Refine
Year of publication
Document Type
- Article (12) (remove)
Language
- English (12)
Has Fulltext
- yes (12)
Is part of the Bibliography
- no (12)
Keywords
- 900 GeV (1)
- ALICE (1)
- ATO (1)
- Animal behavior (1)
- Animal personality (1)
- Anterior cruciate ligament (1)
- Assortative mating (1)
- Bone density (1)
- Bone disease (1)
- CAC-DRS Score (1)
Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
(2019)
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
The existence of individual variation in males' motivation to mate remains a conundrum as directional selection should favour high mating frequencies. Balancing selection resulting from (context-dependent) female mate choice could contribute to the maintenance of this behavioural polymorphism. In dichotomous choice tests, mosquitofish (Gambusia holbrooki) females preferred virtual males showing intermediate mating frequencies, reflecting females' tendencies to avoid harassment by highly sexually active males. When tested in the presence of a female shoal—which protects females from male harassment—focal females showed significantly stronger preferences for high sexual activity. A trade-off between (indirect) benefits and (direct) costs of mating with sexually active males probably explains context-dependent female mate choice, as costs depend on the social environment in which females choose their mates. No preference was observed when we tested virgin females, suggesting that the behavioural pattern described here is part of the learned behavioural repertoire of G. holbrooki females.
Highlights
• Early reconstruction of injured cruciate ligaments improves functional outcomes.
• Modern CT imaging can be used to rapidly identify patients with injury to the cruciate ligaments and streamline therapeutic pathways.
• Dual-energy CT demonstrates superior diagnostic accuracy compared to single-energy CT.
Abstract
Background: This study aimed to evaluate the clinical utility of modern single and dual-energy computed tomography (CT) for assessing the integrity of the cruciate ligaments in patients that sustained acute trauma.
Methods: Patients who underwent single- or dual-energy CT followed by 3 Tesla magnetic resonance imaging (MRI) or knee joint arthroscopy between 01/2016 and 12/2022 were included in this retrospective, monocentric study. Three radiologists specialized in musculoskeletal imaging independently evaluated all CT images for the presence of injury to the cruciate ligaments. An MRI consensus reading of two experienced readers and arthroscopy provided the reference standard. Diagnostic accuracy parameters and area under the receiver operator characteristic curve (AUC) were the primary metrics for diagnostic performance.
Results: CT images of 204 patients (median age, 49 years; IQR 36 – 64; 113 males) were evaluated. Dual-energy CT yielded significantly higher diagnostic accuracy and AUC for the detection of injury to the anterior (94% [240/255] vs 75% [266/357] and 0.89 vs 0.66) and posterior cruciate ligaments (95% [243/255] vs 87% [311/357] and 0.90 vs 0.61) compared to single-energy CT (all parameters, p <.005). Diagnostic confidence and image quality were significantly higher in dual-energy CT compared to single-energy CT (all parameters, p <.005).
Conclusions: Modern dual-energy CT is readily available and can serve as a screening tool for detecting or excluding cruciate ligament injuries in patients with acute trauma. Accurate diagnosis of cruciate ligament injuries is crucial to prevent adverse outcomes, including delayed treatment, chronic instability, or long-term functional limitations.
Background: One aspect of premating isolation between diverging, locally-adapted population pairs is female mate choice for resident over alien male phenotypes. Mating preferences often show considerable individual variation, and whether or not certain individuals are more likely to contribute to population interbreeding remains to be studied. In the Poecilia mexicana-species complex different ecotypes have adapted to hydrogen sulfide (H2S)-toxic springs, and females from adjacent non-sulfidic habitats prefer resident over sulfide-adapted males. We asked if consistent individual differences in behavioral tendencies (animal personality) predict the strength and direction of the mate choice component of premating isolation in this system.
Results: We characterized focal females for their personality and found behavioral measures of ‘novel object exploration’, ‘boldness’ and ‘activity in an unknown area’ to be highly repeatable. Furthermore, the interaction term between our measures of exploration and boldness affected focal females’ strength of preference (SOP) for the resident male phenotype in dichotomous association preference tests. High exploration tendencies were coupled with stronger SOPs for resident over alien mating partners in bold, but not shy, females. Shy and/or little explorative females had an increased likelihood of preferring the non-resident phenotype and thus, are more likely to contribute to rare population hybridization. When we offered large vs. small conspecific stimulus males instead, less explorative females showed stronger preferences for large male body size. However, this effect disappeared when the size difference between the stimulus males was small.
Conclusions: Our results suggest that personality affects female mate choice in a very nuanced fashion. Hence, population differences in the distribution of personality types could be facilitating or impeding reproductive isolation between diverging populations depending on the study system and the male trait(s) upon which females base their mating decisions, respectively.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
The plastids of cryptophytes, haptophytes, and heterokontophytes (stramenopiles) (together once known as chromists) are surrounded by four membranes, reflecting the origin of these plastids through secondary endosymbiosis. They share this trait with apicomplexans, which are alveolates, the plastids of which have been suggested to stem from the same secondary symbiotic event and therefore form a phylogenetic clade, the chromalveolates. The chromists are quantitatively the most important eukaryotic contributors to primary production in marine ecosystems. The mechanisms of protein import across their four plastid membranes are still poorly understood. Components of an endoplasmic reticulum-associated degradation (ERAD) machinery in cryptophytes, partially encoded by the reduced genome of the secondary symbiont (the nucleomorph), are implicated in protein transport across the second outermost plastid membrane. Here, we show that the haptophyte Emiliania huxleyi, like cryptophytes, stramenopiles, and apicomplexans, possesses a nuclear-encoded symbiont-specific ERAD machinery (SELMA, symbiont-specific ERAD-like machinery) in addition to the host ERAD system, with targeting signals that are able to direct green fluorescent protein or yellow fluorescent protein to the predicted cellular localization in transformed cells of the stramenopile Phaeodactylum tricornutum. Phylogenies of the duplicated ERAD factors reveal that all SELMA components trace back to a red algal origin. In contrast, the host copies of cryptophytes and haptophytes associate with the green lineage to the exclusion of stramenopiles and alveolates. Although all chromalveolates with four membrane-bound plastids possess the SELMA system, this has apparently not arisen in a single endosymbiotic event. Thus, our data do not support the chromalveolate hypothesis. Key words: Emiliania huxleyi, secondary endosymbiosis, chromalveolate, hypothesis, complex plastid, plastid protein import, algal evolution
Background: Dual-energy CT (DECT)-derived bone mineral density (BMD) of the distal radius and other CT-derived metrics related to bone health have been suggested for opportunistic osteoporosis screening and risk evaluation for sustaining distal radius fractures (DRFs).
Methods: The distal radius of patients who underwent DECT between 01/2016 and 08/2021 was retrospectively analyzed. Cortical Hounsfield Unit (HU), trabecular HU, cortical thickness, and DECT-based BMD were acquired from a non-fractured, metaphyseal area in all examinations. Receiver-operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC) values for predicting DRFs based on DECT-derived BMD, HU values, and cortical thickness. Logistic regression models were then employed to assess the associations of these parameters with the occurrence of DRFs.
Results: In this study, 263 patients (median age: 52 years; interquartile range: 36–64; 132 women; 192 fractures) were included. ROC curve analysis revealed a higher area under the curve (AUC) value for DECT-derived BMD compared to cortical HU, trabecular HU, and cortical thickness (0.91 vs. 0.61, 0.64, and 0.69, respectively; p <.001). Logistic regression models confirmed the association between lower DECT-derived BMD and the occurrence of DRFs (Odds Ratio, 0.83; p <.001); however, no influence was observed for cortical HU, trabecular HU, or cortical thickness.
Conclusions: DECT can be used to assess the BMD of the distal radius without dedicated equipment such as calibration phantoms to increase the detection rates of osteoporosis and stratify the individual risk to sustain DRFs. In contrast, assessing HU-based values and cortical thickness does not provide clinical benefit.
Highlights
• Assessment of coronary artery plaque burden according to the CAC-DRS Score correlated well with pulmonary involvement of SARS-CoV-2 pneumonia (min. r=0.81, 95% CI 0.76 to 0.86).
• Visual and quantitative CAC-DRS Score of coronary artery plaque burden provided independent prognostic information on all-cause mortality in patients with SARS-CoV-2 pneumonia (p=0.0016 and p<0.0001, respectively).
• Incorporating CAC-DRS Score and pulmonary involvement into clinical decision making revealed great potential to discriminate patients with fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89 to 0.97) and the need for intensive care treatment (AUC 0.801, 95% CI 0.77 to 0.83).
Purpose: To assess and correlate pulmonary involvement and outcome of SARS-CoV-2 pneumonia with the degree of coronary plaque burden based on the CAC-DRS classification (Coronary Artery Calcium Data and Reporting System).
Methods: This retrospective study included 142 patients with confirmed SARS-CoV-2 pneumonia (58 ± 16 years; 57 women) who underwent non-contrast CT between January 2020 and August 2021 and were followed up for 129 ± 72 days. One experienced blinded radiologist analyzed CT series for the presence and extent of calcified plaque burden according to the visual and quantitative HU-based CAC-DRS Score. Pulmonary involvement was automatically evaluated with a dedicated software prototype by another two experienced radiologists and expressed as Opacity Score.
Results: CAC-DRS Scores derived from visual and quantitative image evaluation correlated well with the Opacity Score (r=0.81, 95% CI 0.76-0.86, and r=0.83, 95% CI 0.77-0.89, respectively; p<0.0001) with higher correlation in severe than in mild stage SARS-CoV-2 pneumonia (p<0.0001). Combined, CAC-DRS and Opacity Scores revealed great potential to discriminate fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89-0.97), and the need for intensive care treatment (AUC 0.801, 95% CI 0.77-0.83). Visual and quantitative CAC-DRS Scores provided independent prognostic information on all-cause mortality (p=0.0016 and p<0.0001, respectively), both in univariate and multivariate analysis.
Conclusions: Coronary plaque burden is strongly correlated to pulmonary involvement, adverse outcome, and death due to respiratory failure in patients with SARS-CoV-2 pneumonia, offering great potential to identify individuals at high risk.
Consistent individual differences in behavioral tendencies (animal personality) can affect individual mate choice decisions. We asked whether personality traits affect male and female mate choice decisions similarly and whether potential personality effects are consistent across different mate choice situations. Using western mosquitofish (Gambusia affinis) as our study organism, we characterized focal individuals (males and females) twice for boldness, activity, and sociability/shoaling and found high and significant behavioral repeatability. Additionally, each focal individual was tested in two different dichotomous mate choice tests in which it could choose between computer-animated stimulus fish of the opposite sex that differed in body size and activity levels, respectively. Personality had different effects on female and male mate choice: females that were larger than average showed stronger preferences for large-bodied males with increasing levels of boldness/activity (i.e., towards more proactive personality types). Males that were larger than average and had higher shoaling tendencies showed stronger preferences for actively swimming females. Size-dependent effects of personality on the strength of preferences for distinct phenotypes of potential mating partners may reflect effects of age/experience (especially in females) and social dominance (especially in males). Previous studies found evidence for assortative mate choice based on personality types or hypothesized the existence of behavioral syndromes of individuals’ choosiness across mate choice criteria, possibly including other personality traits. Our present study exemplifies that far more complex patterns of personality-dependent mate choice can emerge in natural systems.
Purpose: To evaluate the prevalence and treatment patterns of speech and language disorders in Germany.
Methods: A retrospective analysis of data collected from 32% of the German population, insured by the statutory German health insurance (AOK, Local Health Care Funds). We used The International Statistical Classification of Diseases and Related Health Problems, 10th revision, German Modification (ICD-10 GM) codes for stuttering (F98.5), cluttering (F98.6), and developmental disorders of speech and language (F80) to identify prevalent and newly diagnosed cases each year. Prescription and speech therapy reimbursement data were used to evaluate treatment patterns.
Results: In 2017, 27,977 patients of all ages were diagnosed with stuttering (21,045 males, 75% and 6,932 females, 25%). Stuttering prevalence peaks at age 5 years (boys, 0.89% and girls, 0.40%). Cluttering was diagnosed in 1,800 patients of all ages (1,287 males, 71.5% and 513 females, 28.5%). Developmental disorders of speech and language were identified in 555,774 AOK-insurants (61.2% males and 38.8% females). Treatment data indicate a substantial proportion newly diagnosed stuttering individuals receive treatment (up to 45% of 6-year-old patients), with slightly fewer than 20 sessions per year, on average. We confirmed a previous study showing increased rates of atopic disorders and neurological and psychiatric comorbidities in individuals with stuttering, cluttering, and developmental disorders of speech and language.
Conclusion: This is the first nationwide study using health insurance data to analyze the prevalence and newly diagnosed cases of a speech and language disorder. Prevalence and gender ratio data were consistent with the international literature. The crude prevalence of developmental disorders of speech and language increased from 2015 to 2018, whereas the crude prevalence for stuttering remained stable. For cluttering, the numbers were too low to draw reliable conclusions. Proportional treatment allocation for stuttering peaked at 6 years of age, which is the school entrance year, and is later than the prevalence peak of stuttering.