand per hour. Requests per day were compared to the number of regional COVID-19 cases.

Results: 551 COVID-19 related chest imagings (32.8% outpatients, 67.2% in-patients) of 243 patients were conducted (33.3% female, 66.7% male, mean age 60 ± 17 years). Most exams for outpatients were required during I2 (I1 vs. I2: odds ratio (OR) = 0.73, 95% confidence interval (CI) 0.62-0.86, p = 0.01; I2 vs. I3: OR = 1.24, 95% CI 1.04-1.48, p = 0.03) with an acrophase at 7:29 pm. Requests for in-patients decreased from I1 to I3 (I1 vs. I2: OR = 1.24, 95% CI 1.09-1.41, p = 0.01; I2 vs. I3: OR = 1.16, 95% CI 1.05-1.28, p = 0.01) with an acrophase at 12:51 pm. The number of requests per day for outpatients developed similarly to regional cases while demand for in-patients increased later and persisted longer.

Conclusions: The demand for COVID-19 related chest imaging displayed distinct distribution patterns depending on the sector of patient care and point of time during the SARS-CoV-2 pandemic. These patterns should be considered in the allocation of resources in future pandemic challenges with similar disease characteristics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928469PMC
March 2021

Deep learning for accurately recognizing common causes of shoulder pain on radiographs.

Skeletal Radiol 2021 Feb 20. Epub 2021 Feb 20.

Department of Radiology, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.

Objective: Training a convolutional neural network (CNN) to detect the most common causes of shoulder pain on plain radiographs and to assess its potential value in serving as an assistive device to physicians.

Materials And Methods: We used a CNN of the ResNet-50 architecture which was trained on 2700 shoulder radiographs from clinical practice of multiple institutions. All radiographs were reviewed and labeled for six findings: proximal humeral fractures, joint dislocation, periarticular calcification, osteoarthritis, osteosynthesis, and joint endoprosthesis. The trained model was then evaluated on a separate test dataset, which was previously annotated by three independent expert radiologists. Both the training and the test datasets included radiographs of highly variable image quality to reflect the clinical situation and to foster robustness of the CNN. Performance of the model was evaluated using receiver operating characteristic (ROC) curves, the thereof derived AUC as well as sensitivity and specificity.

Results: The developed CNN demonstrated a high accuracy with an area under the curve (AUC) of 0.871 for detecting fractures, 0.896 for joint dislocation, 0.945 for osteoarthritis, and 0.800 for periarticular calcifications. It also detected osteosynthesis and endoprosthesis with near perfect accuracy (AUC 0.998 and 1.0, respectively). Sensitivity and specificity were 0.75 and 0.86 for fractures, 0.95 and 0.65 for joint dislocation, 0.90 and 0.86 for osteoarthrosis, and 0.60 and 0.89 for calcification.

Conclusion: CNNs have the potential to serve as an assistive device by providing clinicians a means to prioritize worklists or providing additional safety in situations of increased workload.
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http://dx.doi.org/10.1007/s00256-021-03740-9DOI Listing
February 2021

Management and Cure of Gouty Arthritis.

Med Clin North Am 2021 Mar 14;105(2):297-310. Epub 2021 Jan 14.

Department of Rheumatic and Immunologic Diseases, The Cleveland Clinic, 9500 Euclid Avenue A50, Cleveland, OH 44915, USA.

Gout is the most common inflammatory arthritis in the United States. Gouty arthritis is associated with significant morbidity and mortality and is caused by hyperuricemia. Gout is effectively managed and potentially cured by decreasing the overall urate burden with serum urate-lowering therapy. When serum urate is maintained at less than 6.0 mg/dL urate deposition is resolved and gout can be cured. Unfortunately, owing to a lack of physician monitoring and dose escalation the majority of patients do not achieve these urate levels.
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http://dx.doi.org/10.1016/j.mcna.2020.09.013DOI Listing
March 2021

Assessment of the hepatic tumor extracellular matrix using elastin-specific molecular magnetic resonance imaging in an experimental rabbit cancer model.

Sci Rep 2020 11 27;10(1):20785. Epub 2020 Nov 27.

Department of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Twelve rabbits with hepatic VX2 tumors were examined using 3 T MRI 14, 21, and 28 days after tumor implantation for two subsequent days (gadobutrol, day 1; elastin-specific probe, day 2). The relative enhancement (RE) of segmented tumor regions (central and margin) and the peritumoral matrix was calculated using pre-contrast and delayed-phase T1w sequences. MRI measurements were correlated to histopathology and element-specific and spatially resolved mass spectrometry (MS). Mixed-model analysis was performed to assess the performance of the elastin-specific probe. In comparison to gadobutrol, the elastin probe showed significantly stronger RE, which was pronounced in the tumor margin (day 14-28: P ≤ 0.007). In addition, the elastin probe was superior in discriminating between tumor regions (χ(4) = 65.87; P < 0.001). MRI-based measurements of the elastin probe significantly correlated with the ex vivo elastinstain (R = .84; P <0 .001) and absolute gadolinium concentrations (ICP-MS: R = .73, P <0 .01). LA-ICP-MS imaging confirmed the colocalization of the elastin-specific probe with elastic fibers. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue.
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http://dx.doi.org/10.1038/s41598-020-77624-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695832PMC
November 2020

Native T1 Mapping Magnetic Resonance Imaging as a Quantitative Biomarker for Characterization of the Extracellular Matrix in a Rabbit Hepatic Cancer Model.

Biomedicines 2020 Oct 13;8(10). Epub 2020 Oct 13.

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

To characterize the tumor extracellular matrix (ECM) using native T1 mapping magnetic resonance imaging (MRI) in an experimental hepatic cancer model, a total of 27 female New Zealand white rabbits with hepatic VX2 tumors were examined by MRI at different time points following tumor implantation (day 14, 21, 28). A steady-state precession readout single-shot MOLLI sequence was acquired in a 3 T MRI scanner in prone position using a head-neck coil. The tumors were segmented into a central, marginal, and peritumoral region in anatomical images and color-coded T1 maps. In histopathological sections, stained with H&E and Picrosirius red, the regions corresponded to central tumor necrosis and accumulation of viable cells with fibrosis in the tumor periphery. Another region of interest (ROI) was placed in healthy liver tissue. T1 times were correlated with quantitative data of collagen area staining. A two-way repeated-measures ANOVA was used to compare cohorts and tumor regions. Hepatic tumors were successfully induced in all rabbits. T1 mapping demonstrated significant differences between the different tumor regions ((1.43,34.26) = 106.93, < 0.001) without interaction effects between time points and regions ((2.86,34.26) = 0.74, = 0.53). In vivo T1 times significantly correlated with ex vivo collagen stains (area %), (center: r = 0.78, < 0.001; margin: r = 0.84, < 0.001; peritumoral: r = 0.73, < 0.001). Post hoc tests using Sidak's correction revealed significant differences in T1 times between all three regions ( < 0.001). Native T1 mapping is feasible and allows the differentiation of tumor regions based on ECM composition in a longitudinal tumor study in an experimental small animal model, making it a potential quantitative biomarker of ECM remodeling and a promising technique for future treatment studies.
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http://dx.doi.org/10.3390/biomedicines8100412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601966PMC
October 2020

Direct imaging of liquid domains in membranes by cryo-electron tomography.

Proc Natl Acad Sci U S A 2020 08 5;117(33):19713-19719. Epub 2020 Aug 5.

Department of Chemistry, University of Washington, Seattle, WA 98195;

Images of micrometer-scale domains in lipid bilayers have provided the gold standard of model-free evidence to understand the domains' shapes, sizes, and distributions. Corresponding techniques to directly and quantitatively assess smaller (nanoscale and submicron) liquid domains have been limited. Researchers commonly seek to correlate activities of membrane proteins with attributes of the domains in which they reside; doing so hinges on identification and characterization of membrane domains. Although some features of membrane domains can be probed by indirect methods, these methods are often constrained by the limitation that data must be analyzed in the context of models that require multiple assumptions or parameters. Here, we address this challenge by developing and testing two methods of identifying submicron domains in biomimetic membranes. Both methods leverage cryo-electron tomograms of ternary membranes under vitrified, hydrated conditions. The first method is optimized for probe-free applications: Domains are directly distinguished from the surrounding membrane by their thickness. This technique quantitatively and accurately measures area fractions of domains, in excellent agreement with known phase diagrams. The second method is optimized for applications in which a single label is deployed for imaging membranes by both high-resolution cryo-electron tomography and diffraction-limited optical microscopy. For this method, we test a panel of probes, find that a trimeric mCherry label performs best, and specify criteria for developing future high-performance, dual-use probes. These developments have led to direct and quantitative imaging of submicron membrane domains in vitrified, hydrated vesicles.
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http://dx.doi.org/10.1073/pnas.2002245117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443872PMC
August 2020

Dementia Diagnosis Documentation in Patients Presenting to the Emergency Department with Chest Pain.

J Am Geriatr Soc 2020 10 4;68(10):2409-2411. Epub 2020 Aug 4.

Health Services and Care Research Program, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

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http://dx.doi.org/10.1111/jgs.16722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718396PMC
October 2020

Using electronic visits (E-visits) to achieve goal serum urate levels in patients with gout in a rheumatology practice: A pilot study.

Semin Arthritis Rheum 2020 12 16;50(6):1382-1386. Epub 2020 Mar 16.

Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Objective: Achieving goal serum urate levels in patients with gout remains difficult in primary care and rheumatology practices. This study measured the ability of an asynchronous electronic visit (E-visit) program to facilitate achieving a goal serum urate (SU) of less than 6.0 mg/dL.

Methods: We performed a retrospective cohort study in a large academic medical center rheumatology practice between April 1, 2017 and May 31, 2018. Patients with gout and SU levels over 6.0 mg/dL were enrolled in an E-visit program and were compared with historical controls who received usual care, matched 1:1 for age and sex. The primary outcome of interest was the proportion of patients achieving SU target of less than 6.0 mg/dL at six months.

Results: Sixty-two patients were enrolled by their rheumatologist in the gout asynchronous E-visit program and were compared to 62 historical controls who were seen within one year prior to E-visit program initiation. Baseline characteristics including age, sex, body mass index, renal function, and initial SU were similar among patients enrolled in the E-visit program and controls. At six months, a significantly higher proportion of patients in the E-visit program achieved goal SU of less than 6.0 mg/dL compared to controls (63.8% vs 33.9%, respectively, p < 0.01), and the E-visit patients had a lower mean SU level than historical controls (5.5 mg/dL versus 6.7 mg/dL, respectively, p < 0.01).

Conclusion: A physician-initiated E-visit program led to a substantial improvement in the rate of achieving goal SU among patients with gout within an academic rheumatology practice.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492421PMC
December 2020

A Step toward Molecular Evolution of RNA: Ribose Binds to Prebiotic Fatty Acid Membranes, and Nucleosides Bind Better than Individual Bases Do.

Chembiochem 2020 10 5;21(19):2764-2767. Epub 2020 Jun 5.

Department of Chemistry, University of Washington, Seattle, WA 98195, USA.

A major challenge in understanding how biological cells arose on the early Earth is explaining how RNA and membranes originally colocalized. We propose that the building blocks of RNA (nucleobases and ribose) bound to self-assembled prebiotic membranes. We have previously demonstrated that the bases bind to membranes composed of a prebiotic fatty acid, but evidence for the binding of sugars has remained a technical challenge. Here, we used pulsed-field gradient NMR spectroscopy to demonstrate that ribose and other sugars bind to membranes of decanoic acid. Moreover, the binding of some bases is strongly enhanced when they are linked to ribose to form a nucleoside or - with the addition of phosphate - a nucleotide. This enhanced binding could have played a role in the molecular evolution leading to the production of RNA.
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http://dx.doi.org/10.1002/cbic.202000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654510PMC
October 2020

Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole.

Dalton Trans 2020 May;49(20):6616-6626

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 μM and no toxicity to mammalian cells (IC50 >100 μM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.
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http://dx.doi.org/10.1039/d0dt01107jDOI Listing
May 2020

Quantitative MRI for Assessment of Treatment Outcomes in a Rabbit VX2 Hepatic Tumor Model.

J Magn Reson Imaging 2020 09 12;52(3):668-685. Epub 2019 Nov 12.

Department of Radiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Globally, primary and secondary liver cancer is one of the most common cancer types, accounting 8.2% of deaths worldwide in 2018. One of the key strategies to improve the patient's prognosis is the early diagnosis, when liver function is still preserved. In hepatocellular carcinoma (HCC), the typical wash-in/wash-out pattern in conventional magnetic resonance imaging (MRI) reaches a sensitivity of 60% and specificity of 96-100%. However, in recent years functional MRI sequences such as hepatocellular-specific gadolinium-based dynamic-contrast enhanced MRI, diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) have been demonstrated to improve the evaluation of treatment success and thus the therapeutic decision-making and the patient's outcome. In the preclinical research setting, the VX2 liver rabbit tumor, which once originated from a virus-induced anaplastic squamous cell carcinoma, has played a longstanding role in experimental interventional oncology. Especially the high tumor vascularity allows assessing the treatment response of locoregional interventions such as radiofrequency ablation (RFA) and transcatheter arterial embolization (TACE). Functional MRI has been used to monitor the tumor growth and viability following interventional treatment. Besides promising results, a comprehensive overview of functional MRI sequences used so far in different treatment setting is lacking, thus lowering the comparability of study results. This review offers a comprehensive overview of study protocols, results, and limitations of quantitative MRI sequences applied to evaluate the treatment outcome of VX2 hepatic tumor models, thus generating a unique basis for future MRI studies and potential translation into the clinical setting. Level of Evidence: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2020;52:668-685.
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http://dx.doi.org/10.1002/jmri.26968DOI Listing
September 2020

Hinged and Wide: A New P^P Ligand for Emissive [Cu(P^P)(N^N)][PF] Complexes.

Molecules 2019 Oct 31;24(21). Epub 2019 Oct 31.

Department of Chemistry, University of Basel, BPR 1096, Mattenstrasse 24a, CH-4058 Basel, Switzerland.

Heteroleptic [Cu(BIPHEP)(N^N)][PF] complexes (BIPHEP = 1,1'-biphenyl-2,2'-diylbis(diphenylphosphane)), in which N^N is 2,2'-bipyridine (bpy), 6-methyl-2,2'-bipyridine (6-Mebpy), 6-ethyl-2,2'-bipyridine (6-Etbpy), or 5,5'-dimethyl-2,2'-bipyridine (5,5'-Mebpy), have been synthesized and characterized using multinuclear NMR spectroscopies and electrospray ionization mass spectrometry. The single crystal structures of [Cu(BIPHEP)(bpy)][PF]∙CHCl, [Cu(BIPHEP)(5,5'-Mebpy)][PF]∙CHCl, [Cu(BIPHEP)(6-Mebpy)][PF]∙EtO∙0.5HO and [Cu(BIPHEP)(6-Etbpy)][PF] confirm distorted tetrahedral {Cu(P^P)(N^N)} coordination environments. Each compound shows a quasi-reversible Cu/Cu process. In deaerated solution, the compounds are weak emitters. Powdered samples are yellow emitters ( in the range 558-583 nm) and [Cu(BIPHEP)(5,5'-Mebpy)][PF] exhibits the highest photoluminescence quantum yield (PLQY = 14%). On cooling to 77 K (frozen 2-methyloxolane), the emission maxima are red-shifted and the excited state lifetimes increase from < 8 μs, to values of up to 53 μs, consistent with the compounds with N^N = 6-Mebpy, 6-Etbpy and 5,5'-Mebpy exhibiting thermally activated delayed fluorescence (TADF).
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http://dx.doi.org/10.3390/molecules24213934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864541PMC
October 2019

Prebiotic amino acids bind to and stabilize prebiotic fatty acid membranes.

Proc Natl Acad Sci U S A 2019 08 12;116(35):17239-17244. Epub 2019 Aug 12.

Department of Chemistry, University of Washington, Seattle, WA 98195;

The membranes of the first protocells on the early Earth were likely self-assembled from fatty acids. A major challenge in understanding how protocells could have arisen and withstood changes in their environment is that fatty acid membranes are unstable in solutions containing high concentrations of salt (such as would have been prevalent in early oceans) or divalent cations (which would have been required for RNA catalysis). To test whether the inclusion of amino acids addresses this problem, we coupled direct techniques of cryoelectron microscopy and fluorescence microscopy with techniques of NMR spectroscopy, centrifuge filtration assays, and turbidity measurements. We find that a set of unmodified, prebiotic amino acids binds to prebiotic fatty acid membranes and that a subset stabilizes membranes in the presence of salt and Mg Furthermore, we find that final concentrations of the amino acids need not be high to cause these effects; membrane stabilization persists after dilution as would have occurred during the rehydration of dried or partially dried pools. In addition to providing a means to stabilize protocell membranes, our results address the challenge of explaining how proteins could have become colocalized with membranes. Amino acids are the building blocks of proteins, and our results are consistent with a positive feedback loop in which amino acids bound to self-assembled fatty acid membranes, resulting in membrane stabilization and leading to more binding in turn. High local concentrations of molecular building blocks at the surface of fatty acid membranes may have aided the eventual formation of proteins.
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http://dx.doi.org/10.1073/pnas.1900275116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717294PMC
August 2019
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