CIC/ATXN1 ‐rearranged tumors in the central nervous system are mainly represented by sarcomas: A comprehensive clinicopathological and epigenetic series

Abstract CIC fusions have been described in two different central nervous system (CNS) tumor entities. On one hand, fusions of CIC or ATXN1 genes belonging to the same complex of transcriptional repressors, were reported in the CIC‐ rearranged, sarcoma (SARC ‐CIC ). The diagnosis of this tumor type, which was recently added to the World Health Organization (WHO) Classification of CNS tumors, is difficult mainly because the data concerning its histopathology (as compared to its soft tissue counterpart), immunoprofile, and clinical as well as radiological characteristics are scarce in the literature. On the other hand, a recent study, based on DNA‐methylation profiling, has identified a novel high‐grade neuroepithelial tumor characterized by recurrent CIC fusions (HGNET‐ CIC ). The aim of this multicentric study was to characterize a cohort of 15 primary CNS tumors harboring a CIC or ATXN1 fusion in terms of clinical, radiological, histopathological, immunophenotypical, and epigenetic characteristics. According to the integrated diagnoses, 14/15 tumors corresponded to SARC ‐CIC, and only one to HGNET‐ CIC . The tumors showed similar clinical (mainly pediatric), radiological (mostly supratentorial, cystic, and contrast enhancing), immunophenotypical (common expression of glioneuronal markers), and genetic (similar spectrum of fusions) profiles but their histopathological appearance was clearly distinct. Moreover, we found a novel fusion transcript ( CIC::EWSR1 ) in a SARC‐ CIC. Most DNA methylation profiles using the Heidelberg Brain Tumor Classifier (v12.8) annotated the samples to the methylation class “SARC‐ CIC ” (9/14 tumors with available data). By using uniform manifold approximation and projection analysis, four other samples were classified as SARC‐ CIC and another clustered within the methylation class of HGNET‐ CIC . Our findings confirm that CNS CIC ‐fused tumors do not represent a single molecular tumor entity. Further analyses are needed to characterize HGNET‐ CIC in more detail. These results may help to refine the essential diagnostic criteria for SARC‐ CIC and their terminology (with a suggested consensual name of sarcoma, CIC/ATXN1‐ complex rearranged).

The endocannabinoid anandamide mediates anti‐inflammatory effects through activation of NR4A nuclear receptors

Background and purpose Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N‐arachidonoyl‐ethanolamine (anandamide, AEA), this has been linked to an anti‐inflammatory function. In this study, we set out to determine the anti‐inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells. Experimental approach RNA‐sequencing, RT‐qPCR, LC‐MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used. Key results AEA pretreatment attenuated the cytokine‐mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti‐inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA‐mediated anti‐inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C‐DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression. Conclusion and implications By binding to NR4A, AEA elicits an anti‐inflammatory response in vascular smooth muscle cells. NR4A‐binding by AEA analogues may represent novel anti‐inflammatory agents.

Insight into structural properties of viral G protein‐coupled receptors and their role in the viral infection: IUPHAR Review 41

G protein‐coupled receptors (GPCRs) are pivotal in cellular signalling and drug targeting. Herpesviruses encode GPCRs (vGPCRs) to manipulate cellular signalling, thereby regulating various aspects of the virus life cycle, such as viral spreading and immune evasion. vGPCRs mimic host chemokine receptors, often with broader signalling and high constitutive activity. This review focuses on the recent advancements in structural knowledge about vGPCRs, with an emphasis on molecular mechanisms of action and ligand binding. The structures of US27 and US28 from human cytomegalovirus (HCMV) are compared to their closest human homologue, CX 3 CR1. Contrasting US27 and US28, the homotrimeric UL78 structure (HCMV) reveals more distance to chemokine receptors. Open reading frame 74 (ORF74; Kaposi's sarcoma‐associated herpesvirus) is compared to CXCRs, whereas BILF1 (Epstein–Barr virus) is discussed as a putative lipid receptor. Furthermore, the roles of vGPCRs in latency and lytic replication, reactivation, dissemination and immune evasion are reviewed, together with their potential as drug targets for virus infections and virus‐related diseases.

The intricate relationship between stress and animal welfare: from historical perspective to new avenues

ABSTRACT We discuss the intricate relationship between the evolution of the concept of stress and the development of the concept of animal welfare. After a brief review of the main concepts of animal welfare, we analyse important steps in the evolution of the concept of stress, starting from the mechanistic approach of the General Adaptation Syndrome to the recent integrative allostatic theory. We show how, over time, each concept of stress has informed the development of the concept of animal welfare. We discuss the role of emotions and affective states in the response of animals to challenges and how psychological stress is integral to the welfare of animals. Lastly, we discuss briefly the potential role of the gut–brain axis in both the concept of stress and the concept of welfare.

Structure and Stability of Lemur‐Tree Ecological Networks Across Primary and Secondary Forests

ABSTRACT Forest degradation is disrupting species interactions, altering the structure and stability of ecological communities. Understanding the organization of species interactions across human‐modified landscapes is urgent in biodiverse areas experiencing major conservation threats, such as Madagascar. In both primary and secondary forests in northeast Madagascar, we investigated lemur‐tree network structure and stability. We combined ethnobiological data (interviews with 81 local knowledge holders) with direct observations during field work to construct ecological networks representing frugivory, herbivory, and seed predation. In a multilayer approach, we examined interactions both within and between forest types. We found that primary forest networks supported substantially higher interaction abundances, diversity, and evenness compared to secondary forest networks. There were also differences in structure across interaction types; for example, herbivory networks had a more modular structure than frugivory or seed predation networks. Simulated species extirpation showed that primary forests were more stable to perturbations than secondary forests or multilayer systems, even after accounting for how lemurs likely adjust their diets as plants go locally extinct (i.e., interaction rewiring). While seven lemur species connected primary and secondary forests, multilayer networks were consistently less stable than single‐layer networks, emphasizing the likely vulnerability of human‐modified landscapes to environmental change and the ecological importance of species that connect the primary and secondary forest networks.

Risk Factors for Fatal and Near‐Fatal Food Anaphylaxis: Analysis of the Allergy‐Vigilance Network Database

ABSTRACT Background Gaining a better understanding of the risk factors for severe anaphylaxis represents a crucial challenge for physicians. This survey aimed to analyse cases of severe food anaphylaxis and assess potential risk factors for severity. Methods We retrospectively analysed food anaphylaxis cases recorded by the French‐speaking Allergy‐Vigilance Network (2002–2021) and compared the main characteristics of grade 3 (Ring classification) and grade 4 cases using univariate and multivariate statistical analyses. Results Of the 2621 food anaphylaxis cases reported, 731 (27.9%) were considered severe (grade 3, n  = 687 [94%] and grade 4, n  = 44 [6%]; 19 deaths). Overall, 56.1% of cases were adults (mean age: 28.3 years) and 53.7% were male. The most frequent triggers were peanut (13.9%), wheat (9.4%), cashew (5.8%), shrimp (5.3%), and cow's milk (4.6%). More grade 4 anaphylaxis cases occurred in children than in adults (26 vs. 18; p  = 0.01). In univariate analysis, individuals with grade 4 anaphylaxis were more likely to have a history of allergy to the culprit food (71.1% vs. 42.1%; p  < 0.001), asthma diagnosis (59.5% vs. 30.4%; p  < 0.001), and peanut as the culprit food (34.1% vs. 12.6%; p  < 0.001). In multivariate analysis, factors predictive of grade 4 anaphylaxis were asthma diagnosis (OR [95% CI]: 3.41 [1.56–7.44]; p  = 0.002) and peanut as the culprit trigger (OR [95% CI]: 3.46 [1.28–9.34]; p  = 0.014). Conclusions Our data highlight the risk factors for severe food anaphylaxis, notably a history of asthma and peanut as the culprit food. These individuals should benefit from personalised management strategies.

Food Anaphylaxis: Eight Food Allergens Without Mandatory Labelling Highlighted by the French Allergy‐Vigilance Network

ABSTRACT Background The European Regulation list on mandatory labelling of foods includes 14 allergenic foods; however, other foods are also frequently implicated in food‐induced anaphylaxis (FIA). Methods We analysed FIA cases reported to the Allergy Vigilance Network from 2002 to 2023. Allergenic foods involved in ≥ 1% of cases and not included in the list were assessed as emerging food allergens (EFA). We assessed their frequency, severity (Ring classification), recurrence, and potential presence in hidden form to determine which allergens might warrant inclusion on the list. Results Among 2999 FIA cases (Ring grades 2–4), 413 cases (13.8%) met the selection criteria, divided into eight allergenic foods or food groups: goat's and sheep's milk (GSM, n  = 84; 2.8% of the cases), buckwheat ( n  = 71; 2.4%), peas and lentil ( n  = 55; 1.8%), alpha‐gal ( n  = 50; 1.7%), pine nut ( n  = 49; 1.6%), kiwi ( n  = 44; 1.5%), beehive products ( n  = 30; 1.0%), and apple ( n  = 30; 1.0%). Severe reactions (Ring grades 3 and 4) were reported with GSM (46.8% and 4.8%, respectively, including two fatalities), buckwheat (46.5% and1.4%), peas‐lentil (20% and 1.8%), alpha‐gal (54% and 8%), and Grade 3 reactions were reported with pine nut in 49%, kiwi 54.5%, beehive products 33.3% and apple 46.7%. Recurrent reactions and hidden exposures were reported with GSM (56% and 15.5%), buckwheat (49.3% and 16.9%), peas‐lentil (7.3% and 9.0%) and pine nut (12.2% and 4.1%). Conclusion We identified eight foods frequently involved in FIA and not currently listed in the European regulation. Given their frequency, severity, recurrence, and potential for hidden exposure, we propose that four—goat's and sheep's milk, buckwheat, peas‐lentil, and pine nut—be considered for inclusion in the list.

Transitional implants in computer‐assisted implant surgery and fixed complete‐arch provisionalization: A retrospective case series

Abstract Introduction Using mini implants as transitional implants (TIs) for complete arch implant‐supported rehabilitations may overcome limitations associated with mucosa‐supported surgical guides and facilitate immediate fixed provisionalization. This study aimed to assess the success of TIs in supporting surgical guides for implant placement and fixed provisional prostheses. Methods Patients who received TIs between 2012 and 2023 for a complete arch implant‐supported prosthesis were evaluated retrospectively. Patient demographic data, TI functionality in supporting a surgical guide and supporting a complete arch provisional prosthesis, and dates of TI placement and regular implant placement were collected. Descriptive statistics were used to determine the survival rate and success rate for TIs. Results Twenty‐six patients, 35 jaws, 136 TIs, and 216 regular implants were included. The survival rate of TIs was 74.26%; however, the use of TIs yielded success in 97% of jaws for supporting a surgical guide and a fixed complete‐arch provisional prosthesis throughout the complete provisional phase. An average of 4 TIs per maxilla and 3 TIs per mandible supported surgical guides. Thirty‐five provisional prostheses were placed on an average of 4 TIs in the maxilla and 3 TIs in the mandible. Thirty‐four provisional prostheses were successfully supported by TIs and regular implants until final restoration delivery. The survival of regular implants placed in conjunction with the use of TIs was 98%. Conclusions Using TIs to support a surgical guide and provisional prosthesis may be a predictable approach with a high success rate. All surgical guides planned to be supported on TIs were successful. Despite premature loss or replacement of TIs, this approach was able to support most provisional prostheses until the regular implants could be loaded.

Feasibility of Indocyanine Green Fluorescence Endoscopic Assisted Resection of Sinonasal Tumours

Improving obesity management: Insights from the ACTION Switzerland survey of people with obesity, physicians and dietitians

Summary ACTION Switzerland (NCT05232786) examined obesity‐related perceptions, attitudes, behaviours and potential barriers to treatment among people with obesity (PwO) and healthcare professionals (HCPs). In March/April 2022, adult PwO (body mass index ≥30 kg/m 2 , per self‐reported height/weight) and physicians/certified dietitians who manage PwO in Switzerland completed online surveys in a cross‐sectional design. Overall, 1002 PwO, 125 physicians and 25 dietitians completed the survey. Most physicians (97%) and dietitians (100%), but only 57% of PwO, recognized obesity as a chronic disease. Only 42% of PwO considered themselves to have obesity/extreme obesity, while 61% who had discussed weight with an HCP reported receiving an obesity diagnosis. Many PwO (76%) believed weight loss was entirely their responsibility; physicians were less likely than dietitians to agree it was completely their patients' responsibility (28% vs. 68%). Physicians and dietitians report primarily initiating conversations about weight when patients have obesity‐related comorbidities (85% and 64%); their top reasons for not discussing obesity were patients' perceived lack of motivation (76% and 60%) or interest (72% and 64%) in losing weight. In conclusion, some PwO are not aware that obesity is a chronic disease and incorrectly assume complete responsibility for weight loss. Improved communication between PwO and HCPs is required.