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Chromosomal translocations constitute driver mutations in solid tumors and leukemias. The mechanisms of how related or even identical gene fusions drive the pathogenesis of various tumor types remain elusive. One remarkable example is the presence of EWSR1 fusions with CREB1 and ATF1 , members of the CREB family of transcription factors, in a variety of sarcomas, carcinomas and mesotheliomas. To address this, we have developed in vitro models of oncogenic fusions, in particular, EWSR1-CREB1 and EWSR1-ATF1 , in human embryonic stem (hES) cells, which are capable of multipotent differentiation, using CRISPR-Cas9 technology and HDR together with conditional fusion gene expression that allows investigation into the early steps of cellular transformation. We show that expression of EWSR1-CREB1/ATF1 fusion in hES cells recapitulates the core gene signatures, respectively, of angiomatoid fibrous histiocytoma (AFH) and gastrointestinal clear cell sarcoma (GI-CCS), although both fusions lead to cell lethality. Conversely, expression of the fusions in hES cells differentiated to mesenchymal progenitors is compatible with prolonged viability while maintaining the core gene signatures. Moreover, in the context of a mesenchymal lineage, the proliferation of cells expressing the EWSR1-CREB1 fusion is further extended by deletion of the tumor suppressor TP53 . We expect the generation of isogenic lines carrying oncogenic fusions in various cell lineages to expand our general understanding of how those single genetic events drive tumorigenesis while providing valuable resources for drug discovery.

The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has led to new personalized therapies in oncology. Recent studies investigating NTRK fusions among mesenchymal neoplasms have identified several emerging soft tissue tumor entities displaying various phenotypes and clinical behaviors. Among them, tumors resembling lipofibromatosis or malignant peripheral nerve sheath tumors often harbor intra-chromosomal NTRK1 rearrangements, while most infantile fibrosarcomas are characterized by canonical ETV6::NTRK3 fusions. However, appropriate cellular models to investigate mechanisms of how kinase oncogenic activation through gene fusions drives such a wide spectrum of morphology and malignancy are lacking. Progress in genome editing has facilitated the efficient generation of chromosomal translocations in isogenic cell lines. In this study we employ various strategies to model NTRK fusions, including LMNA::NTRK1 (interstitial deletion) and ETV6::NTRK3 (reciprocal translocation) in human embryonic stem (hES) cells and mesenchymal progenitors (hES-MP). Here, we undertake various methods to model non-reciprocal, intrachromosomal deletions/translocations by induction of DNA double strand breaks (DSBs) exploiting either the repair mechanisms of homology directed repair (HDR) or non-homologous end joining (NHEJ). Expression of LMNA::NTRK1 or ETV6::NTRK3 fusions in either hES cells or hES-MP did not affect cell proliferation. However, the level of mRNA expression of the fusion transcripts was significantly upregulated in hES-MP, and phosphorylation of the LMNA::NTRK1 fusion oncoprotein was noted only in hES-MP but not in hES cells. Similarly, an NTRK1-driven transcriptional profile related to neuronal and neuroectodermal lineage was upregulated mainly in hES-MP, supporting the importance of appropriate cellular context in modeling cancer relevant aberrations. As proof of concept of the validity of our in vitro models, phosphorylation was depleted by two TRK inhibitors, Entrectinib and Larotrectinib, currently used as targeted therapy for tumors with NTRK fusions.

Seminal fluid RNA is essential for embryonic development, but the mechanism by which extracellular RNA is transferred from seminal fluid to sperm remains unclear. Here, we identify a role for functional amyloid fibrils in seminal fluid that bind and traffic RNA to mammalian sperm and, upon fertilization, the zygote. We show that highly cationic peptides in seminal fluid phase separate with RNA to form amyloid fibrils. Cryo-electron tomography reveals that these amyloid fibrils are internalized by sperm. Furthermore, biophysical and fertilization experiments show that amyloid-bound RNA reaches the zygote where molecular chaperones control release of RNA for translation. Our work uncovers a mechanism for RNA trafficking from seminal fluid to the zygote, establishing amyloid fibrils as potential tools for RNA delivery during fertilization.

It's not easy for one body to accommodate the imputes of both Ebenezer Scrooge and Santa Claus, but Philip Johnston was in town Thursday talking about how he does it.

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients’ and clinicians’ values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

The Interior of Alaska is one of the few remaining places in the world with intact ecosystems. Protected areas in this region, particularly Denali National Park and Preserve and Denali State Park, are high-profile tourism destinations situated in a rural landscape that is inhabited by a diverse array of stakeholders. Public land management agencies are faced with the challenging task of engaging these rural residents in discussions about their relationships with a rapidly changing landscape to understand change and growth. This study evaluated residents’ perceptions of social and ecological dynamics of protected areas in Interior Alaska using data from fuzzy cognitive mapping exercises that were part of focus groups and interviews across six local communities. Guided by an exploratory resilience framework, we established a baseline understanding of features that characterized social and ecological conditions at a regional scale. Results showed how residents valued a variety of socio-cultural, socioeconomic, and ecological features of the landscape. The region was predominantly characterized by tourism, sense of community, subsistence, and wilderness. Climate change and large-scale development were the primary drivers of change. Our findings also showed that although the characterization of the region was shared in many ways, there were nuanced differences articulated by residents in each community that warrant attention. These findings provide a structured platform for building resilience and interpreting variability in visions for the future.

Objective: The aim was to determine the impact of PMR on intimate and sexual relationships over time. Methods: The PMR Cohort study is a longitudinal study of patients with incident PMR in English primary care. Participants were sent questionnaires about their PMR symptoms, treatments and overall health, including an item about how their PMR symptoms affected intimate and sexual relationships. The proportions reporting the relevance of intimate and sexual relationships, the effect of PMR on these relationships and the associations with PMR symptoms and general health were explored. Results: The baseline survey was completed by 652 of 739 patients (response 90.1%), with 446 of 576 (78.0%) responding at 2 years. The mean age of respondents was 72.4 years, and 62.2% were female. At baseline, 363 of 640 (56.7%) respondents reported that intimate and sexual relationships were not relevant to them. One hundred and thirteen of 277 (40.8%) respondents reported that PMR had a large effect on intimate relationships. This proportion decreased over time in those responding to 12- and 24-month surveys, but continued to be associated with younger age, male gender, worse PMR symptoms, poorer physical function and worse mental health. Conclusion: Intimate and sexual relationships are increasingly recognized as important for healthy ageing, and health professionals should consider this as part of a holistic approach to the management of PMR. Study registration: UKCRN ID16477. Lay summary What does this mean for patients? Polymyalgia rheumatica (PMR) is a condition that affects older people. It causes pain and stiffness in the hips and shoulders and makes people feel very tired. It can stop people from doing routine things that they previously did with no problem (e.g. walking upstairs, getting out of a car). We know very little about how PMR affects people's personal lives. Therefore, we sent a questionnaire to 652 people in England with newly diagnosed PMR. One question asked people whether their PMR affected their 'intimate and sexual relationships'. We asked the same question again 1 and 2 years later. Just over half of people said this was not relevant for them. For those people to whom it mattered, 4 in 10 said that PMR had a large effect on their relationships. Men, people who were younger, those with worse PMR symptoms and those with worse mental health were more likely to report a negative effect of PMR on their relationships. The proportion of people reporting a problem reduced over time, as their PMR symptoms improved. We suggest that doctors should consider people's intimate and sexual relationships as part of their care for people with PMR. Keywords: PMR, primary health care, cohort study, sexual relationships

Background To examine the frequency of possible giant cell arteritis (GCA) symptoms (including headache, temporal/scalp tenderness, jaw claudication and visual symptoms) in newly diagnosed polymyalgia rheumatica (PMR) patients in UK primary care. Methods The PMR Cohort Study is a primary care inception cohort of 652 adults with newly diagnosed polymyalgia rheumatica (PMR). At baseline, participants were asked to report (yes/no) on the presence of seven potential GCA symptoms: sudden headache, tender scalp, disturbed/double vision, jaw claudication, fever, appetite loss and unintentional weight loss. Results Of the 652 patients, 405 (62%) were female, with a mean (SD) age of 72.5 (8.9) years. Sudden headache was the commonest symptom in 161 patients (24.7%). The least commonly reported symptom was jaw claudication in 66 (10.1%) patients. Females had a higher prevalence of headache, tender scalp and jaw pain. Sudden onset headache and fever were commoner in younger patients, (OR (95% CI) per 10 year age band increase: headache 0.76 (0.62–0.92), fever 0.63 (0.49, 0.79)). In those reporting sudden headache ( n  = 161), 19.9% ( n  = 32) also reported double/disturbed vision and a tender scalp, whilst 11.8% ( n  = 19) reported double/disturbed vision and jaw pain. Conclusion The data suggests possible GCA symptoms are common in PMR patients, particularly sudden headache, appetite loss and weight loss. These symptomatic PMR patients warrant careful monitoring and consideration for early referral to specialist services.

Objectives: To understand why some family practices with a facilitator improved preventive performance more than others. Sustainability of practice improvements one year after the intervention was also explored. Methods: Interviews with physicians and nurses from seven practices and data gathered during the intervention were used to form case studies of three high performing and four low performing family practices. Case studies were developed using cross-case analysis with a combination of the constant-comparative method and memoing-diagramming. Two researchers independently conducted in-depth coding of transcripts and documents, individual case construction for each study site, and then cross-case analysis of the identified themes between study sites. Results: Staff involvement and a positive attitude toward implementation of changes were central to high improvement in performance. A lack of computers, low staff involvement or high staff turnover were associated with low improvement in performance. Personal characteristics of the facilitator are important. Six of the seven practices still had the prevention tools in place one year after the intervention and all noted that participation had improved their understanding of preventive medicine. Conclusions: When using facilitators, one should avoid practices in turmoil, strive for continuity over time, and recognise the importance of the relationship between the facilitator and the practice.

Previous research addressing the association between leisure and happiness has given rise to the hypothesis that informal social activities might contribute more to happiness than solitary activities. In the current study, we tested how the two types of leisure--social and solitary--contribute to a person's subjective sense of well-being. For the empirical estimate, we used four consecutive quarters of data collected from 533 people over the age of 16, from 13 Tsimane' hunter-farmer villages in the Bolivian Amazon. Results suggest that only social, not solitary, leisure has a positive and statistically significant association with subjective well-being. The association between solitary leisure and subjective well-being was negligible or negative. Future research should focus on emic definitions of social and solitary time, for solitary time might not always be equivalent to leisure and productive group activities might substitute for social leisure. Adapted from the source document.