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- Institute of Cancer Research (ICR) London (1)
Simple Summary
FAP-targeted radiotracers, recently introduced in cancer treatment, accumulate in Cancer-Associated Fibroblasts (CAFs). CAFs are present in tumor lesions but do not correspond to genuine cancer cells, although they behave in an abnormal and disease-promoting manner. One of their characteristic features, the expression of the surface protein FAP, can be utilized to discriminate between cancerous and healthy tissues. By the choice of an appropriate radionuclide, FAP-targeted tracers can be used for imaging or therapy in many cancer types. Therefore, the first successful application of FAP-targeted imaging has led to an enormous and growing interest in nuclear medicine and radiopharmacy.
Abstract
Targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs) has attracted significant attention in nuclear medicine. Since these cells are present in most cancerous tissues and FAP is rarely expressed in healthy tissues, anti-FAP tracers have a potential as pan-tumor agents. Compared to the standard tumor tracer [\(^{18}\)F]FDG, these tracers show better tumor-to-background ratios (TBR) in many indications. Unlike [\(^{18}\)F]FDG, FAP-targeted tracers do not require exhausting preparations, such as dietary restrictions on the part of the patient, and offer the possibility of radioligand therapy (RLT) in a theragnostic approach. Although a radiolabeled antibody was clinically investigated as early as the 1990s, the breakthrough event for FAP-targeting in nuclear medicine was the introduction and clinical application of the so-called FAPI-tracers in 2018. From then, the development and application of FAP-targeted tracers became hot topics for the radiopharmaceutical and nuclear medicine community, and attracted the interest of pharmaceutical companies. The aim of this review is to provide a comprehensive overview of the development of FAP-targeted radiopharmaceuticals and their application in nuclear medicine.
Body representations are readily expanded based on sensorimotor experience. A dynamic view of body representations, however, holds that these representations cannot only be expanded but that they can also be narrowed down by disembodying elements of the body representation that are no longer warranted. Here we induced illusory ownership in terms of a moving rubber hand illusion and studied the maintenance of this illusion across different conditions. We observed ownership experience to decrease gradually unless participants continued to receive confirmatory multisensory input. Moreover, a single instance of multisensory mismatch – a hammer striking the rubber hand but not the real hand – triggered substantial and immediate disembodiment. Together, these findings support and extend previous theoretical efforts to model body representations through basic mechanisms of multisensory integration. They further support an updating model suggesting that embodied entities fade from the body representation if they are not refreshed continuously.
Arapaima gigas is one of the largest freshwater fish species of high ecological and economic importance. Overfishing and habitat destruction are severe threats to the remaining wild populations. By incorporating a chromosomal Hi-C contact map, we improved the arapaima genome assembly to chromosome-level, revealing an unexpected high degree of chromosome rearrangements during evolution of the bonytongues (Osteoglossiformes). Combining this new assembly with pool-sequencing of male and female genomes, we identified id2bbY, a duplicated copy of the inhibitor of DNA binding 2b (id2b) gene on the Y chromosome as candidate male sex-determining gene. A PCR-test for id2bbY was developed, demonstrating that this gene is a reliable male-specific marker for genotyping. Expression analyses showed that this gene is expressed in juvenile male gonads. Its paralog, id2ba, exhibits a male-biased expression in immature gonads. Transcriptome analyses and protein structure predictions confirm id2bbY as a prime candidate for the master sex-determiner. Acting through the TGF beta signaling pathway, id2bbY from arapaima would provide the first evidence for a link of this family of transcriptional regulators to sex determination. Our study broadens our current understanding about the evolution of sex determination genetic networks and provide a tool for improving arapaima aquaculture for commercial and conservation purposes.
Treatment-induced neuropathy in diabetes (TIND) — Developing a disease model in type 1 diabetic rats
(2021)
Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.
This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1–1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42–0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.
Background
Breast cancer (BC), which is most common in elderly women, requires a multidisciplinary and continuous approach to care. With demographic changes, the number of patients with chronic diseases such as BC will increase. This trend will especially hit rural areas, where the majority of the elderly live, in terms of comprehensive health care.
Methods
Accessibility to several cancer facilities in Bavaria, Germany, was analyzed with a geographic information system. Facilities were identified from the national BC guideline and from 31 participants in a proof‐of‐concept study from the Breast Cancer Care for Patients With Metastatic Disease registry. The timeframe for accessibility was defined as 30 or 60 minutes for all population points. The collection of address information was performed with different sources (eg, a physician registry). Routine data from the German Census 2011 and the population‐based Cancer Registry of Bavaria were linked at the district level.
Results
Females from urban areas (n = 2,938,991 [ie, total of females living in urban areas]) had a higher chance for predefined accessibility to the majority of analyzed facilities in comparison with females from rural areas (n = 3,385,813 [ie, total number of females living in rural areas]) with an odds ratio (OR) of 9.0 for cancer information counselling, an OR of 17.2 for a university hospital, and an OR of 7.2 for a psycho‐oncologist. For (inpatient) rehabilitation centers (OR, 0.2) and genetic counselling (OR, 0.3), women from urban areas had lower odds of accessibility within 30 or 60 minutes.
Conclusions
Disparities in accessibility between rural and urban areas exist in Bavaria. The identification of underserved areas can help to inform policymakers about disparities in comprehensive health care. Future strategies are needed to deliver high‐quality health care to all inhabitants, regardless of residence.
The high diversity of insects has limited the volume of long-term community data with a high taxonomic resolution and considerable geographic replications, especially in forests. Therefore, trends and causes of changes are poorly understood. Here we analyse trends in species richness, abundance and biomass of nocturnal macro moths in three quantitative data sets collected over four decades in forests in southern Germany. Two local data sets, one from coppiced oak forests and one from high oak forests included 125K and 48K specimens from 559 and 532 species, respectively. A third regional data set, representing all forest types in the temperate zone of central Europe comprised 735K specimens from 848 species. Generalized additive mixed models revealed temporal declines in species richness (−38%), abundance (−53%) and biomass (−57%) at the regional scale. These were more pronounced in plant host specialists and in dark coloured species. In contrast, the local coppiced oak forests showed an increase, in species richness (+62%), while the high oak forests showed no clear trends. Left and right censoring as well as cross validation confirmed the robustness of the analyses, which led to four conclusions. First, the decline in insects appears in hyper diverse insect groups in forests and affects species richness, abundance and biomass. Second, the pronounced decline in host specialists suggests habitat loss as an important driver of the observed decline. Third, the more severe decline in dark species might be an indication of global warming as a potential driver. Fourth, the trends in coppiced oak forests indicate that maintaining complex and diverse forest ecosystems through active management may be a promising conservation strategy in order to counteract negative trends in biodiversity, alongside rewilding approaches.
Modulating emotional responses to virtual stimuli is a fundamental goal of many immersive interactive applications. In this study, we leverage the illusion of illusory embodiment and show that owning a virtual body provides means to modulate emotional responses. In a single-factor repeated-measures experiment, we manipulated the degree of illusory embodiment and assessed the emotional responses to virtual stimuli. We presented emotional stimuli in the same environment as the virtual body. Participants experienced higher arousal, dominance, and more intense valence in the high embodiment condition compared to the low embodiment condition. The illusion of embodiment thus intensifies the emotional processing of the virtual environment. This result suggests that artificial bodies can increase the effectiveness of immersive applications psychotherapy, entertainment, computer-mediated social interactions, or health applications.
Vocalization is an important part of social communication, not only for humans but also for mice. Here, we show in a mouse model that functional deficiency of Sprouty-related EVH1 domain-containing 2 (SPRED2), a protein ubiquitously expressed in the brain, causes differences in social ultrasound vocalizations (USVs), using an uncomplicated and reliable experimental setting of a short meeting of two individuals. SPRED2 mutant mice show an OCD-like behaviour, accompanied by an increased release of stress hormones from the hypothalamic–pituitary–adrenal axis, both factors probably influencing USV usage. To determine genotype-related differences in USV usage, we analyzed call rate, subtype profile, and acoustic parameters (i.e., duration, bandwidth, and mean peak frequency) in young and old SPRED2-KO mice. We recorded USVs of interacting male and female mice, and analyzed the calls with the deep-learning DeepSqueak software, which was trained to recognize and categorize the emitted USVs. Our findings provide the first classification of SPRED2-KO vs. wild-type mouse USVs using neural networks and reveal significant differences in their development and use of calls. Our results show, first, that simple experimental settings in combination with deep learning are successful at identifying genotype-dependent USV usage and, second, that SPRED2 deficiency negatively affects the vocalization usage and social communication of mice.
This study examines the relationship between variations of the Southern Annular Mode (SAM) and black carbon (BC) at 550 nm aerosol optical depth (AOD) in the Western Cape province (WC). Variations of the positive (negative) phase of the SAM are found to be related to regional circulation types (CTs) in southern Africa, associated with suppressed (enhanced) westerly wind over the WC through the southward (northward) migration of Southern Hemisphere mid-latitude cyclones. The CTs related to positive (negative) SAM anomalies induce stable (unstable) atmospheric conditions over the southwestern regions of the WC, especially during the austral winter and autumn seasons. Through the control of CTs, positive (negative) SAM phases tend to contribute to the build-up (dispersion and dilution) of BC in the study region because they imply dry (wet) conditions which favor the build-up (washing out) of pollutant particles in the atmosphere. Indeed, recent years with an above-average frequency of CTs related to positive (negative) SAM anomalies are associated with a high (low) BC AOD over southwesternmost Africa.
High‐Sensitivity Cardiac Troponin T and Recurrent Vascular Events After First Ischemic Stroke
(2021)
Background
Recent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high‐sensitivity cardiac troponin T (hs‐cTnT) are associated with recurrent vascular events and death in patients with first‐ever, mild to moderate ischemic stroke.
Methods and Results
We used data from the PROSCIS‐B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs‐cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all‐cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs‐cTnT above upper reference limit, 39.2%). During a mean follow‐up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all‐cause death. The primary outcome occurred more often in patients with hs‐cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3–3.3), with a dose‐response relationship when the highest and lowest hs‐cTnT quartiles were compared (15.2 versus 1.8 events per 100 person‐years; adjusted hazard ratio, 4.8; 95% CI, 1.9–11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex.
Conclusions
Hs‐cTnT is dose‐dependently associated with an increased risk of recurrent vascular events and death within 3 years after first‐ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs‐cTnT for individualized risk stratification after stroke.
Due to the lack of data on asymptomatic SARS-CoV-2-positive persons in healthcare institutions, they represent an inestimable risk. Therefore, the aim of the current study was to evaluate the first 1,000,000 reported screening tests of asymptomatic staff, patients, residents, and visitors in hospitals and long-term care (LTC) facilities in the State of Bavaria over a period of seven months. Data were used from the online database BayCoRei (Bavarian Corona Screening Tests), established in July 2020. Descriptive analyses were performed, describing the temporal pattern of persons that tested positive for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) or antigen tests, stratified by facility. Until 15 March 2021, this database had collected 1,038,146 test results of asymptomatic subjects in healthcare facilities (382,240 by RT-PCR, and 655,906 by antigen tests). Of the RT-PCR tests, 2.2% (n = 8380) were positive: 3.0% in LTC facilities, 2.2% in hospitals, and 1.2% in rehabilitation institutions. Of the antigen tests, 0.4% (n = 2327) were positive: 0.5% in LTC facilities, and 0.3% in both hospitals and rehabilitation institutions, respectively. In LTC facilities and hospitals, infection surveillance using RT-PCR tests, or the less expensive but less sensitive, faster antigen tests, could facilitate the long-term management of the healthcare workforce, patients, and residents.
Background
Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting.
Objectives
To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10–17 years.
Methods
In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10–17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician’s Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82.
Results
At week 20, 55% [95% confidence interval (CI) 0·44–0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08–0·33) in the placebo group (absolute difference 36%, 95% CI 0·20–0·53; P < 0·001). In total, 42% (95% CI 0·32–0·53) in the FAE group vs. 7% (95% CI 0·01–0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21–0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events.
Conclusions
FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.
The bounded input bounded output (BIBO) stability for a nonlinear Caputo fractional system with time‐varying bounded delay and nonlinear output is studied. Utilizing the Razumikhin method, Lyapunov functions and appropriate fractional derivatives of Lyapunov functions some new bounded input bounded output stability criteria are derived. Also, explicit and independent on the initial time bounds of the output are provided. Uniform BIBO stability and uniform BIBO stability with input threshold are studied. A numerical simulation is carried out to show the system's dynamic response, and demonstrate the effectiveness of our theoretical results.
The observation of electromagnetic counterparts to both high energy neutrinos and gravitational waves marked the beginning of a new era in astrophysics. The multi-messenger approach allows us to gain new insights into the most energetic events in the Universe such as gamma-ray bursts, supernovas, and black hole mergers. Real-time multi-messenger alerts are the key component of the observational strategies to unravel the transient signals expected from astrophysical sources. Focusing on the high-energy regime, we present a historical perspective of multi-messenger observations, the detectors and observational techniques used to study them, the status of the multi-messenger alerts and the most significant results, together with an overview of the future prospects in the field.
Biological soil crusts (BSCs) are thin microbiological vegetation layers that naturally develop in unfavorable higher plant conditions (i.e., low precipitation rates and high temperatures) in global drylands. They consist of poikilohydric organisms capable of adjusting their metabolic activities depending on the water availability. However, they, and with them, their ecosystem functions, are endangered by climate change and land-use intensification. Remote sensing (RS)-based studies estimated the BSC cover in global drylands through various multispectral indices, and few of them correlated the BSCs’ activity response to rainfall. However, the allocation of BSCs is not limited to drylands only as there are areas beyond where smaller patches have developed under intense human impact and frequent disturbance. Yet, those areas were not addressed in RS-based studies, raising the question of whether the methods developed in extensive drylands can be transferred easily. Our temperate climate study area, the ‘Lieberoser Heide’ in northeastern Germany, is home to the country’s largest BSC-covered area. We applied a Random Forest (RF) classification model incorporating multispectral Sentinel-2 (S2) data, indices derived from them, and topographic information to spatiotemporally map the BSC cover for the first time in Central Europe. We further monitored the BSC response to rainfall events over a period of around five years (June 2015 to end of December 2020). Therefore, we combined datasets of gridded NDVI as a measure of photosynthetic activity with daily precipitation data and conducted a change detection analysis. With an overall accuracy of 98.9%, our classification proved satisfactory. Detected changes in BSC activity between dry and wet conditions were found to be significant. Our study emphasizes a high transferability of established methods from extensive drylands to BSC-covered areas in the temperate climate. Therefore, we consider our study to provide essential impulses so that RS-based biocrust mapping in the future will be applied beyond the global drylands.
Semi-arid tree covers, in both high and coppice growth forms, play an essential role in protecting water and soil resources and provides multiple ecosystem services across fragile ecosystems. Thus, they require continuous inventories. Quantification of forest structure in these tree covers provides important measures for their management and biodiversity conservation. We present a framework, based on consumer-grade UAV photogrammetry, to separately estimate primary variables of tree height (H) and crown area (A) across diverse coppice and high stands dominated by Quercus brantii Lindl. along the latitudinal gradient of Zagros mountains of western Iran. Then, multivariate linear regressions were parametrized with H and A to estimate the diameter at breast height (DBH) of high trees because of its importance to accelerate the existing practical DBH inventories across Zagros Forests. The estimated variables were finally applied to a model tree aboveground biomass (AGB) for both vegetative growth forms by local allometric equations and Random Forest models. In each step, the estimated variables were evaluated against the field reference values, indicating practically high accuracies reaching root mean square error (RMSE) of 0.68 m and 4.74 cm for H and DBH, as well as relative RMSE < 10% for AGB estimates. The results generally suggest an effective framework for single tree-based attribute estimation over mountainous, semi-arid coppice, and high stands.
Earth observation time series are well suited to monitor global surface dynamics. However, data products that are aimed at assessing large-area dynamics with a high temporal resolution often face various error sources (e.g., retrieval errors, sampling errors) in their acquisition chain. Addressing uncertainties in a spatiotemporal consistent manner is challenging, as extensive high-quality validation data is typically scarce. Here we propose a new method that utilizes time series inherent information to assess the temporal interpolation uncertainty of time series datasets. For this, we utilized data from the DLR-DFD Global WaterPack (GWP), which provides daily information on global inland surface water. As the time series is primarily based on optical MODIS (Moderate Resolution Imaging Spectroradiometer) images, the requirement of data gap interpolation due to clouds constitutes the main uncertainty source of the product. With a focus on different temporal and spatial characteristics of surface water dynamics, seven auxiliary layers were derived. Each layer provides probability and reliability estimates regarding water observations at pixel-level. This enables the quantification of uncertainty corresponding to the full spatiotemporal range of the product. Furthermore, the ability of temporal layers to approximate unknown pixel states was evaluated for stratified artificial gaps, which were introduced into the original time series of four climatologic diverse test regions. Results show that uncertainty is quantified accurately (>90%), consequently enhancing the product's quality with respect to its use for modeling and the geoscientific community.
As a promising biofabrication technology, extrusion-based bioprinting has gained significant attention in the last decade and major advances have been made in the development of bioinks. However, suitable synthetic and stimuli-responsive bioinks are underrepresented in this context. In this work, we described a hybrid system of nanoclay Laponite XLG and thermoresponsive block copolymer poly(2-methyl-2-oxazoline)-b-poly(2-n-propyl-2-oxazine) (PMeOx-b-PnPrOzi) as a novel biomaterial ink and discussed its critical properties relevant for extrusion-based bioprinting, including viscoelastic properties and printability. The hybrid hydrogel retains the thermogelling properties but is strengthened by the added clay (over 5 kPa of storage modulus and 240 Pa of yield stress). Importantly, the shear-thinning character is further enhanced, which, in combination with very rapid viscosity recovery (~ 1 s) and structure recovery (~ 10 s), is highly beneficial for extrusion-based 3D printing. Accordingly, various 3D patterns could be printed with markedly enhanced resolution and shape fidelity compared to the biomaterial ink without added clay.