Genome-wide Transcriptional Characterization of the ETV6-RUNX1-positive Childhood Leukemia

Akuutti lymfoblastileukemia (ALL) on lasten yleisin syöpä. Useimmiten se saa alkunsa epäkypsästä B-solusta (preB), jossa tapahtuu tietty altistava geneettinen muutos. Yksi yleisimmistä muutoksista on translokaatio, joka johtaa ETV6-RUNX1 (E/R) fuusiogeenin syntymiseen. Leukemian puhkeamiseen vaaditaan lisäksi muita geneettisiä muutoksia, jotka usein osuvat B-solun identiteetille tärkeisiin geeneihin. DNA-vaurioiden lisäksi solun toiminta voi häiriintyä RNA-molekyylien ja proteiinien toiminnan muutoksista. E/R on epänormaali transkriptiotekijä ja sen suorat säätelykohteet ovat vielä jääneet epäselviksi. Tässä työssä tutkimme lasten prekursori B-ALL:ssa (preB-ALL) tapahtuvaa genominlaajuista geeniensäätelyä tarkastelemalla varhaista RNA-transkriptiota solulinjoissa ja potilasnäytteissä. E/R-fuusion kohdegeenien kartoittamista varten teimme solulinjamallin, jossa fuusion tuotantoa voidaan säädellä. Määritimme tehostaja-alueet tehostaja-RNA:iden (eRNA) ilmentymisen perusteella sekä niiden mahdolliset kohdegeenit perustuen signaalimuutosten samankaltaisuuteen. E/R- fuusion säätelemistä geeneistä kaksi kolmasosaa hiljeni suoran RUNX1-välitteisen DNA-sitoutumisen kautta. Lisäksi E/R vähensi B-solu-spesifisten tehostaja- alueiden luentaa. Osa geeneistä myös ilmentyi eri tavalla E/R-potilaiden leukemiasoluissa verrattuna muiden preB-ALL alityyppien potilaiden soluihin. RAG ja AID entsyymit on liitetty DNA-katkosten syntymiseen B-solu- leukemiassa ja niiden toimintaan tiedetään liittyvän avoimena oleva kromatiini. Tutkimme RNA-transkriptiota B-linjan soluissa keskittyen lasten leukemiassa usein nähtäviin DNA-katkoskohtiin. Huomasimme, että katkoskohtiin assosioituvat tietyt transkriptionaaliset ominaisuudet: RNA-polymeraasin pysähtyminen sekä yhtäaikainen geenienluenta päällekkäisiltä DNA-juosteilta. Nämä piirteet näyttävät altistavan DNA:n katkoksille erityisesti paljastamalla RAG-entsyymin rekombinaatiosignaalisekvenssejä. Huomasimme myös korkean RAG1-geenin luennan erityisesti E/R-potilailla sekä AID-entsyymiä koodaavan geenin epätavallisen luennan osalla korkean riskin preB-ALL potilaita. Tässä väitöskirjassa tunnistettiin E/R-fuusion genominlaajuisia säätelykohteita sekä toistuvien DNA-katkosten kohdille ominaisia transkriptionaalisia piirteitä lasten leukemiassa.Acute lymphoblastic leukemia (ALL) is the most common cancer affecting in childhood. It occurs typically in early B-lineage cells and is characterized by a few specific initiating genomic alterations. One of the most common alterations is the translocation resulting in the ETV6-RUNX1 (E/R) fusion gene. Progression to overt ALL requires additional genetic abnormalities that are recurrently found at essential B-cell lineage identity determining genes. Besides DNA, alterations in various RNA species and proteins could also have marked unwanted effects on cell behavior. E/R functions as an aberrant transcription factor but its direct target genes have thus far remained uncertain. We set out to study genome-wide gene regulation in childhood precursor B-ALL (preB-ALL) by studying nascent RNA transcription in cell lines and patient samples. For the examination of target sites, we generated a cell line model with an inducible E/R. We detected enhancer regions by the expression of eRNA transcripts and deciphered a possible target gene by correlating between expression level changes. Two thirds of the E/R-regulated genes were repressed by direct regulation via RUNX1 DNA binding. We further showed E/R-mediated downregulation of B-cell specific super-enhancers. Some of the regulated genes were observed to be differentially expressed among E/R patients when compared to other preB-ALL patients. RAG and AID are enzymes that have been linked to the genesis of secondary genetic alterations in B-cell leukemia. We explored the nascent RNA transcription across B-lymphoid cells at the genomic sites that are often deleted in childhood precursor B-ALL and noticed significant association with specific transcriptional features, namely RNA polymerase II stalling and convergent transcription. These features seem to expose the DNA to double strand breaks especially by revealing RAG recombination signal sequences. We noticed high RAG1 expression in the E/R subtype, and abnormal expression of AICDA among the non-classified precursor B-ALL cases. This thesis identifies genome-wide targets of the E/R fusion and specific transcriptional features that are associated with recurrent DNA breakpoint sites in childhood precursor B-ALL

Combined economic and social impact assessment of affordable housing investments

A method combining economic evaluation and social impact assessment creates information that can be applied when making decisions about a new tenement building or renovation of existing buildings. The aim of the economic evaluation is to ensure that economic aspects are adequately considered and investment is realizable from a monetary point of view. Social impact assessment reveals intangible pros and cons related to an investment or investments to be considered. This paper presents a framework that combines economic and social aspects and supports decision making related to affordable housing.fi=vertaisarvioitu|en=peerReviewed

Interdisciplinary team education promotes innovations in the home care of older people

This article describes a new type of team training that involves undergraduate students of medicine, students from the Aalto University (industrial engineering and management, architecture, information networks, collaborative and industrial design and bioinformation technology) and specialized home care nurses. During the course, the students learned interdisciplinary teamwork and created innovations in the care of older people. The 18 participants formed six microteams (three persons in each team: one specialized nurse, one medical student and one from Aalto University). The course consisted of two seminars and 3 full days of home visits to older people's homes. Participants were encouraged to make one innovation in each home visit that would improve the older person's well-being or streamline the processes of home care. During the course, the participants promptly formed tight teams. They valued the know-how of the other team members and learned openly from each other. They also created a number of practical innovations in home care which they presented to executives of older people's care in a final seminar. The course received very good feedback from the students. This course is an encouraging example of how gerontological interdisciplinary team training may be successfully applied. The article describes both the learning outcomes and the innovations the students produced during their home visits. It also discusses the learning theories behind effective interdisciplinary team learning.Peer reviewe

A Framework for Assessing the Social and Economic Impact of Sustainable Investments

Investments towards sustainable development are vital for the future and they must be carefully planned to deliver immediate and long-term benefits. Hence, the ability to communicate the forms of impact of sustainable investments to local societies, people, investors and other stakeholders can provide a competitive advantage. However, the assessments are often under pressure to demonstrate short-term effects rather than emphasise the long-term impact. In addition, indirect and intangible forms of impacts should not be measured solely in economic terms. This paper proposes an assessment framework to support the integrated economic and social impact assessment of sustainable investments aimed at improving physical and socio-economic wellbeing. The framework is demonstrated in two case studies: new construction and renovation investments in affordable housing and social impact investment in sustainable development. The investments in the case studies are evaluated, selected and prioritized not only in terms of money but also with regard to sustainability, social acceptability and their overall impact on society, as a whole. The results indicate that a systematic integrated assessment of monetary and non-monetary factors can be successfully combined with the sustainable development decisions.fi=vertaisarvioitu|en=peerReviewed

Efficacy of a multicomponent singing intervention on communication and psychosocial functioning in chronic aphasia: A randomized controlled crossover trial

The ability to produce words through singing can be preserved in severe aphasia, but the benefits of group-based singing rehabilitation in aphasia are largely unknown. Our aim was to determine the efficacy of a multicomponent singing intervention on communication and speech production, emotional-social functioning and caregiver well-being in aphasia. Fifty-four patients with acquired brain injury and chronic aphasia and their family caregivers (n = 43) were recruited. Using a crossover randomized controlled trial design, participants were randomized to two groups who received a 4-month singing intervention either during the first or second half of the study in addition to standard care. The intervention comprised weekly group-based training (including choir singing and group-level melodic intonation therapy) and tablet-assisted singing training at home. At baseline, 5- and 9-month stages, patients were assessed with tests and questionnaires on communication and speech production, mood, social functioning, and quality of life and family caregivers with questionnaires on caregiver burden. All participants who participated in the baseline measurement (n = 50) were included in linear mixed model analyses. Compared with standard care, the singing intervention improved everyday communication and responsive speech production from baseline to 5-month stage, and these changes were sustained also longitudinally (baseline to 9-month stage). Additionally, the intervention enhanced patients’ social participation and reduced caregiver burden. This study provides novel evidence that group-based multicomponent singing training can enhance communication and spoken language production in chronic aphasia as well as improve psychosocial wellbeing in patients and caregivers.Peer reviewe

Neuroanatomical correlates of speech and singing production in chronic post-stroke aphasia

A classical observation in neurology is that aphasic stroke patients with impairments in speech production can nonetheless sing the same utterances. This preserved ability suggests a distinctive neural architecture for singing that could contribute to speech recovery. However, to date, these structural correlates remain unknown. Here, we combined a multivariate lesion–symptom mapping and voxel-based morphometry approach to analyse the relationship between lesion patterns and grey matter volume and production rate in speech and singing tasks. Lesion patterns for spontaneous speech and cued repetition extended into frontal, temporal and parietal areas typically reported within the speech production network. Impairment in spontaneous singing was associated with damage to the left anterior–posterior superior and middle temporal gyri. Preservation of grey matter volume in the same regions where damage led to poor speech and singing production supported better performance in these tasks. When dividing the patients into fluent and dysfluent singers based on the singing performance from demographically matched controls, we found that the preservation of the left middle temporal gyrus was related to better spontaneous singing. These findings provide insights into the structural correlates of singing in chronic aphasia and may serve as biomarkers to predict treatment response in clinical trials using singing-based interventions for speech rehabilitation.Peer reviewe

Choir singing is associated with enhanced structural connectivity across the adult lifespan

The global ageing of populations calls for effective, ecologically valid methods to support brain health across adult life. Previous evidence suggests that music can promote white matter (WM) microstructure and grey matter (GM) volume while supporting auditory and cognitive functioning and emotional well-being as well as counteracting age-related cognitive decline. Adding a social component to music training, choir singing is a popular leisure activity among older adults, but a systematic account of its potential to support healthy brain structure, especially with regard to ageing, is currently missing. The present study used quantitative anisotropy (QA)-based diffusion MRI connectometry and voxel-based morphometry to explore the relationship of lifetime choir singing experience and brain structure at the whole-brain level. Cross-sectional multiple regression analyses were carried out in a large, balanced sample (N = 95; age range 21–88) of healthy adults with varying levels of choir singing experience across the whole age range and within subgroups defined by age (young, middle-aged, and older adults). Independent of age, choir singing experience was associated with extensive increases in WM QA in commissural, association, and projection tracts across the brain. Corroborating previous work, these overlapped with language and limbic networks. Enhanced corpus callosum microstructure was associated with choir singing experience across all subgroups. In addition, choir singing experience was selectively associated with enhanced QA in the fornix in older participants. No associations between GM volume and choir singing were found. The present study offers the first systematic account of amateur-level choir singing on brain structure. While no evidence for counteracting GM atrophy was found, the present evidence of enhanced structural connectivity coheres well with age-typical structural changes. Corroborating previous behavioural studies, the present results suggest that regular choir singing holds great promise for supporting brain health across the adult life span.Peer reviewe

Effects of neurological music therapy on behavioural and emotional recovery after traumatic brain injury : A randomized controlled cross-over trial

Traumatic brain injury (TBI) causes deficits in executive function (EF), as well as problems in behavioural and emotional self-regulation. Neurological music therapy may aid these aspects of recovery. We performed a cross-over randomized controlled trial where 40 persons with moderate-severe TBI received a 3-month neurological music therapy intervention (2 times/week, 60 min/session), either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. The evidence from this RCT previously demonstrated that music therapy enhanced general EF and set shifting. In the current study, outcome was assessed with self-report and caregiver-report questionnaires performed at baseline, 3-month, 6-month, and 18-month stages. The results showed that the self-reported Behavioural Regulation Index of the Behaviour Rating Inventory of Executive Function (BRIEF-A) improved more in the AB than BA group from baseline to 3-month stage and the effect was maintained in the 6-month follow-up. No changes in mood or quality of life questionnaires were observed. However, a qualitative content analysis of the feedback revealed that many participants experienced the intervention as helpful in terms of emotional well-being and activity. Our results suggest that music therapy has a positive effect on everyday behavioural regulation skills after TBI.Peer reviewe

Caveolin-1 accumulation in the tongue cancer tumor microenvironment is significantly associated with poor prognosis : an in-vivo and in-vitro study

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Music therapy enhances executive functions and prefrontal structural neuroplasticity after traumatic brain injury : Evidence from a randomized controlled trial

Traumatic brain injury (TBI) causes lifelong cognitive deficits, particularly impairments of executive functioning (EF). Musical training and music-based rehabilitation have been shown to enhance cognitive functioning and neuroplasticity, but the potential rehabilitative effects of music in TBI are still largely unknown. The aim of the present crossover randomized controlled trial (RCT) was to determine the clinical efficacy of music therapy on cognitive functioning in TBI and to explore its neural basis. Using an AB/BA design, 40 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. Neuropsychological and motor testing and magnetic resonance imaging (MRI) were performed at baseline and at the 3-month and 6-month stage. Thirty-nine subjects who participated in baseline measurement were included in an intention-to-treat analysis using multiple imputation. Results showed that general EF (as indicated by the Frontal Assessment Battery [FAB]) and set shifting improved more in the AB group than in the BA group over the first 3-month period and the effect on general EF was maintained in the 6-month follow-up. Voxel-based morphometry (VBM) analysis of the structural MRI data indicated that gray matter volume (GMV) in the right inferior frontal gyrus (IFG) increased significantly in both groups during the intervention versus control period, which also correlated with cognitive improvement in set shifting. These findings suggest that neurological music therapy enhances EF and induces fine-grained neuroanatomical changes in prefrontal areasPeer reviewe