Benefits of Psychological Androgyny in Adolescence: The Role of Gender Role Self-Concept in School-Related Well-Being

It has been repeatedly shown that the extent to which individuals adopt stereotypically masculine and feminine traits in their self-concept impacts their health and well-being. This is especially important in adolescence, when developmental changes and social pressures to conform to stereotypical gender roles can affect psychological functioning. However, previous studies investigating relationship between gender role self-concept and well-being in adolescents focused mostly on general well-being rather than well-being in specific contexts. Given that school is one of the most important contexts for adolescents’ development and well-being, the aim of this study was to investigate differences between adolescents with different gender role self-concepts (masculine, feminine, androgynous and undifferentiated) in school-related well-being. In line with the new conceptualization of well-being uniting hedonic (pleasure attainment and pain avoidance) and eudemonic (self-actualization and having meaningful purpose in one’s life) approaches, the present study used a measure of school-related well-being encompassing five domains suggested in the EPOCH (Engagement, Perseverance, Optimism, Connectedness and Happiness) model as well as a superordinate well-being factor. A total of 999 Austrian adolescents (52.2% girls, M(age) = 13.79, SD(age) = 1.53) answered inventories assessing adolescents’ gender role self-concept (GRI-JUG) and school-related well-being (EPOCH-G-S). The results supported the androgyny model of well-being, showing clear advantages of having both positive masculine and feminine qualities in one’s self-concept for optimal levels of school-related well-being. In addition, our results indicated the strong importance of femininity in adolescence and the school context. Theoretical and practical implications are discussed

Daratumumab for autoimmune diseases: a systematic review

Objective Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases.Methods A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome.Results 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%).Conclusion Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogues. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors

Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument

The p53–MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein–protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53–MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53–MDM2 inhibitor that recently entered phase I clinical trial

Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes

Hdm2 (human MDM2) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Here, we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds. We also reveal the key additive 18-crown-ether, which we have discovered to enable HdmX crystallization and show its stabilization of various Lys-residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insights into the possible adaptations and structural states of Hdm2 (e.g. flip of F55; flip of Y67; reorientation of H96) and HdmX (e.g. flip of H55; dimer induction), enabling key binding interactions for different compound classes. In order to make comparisons easier, we have used the same numbering for Hdm2 and HdmX. Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors

PAX8 and MECOM are interaction partners driving Ovarian Carcinogenesis

The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian carcinogenesis. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. This includes PRDM3 (also called MDS1-EVI1) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulate a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, PTXs and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in Ovarian Cancers and we show that the MECOM locus and PAX8 sustain in-vivo ovarian cancer growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer

Long-term safety of COVID vaccination in individuals with idiopathic inflammatory myopathies: results from the COVAD study

Limited evidence on long-term COVID-19 vaccine safety in patients with idiopathic inflammatory myopathies (IIMs) continues to contribute to vaccine hesitancy. We studied delayed-onset vaccine adverse events (AEs) in patients with IIMs, other systemic autoimmune and inflammatory disorders (SAIDs), and healthy controls (HCs), using data from the second COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. A validated self-reporting e-survey was circulated by the COVAD study group (157 collaborators, 106 countries) from Feb-June 2022. We collected data on demographics, comorbidities, IIM/SAID details, COVID-19 history, and vaccination details. Delayed-onset (> 7 day) AEs were analyzed using regression models. A total of 15165 respondents undertook the survey, of whom 8759 responses from vaccinated individuals [median age 46 (35-58) years, 74.4% females, 45.4% Caucasians] were analyzed. Of these, 1390 (15.9%) had IIMs, 50.6% other SAIDs, and 33.5% HCs. Among IIMs, 16.3% and 10.2% patients reported minor and major AEs, respectively, and 0.72% (n = 10) required hospitalization. Notably patients with IIMs experienced fewer minor AEs than other SAIDs, though rashes were expectedly more than HCs [OR 4.0; 95% CI 2.2-7.0, p < 0.001]. IIM patients with active disease, overlap myositis, autoimmune comorbidities, and ChadOx1 nCOV-19 (Oxford/AstraZeneca) recipients reported AEs more often, while those with inclusion body myositis, and BNT162b2 (Pfizer) recipients reported fewer AEs. Vaccination is reassuringly safe in individuals with IIMs, with AEs, hospitalizations comparable to SAIDs, and largely limited to those with autoimmune multimorbidity and active disease. These observations may inform guidelines to identify high-risk patients warranting close monitoring in the post-vaccination period