Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor ...type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2
induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2
rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.
INTRODUCTION
Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma ...phosphorylated tau 217 (p‐tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.
METHODS
We employed a novel p‐tau217 immunoassay (University of Gothenburg UGOT p‐tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker‐classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population‐based cohort of individuals with SCD (Barcelonaβeta Brain Research Center's Alzheimer's At‐Risk Cohort β‐AARC).
RESULTS
UGOT p‐tau217 showed high accuracy (area under the curve AUC = 0.80–0.91) identifying amyloid beta (Aβ) pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p‐tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC = 0.91).
DISCUSSION
UGOT p‐tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
The main objective of this review is to give a general overview of the structure, electrochemistry (when available), and catalytic performance of the Ru complexes, which are capable of oxidizing ...water to molecular dioxygen, and to highlight their more relevant features. The description of the Ru catalysts is mainly divided into complexes that contain a Ru−O−Ru bridging group and those that do not. Finally a few conclusions are drawn from the global description of all of the catalysts presented here, and some guidelines for future catalyst design are given.
Neovascular age-related macular degeneration (nAMD) leads to severe and permanent visual impairment, significantly impacting patients' quality of life and functional independence. Although treatment ...with anti- vascular endothelial growth factor (VEGF) prevents and, in some cases, reverses visual damage, the need for frequent monitoring visits and intravitreal injections represents a significant burden on patients, caregivers and retina specialists.
To elicit preferences for nAMD treatment characteristics from the perspectives of patients and retina specialists.
A discrete choice experiment was conducted. Participants (patients > 50 years with nAMD receiving anti-VEGF drugs for at least 2 years and without previous experience with anti-VEGF and retina specialists working in the Spanish National Healthcare System) were asked to select one of two hypothetical treatments resulting from the combination of five attributes (effects on visual function, effects on retinal fluid, treatment regimen, monitoring frequency, and cost); their levels were identified by reviewing the literature and two focus groups. The relative importance (RI) given to each attribute was estimated using a mixed logit model. The marginal rates of substitution (MRS) were calculated taking cost as the risk attribute.
A total of 110 patients (P) aged 79.0 (SD:7.4) years; 57.3% women; 2.3 (SD:0.7) years with nAMD; 2.1 years (SD:0.1) in treatment and 66 retina specialists (RS) participated in the study. Participants gave greater RI to improvements in their visual function 60.0% (P); 52.7% (RS), lower monitoring frequency 20.2% (P); 27.1% (RS) and reduction in retinal fluid 9.8% (P); 13.0%(RS). Patients and retina specialists would agree to an increase in cost by 65.0% and 56.5%, respectively, in exchange for improvements of visual function; and 25.5% and 43.3% on delaying monitoring frequency by one month.
Efficacy of treatment, in terms of visual function improvements, is the main driver for treatment election for both patients and retina specialists. Treatment monitoring requirements are also considered, mainly from the retina specialist's perspective. These results suggest that the use of more efficacious anti-VEGF agents with a longer duration of action may contribute to aligning treatment characteristics with patients/specialists' preferences. A better alignment would facilitate better disease management, fulfilling the unmet needs of patients and retina specialists.
Dog-assisted therapy (DAT) has shown benefits in people with mental health disorders. A child psychiatric day hospital would be a suitable setting to implement DAT and evaluate the benefits in a ...pediatric population. Methods: Mixed methods research in a naturalistic setting was considered in this pre-post quantitative study including 23 children under 13 treated in a day hospital over 2 years. Quantitative analysis included the number of emotional and behavioral outbursts and attendance rate and self-control and social impairment questionnaires completed by family members and therapists. In the qualitative study, the experiences of 12 mental health professionals involved in DAT were documented through semi-structured interviews. Results: On DAT days, there were fewer emotional and behavioral outbursts and higher attendance. Significant differences were obtained between pre- and post-test scores on the SCRS and the SRS-2 completed by the therapists, while no significant differences were obtained on the questionnaires completed by the parents. Observations based on the qualitative study were as follows: (1) DAT improves emotional self-regulation; (2) DAT could facilitate the work of therapists in day hospitals; (3) health professionals displayed uncertainty due to a lack of familiarity with DAT. Conclusions: DAT improved emotional self-regulation, attendance rate and self-control and social response in children with mental disorders attending a day hospital.
Purpose
The many studies examining the relationship between anorexia nervosa (AN) and personality abnormalities have observed high comorbidity. However, no definitive studies to date have established ...whether there is a causal connection or whether it is a complication. The current study aimed to explore the nature of the relationship between personality disorder (PD) traits, obsessionality and perfectionism, using a study design that allows the testing of some comorbidity models.
Methods
Twenty-nine women were recruited from a group of former AN patients treated during their adolescence in a specialized unit around 20 years before the time of this study. They were divided into two groups according to the current presence of eating disorder (ED) symptoms (current-ED,
n
= 11; recovered,
n
= 18). Both groups were compared to a matched control group (
n
= 29) regarding current PD traits, obsessive beliefs and perfectionism.
Results
Borderline PD traits, most cluster C PD traits and overestimation of threat were more common in the current-ED group than in the control and recovered groups. Obsessive–compulsive PD traits, intolerance of uncertainty, and perfectionism were also significantly more prevalent in the current-ED group compared to controls but did not reach significance when compared to the recovered group. No significant differences were found between the recovered and control groups.
Conclusion
Our results mostly support the personality abnormalities observed as a transient effect related to the presence of ED psychopathology in patients with adolescent-onset AN.
Level of evidence
Level III, case–control analytic studies.
Using commercially available automated insulin delivery (AID) systems for treating type 1 diabetes during pregnancy remains controversial. This retrospective study assessed six pregnant women with ...type 1 diabetes who underwent AID therapy. Our observations revealed that AID treatment, in most cases, did not achieve the desired glycemic targets for pregnancy.
Aim
Species biogeography mainly focuses on palaeogeographical events, while environmental factors are generally overlooked despite their importance in species diversification. Here, we use an ...integrative approach to understand how palaeogeographical and environmental processes shape species distribution and focus on freshwater planarians as the model system.
Location
Western Mediterranean.
Taxon
Dugesia.
Methods
We inferred the phylogenetic relationships of most known Dugesia species in the area using six molecular markers. We then estimated their divergence times and reconstructed their ancestral distribution ranges. We also performed environmental niche modelling analyses using Dugesia subtentaculata as a model to evaluate the effects of several hydro‐environmental variables and the likely existence of interspecific competition on Dugesia distributions.
Results
Our results provide a new phylogenetic scheme for Dugesia from the Western Mediterranean and show that the time splits between the lineages and their putative ancestral distribution ranges are correlated with microplate tectonic dynamics within the region during the Oligocene–Miocene period. Our environmental niche modelling analyses indicate that the type of land cover and the slope of the terrain are the most important abiotic factors driving the distribution of Dugesia from this region. Finally, we found a partial niche overlap between D. subtentaculata and two other common planarian species from the Iberian Peninsula.
Main conclusions
The microplate tectonic dynamics of the Western Mediterranean during the Oligocene–Miocene period, together with the position of the mountain ranges and posterior climate changes, may have played crucial roles in driving the biogeographical history of Dugesia in this region. Moreover, both interspecific competition and changes in fluvial characteristics driven by human activities may affect the current diversity and distribution of Dugesia in the Western Mediterranean. This study highlights the importance of integrating different types of information to study the biogeographical history of a species.
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