Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours.

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

Particulate matter flux interception in oceanic mesoscale eddies by the polychaete Poeobius sp.

Gelatinous zooplankton hold key functions in the ocean and have been shown to significantly influence the transport of organic carbon to the deep sea. We discovered a gelatinous, flux‐feeding polychaete of the genus Poeobius in very high abundances in a mesoscale eddy in the tropical Atlantic Ocean, where it co‐occurred with extremely low particle concentrations. Subsequent analysis of an extensive in situ imaging dataset revealed that Poeobius sp. occurred sporadically between 5°S–20°N and 16°W–46°W in the upper 1000 m. Abundances were significantly elevated and the depth distribution compressed in anticyclonic modewater eddies (ACMEs). In two ACMEs, high Poeobius sp. abundances were associated with strongly reduced particle concentrations and fluxes in the layers directly below the polychaete. We discuss possible reasons for the elevated abundances of Poeobius sp. in ACMEs and provide estimations showing that a single zooplankton species can completely intercept the downward particle flux by feeding with their mucous nets, thereby substantially altering the biogeochemical setting within the eddy

The long-term effects of naprapathic manual therapy on back and neck pain - Results from a pragmatic randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Back and neck pain are very common, disabling and recurrent disorders in the general population and the knowledge of long-term effect of treatments are sparse. The aim of this study was to compare the long-term effects (up to one year) of naprapathic manual therapy and evidence-based advice on staying active regarding non-specific back and/or neck pain. Naprapathy, a health profession mainly practiced in Sweden, Finland, Norway and in the USA, is characterized by a combination of manual musculoskeletal manipulations, aiming to decrease pain and disability in the neuromusculoskeletal system.</p> <p>Methods</p> <p>Subjects with non-specific pain/disability in the back and/or neck lasting for at least two weeks (n = 409), recruited at public companies in Sweden, were included in this pragmatic randomized controlled trial. The two interventions compared were naprapathic manual therapy such as spinal manipulation/mobilization, massage and stretching, (<it>Index Group</it>), and advice to stay active and on how to cope with pain, provided by a physician (C<it>ontrol Group</it>). Pain intensity, disability and health status were measured by questionnaires.</p> <p>Results</p> <p>89% completed the 26-week follow-up and 85% the 52-week follow-up. A higher proportion in the Index Group had a clinically important decrease in pain (risk difference (RD) = 21%, <it>95% CI: 10-30</it>) and disability (RD = 11%, <it>95% CI: 4-22</it>) at 26-week, as well as at 52-week follow-ups (pain: RD = 17%, <it>95% CI: 7-27 </it>and disability: RD = 17%, <it>95% CI: 5-28</it>). The differences between the groups in pain and disability considered over one year were statistically significant favoring naprapathy (p ≤ 0.005). There were also significant differences in improvement in bodily pain and social function (subscales of SF-36 health status) favoring the Index Group.</p> <p>Conclusions</p> <p>Combined manual therapy, like naprapathy, is effective in the short and in the long term, and might be considered for patients with non-specific back and/or neck pain.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN56954776.</p

Planetary Defense team project: READI (Roadmap for EArth Defense Initiatives)

Planetary Defense is a complex problem, not well understood by policy makers and the general public. The recent Chelyabinsk incident in Russia created temporary international attention but has failed to effectively stimulate public action. The lack of long-term attention to cosmic hazards has resulted in limited funding to defend our planet. Hence, it is hard to realistically address this challenge and achieve the high test and operational readiness needed for an effective Planetary Defense strategy. To address this problem, we have created a set of recommendations for the development of a Planetary Defense Program, for the purpose of contributing to the protection of Earth from asteroids and comets. The SSP15 READI Project focused on threats for which there is only a short-term warning, specifically a warning of two years or less from detection of the object to impact. We have provided recommendations in five areas of Planetary Defense including detection and tracking, deflection techniques, global collaboration, outreach and education, and evacuation and recovery. We have applied this set of recommendations in a narrative scenario to make our report more impactful and engaging. We contrast optimistic and pessimistic outcomes for a comet threat, differing from each other in terms of the level of readiness achieved during the years leading up to the discovery of the threat. In our optimistic scenario, the deflection system has achieved high test and operational readiness. The world’s governments have realized the importance of being prepared against cosmic hazards and put in place all of the necessary measures for a successful defense, leading to a positive deflection of the comet. In contrast, in the pessimistic scenario no preparation is done before the detection, and the comet strikes a heavily populated area releasing energy equivalent to 80 times the most powerful nuclear bomb ever detonated. The recommendations that we have identified in this report constitute a roadmap to avoid this horrible outcome, and we believe they should be taken seriously and swiftly implemented

SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors

Abstract Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we study derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids reveals a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently reveal patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 activates patient-specific epigenetic reprogramming underlying MRT tumorigenesis

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours.

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

The influence of work-related exposures on the prognosis of neck/shoulder pain

To determine associations between work-related exposures and the prognosis of self-reported neck/shoulder pain. This prospective cohort study was based on 803 working subjects who reported neck/shoulder pain at baseline. The proportion of subjects who 5–6 years later were symptom-free was calculated. Data concerning work-related biomechanical, psychosocial, and organizational exposures were collected at baseline. The Cox regression analyses were used to calculate the relative chances (RC) of being symptom-free at the end of the study for single exposures, and also for up to three simultaneous work-related exposures. Adjustments were made for sex and age. Only 36% of the subjects were symptom-free 5–6 years later. The relative chance for being symptom-free at the end of the study was 1.32 (95% CI = 0.99–1.74) for subjects who were exposed to sitting ≥75% of the working time and 1.53 (95% CI = 1.02–2.29) for subjects who were exposed to job strain, i.e., the combination of high demands and low decision latitude. The relative chance of being symptom-free at the end of the study was 0.61 (95% CI = 0.40–0.94) for subjects with at least two out of three simultaneous biomechanical exposures at work; manual handling, working with the hands above shoulder level, and working with vibrating tools. In a heterogeneous population with moderate nonspecific neck/shoulder pain, sedentary work enhanced the chance of being symptom-free 5–6 years later, whereas simultaneous exposures to at least two of manual handling, working with hands above shoulder level and working with vibrating tools were associated with a lower chance of being symptom-free at the end of the study. This could imply that subjects with neck/shoulder pain should avoid such simultaneous exposures