Novel aspects of neuroblastoma : to hypoxia and beyond

Neuroblastoma (NB) is a pediatric cancer arising from the neural crest cells forming the sympathetic nervous system. Just as other types of pediatric cancer the driving mutations of neuroblastoma are few and the tumors are instead categorized according to genetic abbreviations such as amplification, loss of heterozygosity, gains and translocations. Neuroblastoma continues to be therapeutically challenging and flabbergasts scientists and doctors with it vast heterogeneity both clinically and biologically. The tumors range from aggressive, fast growing, lethal cancer to metastatic tumors that will spontaneously regress and disappear without any clinical interventions. The survivors of high-risk neuroblastoma struggle with life-long side effects due to the aggressive therapeutic treatment used in these young children. In this thesis I have focused on discovering alternative mechanisms that can contribute to the development and malignancy of neuroblastoma. Paper I. High-risk neuroblastoma has been shown to have high level of DNA methylation of putative tumor suppressors. We designed a therapeutic strategy where we exploited the reversibility of DNA methylation and combined the DNA-demethylating drug 5-Aza- deoxycytidine (AZA) with the differentiation-promoting activity of retinoic acid (RA) as an alternative strategy to treat high-risk neuroblastoma. In this paper we showed that treatment with AZA restores high-risk neuroblastomas sensitivity to RA. Additionally, the combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival in vivo. Genomewide analysis of treated tumors revealed that the combined treatment induced a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. We performed a loss-of- function experiment using a small-molecule inhibitor of HIF2α which resulted in diminished tumor response to AZA+RA treatment. Our study indicated that the increase in HIF2α levels is a key component in the tumor response to AZA+RA and that high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis, but negatively correlate with key features of high-risk tumors. Contrary to previous studies, our findings indicate an unanticipated tumor suppressive role for HIF2α in neuroblastoma. Paper II. We explored the role of hypoxia inducible transcription factor EPAS1/HIF2α in neuroblastoma. We analyzed several neuroblastoma tumor expression datasets which showed that EPAS1 expression is associated with better patient outcome and characteristics of low- risk tumors and did not support an oncogenic role as previously shown in other studies. We continued by treating xenografted mice with HIF2α inhibitors, which did not block in vitro neuroblastoma cell proliferation nor tumor growth. To illuminate the role of EPAS1 during embryonic development we analyzed single cell data sets from the developing mouse sympathoadrenal lineage, wherein expression of Epas1 was a strong predictor of the most differentiated cells and negatively correlated with key progenitor characteristics. Additionally, the genes co-expressed with Epas1 in the sympathoadrenal lineage were associated favorable patient outcome and features of low-risk neuroblastoma. Paper III. Due to the lack of recurrent mutations in neuroblastoma it has become more important to focus on alternative mechanisms that can influence the development of pediatric cancers. We have studied the role of fusion transcripts and proteins in neuroblastoma to illuminate possible oncogenic properties. Utilizing sequenced neuroblastoma datasets we have been able to identify neuroblastoma specific fusion transcripts. We could identify enrichments of fusions in regions frequently gained or lost in high-risk neuroblastoma as well as fusions of well-known drivers of neuroblastoma. To explore potential oncogenic properties of fusion proteins we focused on the ZNF451-BAG2 fusion which generates a truncated BAG2 protein, that we call ΔBAG2. When overexpressing ΔBAG2 in neuroblastoma cell lines we see impaired retinoic acid-induced differentiation. Indicating that ΔBAG2 could play a role in neuronal maturation, potentially leading to a less differentiated and more aggressive tumor. Our findings reveal an overlooked mechanism capable of generating altered gene products, which are relevant for neuroblastoma pathogenesis and presents new potential drug targets

Pharmaceutical Care Network Europe definition of quality indicators for pharmaceutical care: a systematic literature review and international consensus development

Background Over the past 40 years, the tasks of pharmacists have shifted from logistic services to pharmaceutical care (PhC). Despite the increasing importance of measuring quality of care, there is no general defnition of Quality Indicators (QIs) to measure PhC. Recognising this, a working group in a European association of PhC researchers, the Pharmaceutical Care Network Europe (PCNE), was established in 2020. Aim This research aimed to review existing definitions of QIs and develop a definition of QIs for PhC. Method A two-step procedure was applied. Firstly, a systematic literature review was conducted to identify existing QI definitions that were summarised. Secondly, an expert panel, comprised of 17 international experts from 14 countries, participated in two surveys and a discussion using a modifed Delphi technique to develop the definition of QIs for PhC. Results A total of 182 QI definitions were identifed from 174 articles. Of these, 63 QI definitions (35%) cited one of fve references as the source. Sixteen aspects that construct QI definitions were derived from the identifed definitions. As a result of the Delphi study, the panel reached an agreement on a one-sentence defnition of QIs for PhC: “quality indicators for pharmaceutical care are validated measurement tools to monitor structures, processes or outcomes in the context of care provided by pharmacists”. Conclusion Building upon existing defnition of QIs, an international expert panel developed the PCNE definition of QIs for PhC. This definition is intended for universal use amongst researchers and healthcare providers in PhC

A prospective study of cumulative job stress in relation to mental health

BACKGROUND: This study tests associations between psychosocial stress at work measured by the effort-reward imbalance model in a dynamic perspective, and multiple indicators of poor mental health, in a prospective design. METHODS: 1986 male and female employees from four Belgian enterprises were followed-up over one year within the framework of the Somstress study. Based on two consecutive measurements, an index of cumulative job stress was constructed and its associations with five indicators of mental health were studied, excluding caseness at entry (for depression, anxiety, somatisation, chronic fatigue and psychotropic drug consumption respectively). Taking into account the longitudinal design, four categories of job stress are defined: 1) employees free from stress at both measures, 2) job stress present at first measure but not at the second one, 3) recent onset of job stress as evidenced by second measure 4) workers exposed to stress at both measures. Multivariate logistic regression with appropriate adjustments was applied. RESULTS: In bivariate analysis, a clear graded association of cumulative job stress with all five mental health indicators is observed, both in men and women. In multivariate logistic regression analysis, recent onset of stress is strongly associated with poor mental health among men (odds ratios ranging from 1.8 to 4.6), while cumulative stress shows strongest effects on mental health in women (odds ratios ranging from 1.4 to 7.1). CONCLUSION: Cumulative experience and recent onset of job stress in terms of high effort spent and low reward received is associated with elevated risk of all five indicators of poor mental health at follow-up in a large cohort of employees

Assessing Trustworthy AI in times of COVID-19. Deep Learning for predicting a multi-regional score conveying the degree of lung compromise in COVID-19 patients

Abstract—The paper's main contributions are twofold: to demonstrate how to apply the general European Union’s High-Level Expert Group’s (EU HLEG) guidelines for trustworthy AI in practice for the domain of healthcare; and to investigate the research question of what does “trustworthy AI” mean at the time of the COVID-19 pandemic. To this end, we present the results of a post-hoc self-assessment to evaluate the trustworthiness of an AI system for predicting a multi-regional score conveying the degree of lung compromise in COVID-19 patients, developed and verified by an interdisciplinary team with members from academia, public hospitals, and industry in time of pandemic. The AI system aims to help radiologists to estimate and communicate the severity of damage in a patient’s lung from Chest X-rays. It has been experimentally deployed in the radiology department of the ASST Spedali Civili clinic in Brescia (Italy) since December 2020 during pandemic time. The methodology we have applied for our post-hoc assessment, called Z-Inspection®, uses socio-technical scenarios to identify ethical, technical and domain-specific issues in the use of the AI system in the context of the pandemic.</p

Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data

Background Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. Methods We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individuallevel data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) consortium. Summary estimates of the association were obtained using random effects models. Individual-level data analyses were based on a pre-published study protocol (F1000Res 2013;2:233). Results We included 6 published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published (Relative Risk [RR]= 1.77, 95% confidence interval [CI] 1.47-2.13) and unpublished datasets (RR=1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR=1.25, 95% CI: 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR=1.03, 95% CI: 0.81- 1.32). Conclusion Job strain may precipitate clinical depression among employees. Future intervention studies

En informativ affisch om busstrafikens klimatpositiva inverkan på samhället : Att skapa intresseväckande datavisualiseringar som engagerar målgruppen till att utforska informationsmaterialet.

Denna studie avser att undersöka hur informationsgrafik kan användas i ett informationsmaterial för att uppmärksamma personer i samhället om vikten av att färdas klimatsmart.Till år 2030 ska städernas negativa miljöpåverkan minskat per person i Sverige. Att resa kollektivt är ett sätt att delta i arbetet mot minskningen av koldioxidutsläppen. För att öka takten mot renare städer behöver fler personer i samhället informeras om hur deras individuella påverkan på miljön ser ut och vad man kan göra för att förbättra den. Målet med detta arbete är att utforma ett bildmaterial som kan användas för att informera målgruppen, 31–44 åringar, om hur busstrafiken kan bidra i arbetet mot de uppsatta klimatmålen. I studien undersöktes målgruppens ställning och synpunkter på datavisualiseringar baserat på mängd dekoration och vad som tilltalar samt engagerar dem i en informationsgrafik. Arbetet grundades på teori och metodiska undersökningar för hur man med informativ illustration kan skapa ett informationsmaterial. Detta undersöktes genom en kombination av enkät, intervju och prototypande. Den samlade empirin påvisade att målgruppen engageras och tilltalas mer av datavisualiseringar och informationsmaterial med mer dekorativa element. Användandet av färg, typsnitt, layout och illustration på ett sätt målgruppen upplevde som estetiskt tilltalande visade en god inställning till informationsmaterialet. Ett estetiskt tilltalande informationsmaterial uppmuntrade målgruppen till att utforska materialet djupare. Resultatet av den samlade empirin och faktan tog form av en affisch, ämnad för visning i stadscentrum, som kommunicerar busstrafikens inverkan på miljön genom datavisualisering, text och illustration

En informativ affisch om busstrafikens klimatpositiva inverkan på samhället : Att skapa intresseväckande datavisualiseringar som engagerar målgruppen till att utforska informationsmaterialet.

Denna studie avser att undersöka hur informationsgrafik kan användas i ett informationsmaterial för att uppmärksamma personer i samhället om vikten av att färdas klimatsmart.Till år 2030 ska städernas negativa miljöpåverkan minskat per person i Sverige. Att resa kollektivt är ett sätt att delta i arbetet mot minskningen av koldioxidutsläppen. För att öka takten mot renare städer behöver fler personer i samhället informeras om hur deras individuella påverkan på miljön ser ut och vad man kan göra för att förbättra den. Målet med detta arbete är att utforma ett bildmaterial som kan användas för att informera målgruppen, 31–44 åringar, om hur busstrafiken kan bidra i arbetet mot de uppsatta klimatmålen. I studien undersöktes målgruppens ställning och synpunkter på datavisualiseringar baserat på mängd dekoration och vad som tilltalar samt engagerar dem i en informationsgrafik. Arbetet grundades på teori och metodiska undersökningar för hur man med informativ illustration kan skapa ett informationsmaterial. Detta undersöktes genom en kombination av enkät, intervju och prototypande. Den samlade empirin påvisade att målgruppen engageras och tilltalas mer av datavisualiseringar och informationsmaterial med mer dekorativa element. Användandet av färg, typsnitt, layout och illustration på ett sätt målgruppen upplevde som estetiskt tilltalande visade en god inställning till informationsmaterialet. Ett estetiskt tilltalande informationsmaterial uppmuntrade målgruppen till att utforska materialet djupare. Resultatet av den samlade empirin och faktan tog form av en affisch, ämnad för visning i stadscentrum, som kommunicerar busstrafikens inverkan på miljön genom datavisualisering, text och illustration

A Review and Categorization of Artificial Intelligence-Based Opportunities in Wildlife, Ocean and Land Conservation

The scholarly literature on the links between Artificial Intelligence and the United Nations’ Sustainable Development Goals is burgeoning as climate change and the biotic crisis leading to mass extinction of species are raising concerns across the globe. With a focus on Sustainable Development Goals 14 (Life below Water) and 15 (Life on Land), this paper explores the opportunities of Artificial Intelligence applications in various domains of wildlife, ocean and land conservation. For this purpose, we develop a conceptual framework on the basis of a comprehensive review of the literature and examples of Artificial Intelligence-based approaches to protect endangered species, monitor and predict animal behavior patterns, and track illegal or unsustainable wildlife trade. Our findings provide scholars, governments, environmental organizations, and entrepreneurs with a much-needed taxonomy and real-life examples of Artificial Intelligence opportunities for tackling the grand challenge of rapidly decreasing biological diversity, which has severe implications for global food security, nature, and humanity

A Review and Categorization of Artificial Intelligence-Based Opportunities in Wildlife, Ocean and Land Conservation

The scholarly literature on the links between Artificial Intelligence and the United Nations&rsquo; Sustainable Development Goals is burgeoning as climate change and the biotic crisis leading to mass extinction of species are raising concerns across the globe. With a focus on Sustainable Development Goals 14 (Life below Water) and 15 (Life on Land), this paper explores the opportunities of Artificial Intelligence applications in various domains of wildlife, ocean and land conservation. For this purpose, we develop a conceptual framework on the basis of a comprehensive review of the literature and examples of Artificial Intelligence-based approaches to protect endangered species, monitor and predict animal behavior patterns, and track illegal or unsustainable wildlife trade. Our findings provide scholars, governments, environmental organizations, and entrepreneurs with a much-needed taxonomy and real-life examples of Artificial Intelligence opportunities for tackling the grand challenge of rapidly decreasing biological diversity, which has severe implications for global food security, nature, and humanity