The utilization and perceived usefulness of health care and other support services by people exposed to traumatic events related to the war in the Balkans

Objective. To explore which health care and other support services people exposed to traumatic events related to the war use, how helpful they perceive them in the course of their post-war adaptation and whether utilization and perceived usefulness depend on the mental health status of participants. Methods. A community sample of 3304 adults exposed to at least one war-related traumatic event was randomly selected in different regions in the former Yugoslavia. A specifically designed instrument, the Matrix for the Assessment of Community and Healthcare Services, was used to record service utilization and their perceived usefulness. The mental health status of participants was assessed using the Mini International Neuropsychiatric Interview. Results. Primary health care was the most frequently used type of service (80.5%). Services providing help with leisure activities, social support and social contacts were perceived as most helpful. Participants with current post-traumatic stress disorder used all types of health care services and employment support services significantly more often than participants without mental disorders and participants with other mental disorders. They were more satisfied with primary health care services than participants without mental disorders and less satisfied with financial and material support services as compared to participants with other mental disorders. Conclusions. The frequency of utilization of different types of services varies greatly in war affected communities. Medical services are widely used and therefore have a central role in the care provision following a war. Services providing help with leisure activities and social support are most appreciated and may be more widely established

The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is characterized by the presence of a fusion protein EWS/WT1, arising from the t (11;22) (p13;q12) translocation. Here we examine the oncogenic properties of two splice variants of EWS/WT1, EWS/WT1-KTS and EWS/WT1 + KTS. METHODS: We over-expressed both EWS/WT1 variants in murine embryonic fibroblasts (MEFs) of wild-type, p53+/- and p53-/- backgrounds and measured effects on cell-proliferation, anchorage-independent growth, clonogenicity after serum withdrawal, and sensitivity to cytotoxic drugs and gamma irradiation in comparison to control cells. We examined gene expression profiles in cells expressing EWS/WT1. Finally we validated our key findings in a small series of DSRCT. RESULTS: Neither isoform of EWS/WT1 was sufficient to transform wild-type MEFs however the oncogenic potential of both was unmasked by p53 loss. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 enhanced cell-proliferation, clonogenic survival and anchorage-independent growth. EWS/WT1 expression in wild-type MEFs conferred resistance to cell-cycle arrest after irradiation and daunorubicin induced apoptosis. We show DSRCT commonly have nuclear localization of p53, and copy-number amplification of MDM2/MDMX. Expression of either isoform of EWS/WT1 induced characteristic mRNA expression profiles. Gene-set enrichment analysis demonstrated enrichment of WNT pathway signatures in MEFs expressing EWS/WT1 + KTS. Wnt-activation was validated in cell lines with over-expression of EWS/WT1 and in DSRCT. CONCLUSION: In conclusion, we show both isoforms of EWS/WT1 have oncogenic potential in MEFs with loss of p53. In addition we provide the first link between EWS/WT1 and Wnt-pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterize DSRCT

Long-Term Impact of War on Healthcare Costs: An Eight-Country Study

PMCID: PMC3251588This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

© 2019 Elsevier Inc. Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death

Investigation into the Biology of Human Malignant Rhabdoid Tumour

My study focused on Malignant Rhabdoid Tumor (MRT) a resistant pediatric cancer where the primary mutation is loss of SMARCB1, implicating epigenetic deregulation as central to the pathogenesis of the disease. We demonstrated that repurposing the HDACi inhibitor Panobinostat (LBH589) was able to drive multi-lineage differentiation in MRT cells in vitro and in vivo. Further mechanistic analysis revealed that SMARCB1-restoration mirrored low-dose HDACi treatment in vitro and in vivo. Finally, we discerned that potential mechanistic driver of impair lineage maturation in MRT was EZH2, with targeted therapies of catalytic and non-catalytic function demonstrating improved responses in preclinical models of MRT

Mental disorders following war in the Balkans: a study in 5 countries.

CONTEXT: War experience may affect mental health. However, no community-based study has assessed mental disorders several years after war using consistent random sampling of war-affected people across several Western countries. OBJECTIVES: To assess current prevalence rates of mental disorders in an adult population who were directly exposed to war in the Balkans and who still live in the area of conflict, and to identify factors associated with the occurrence of different types of mental disorders. DESIGN, SETTING, AND PARTICIPANTS: War-affected community samples in Bosnia-Herzegovina, Croatia, Kosovo, the Republic of Macedonia, and Serbia were recruited through a random-walk technique. MAIN OUTCOME MEASURE: Prevalence rates of mood, anxiety, and substance use disorders were assessed using the Mini-International Neuropsychiatric Interview. RESULTS: Between 637 and 727 interviewees were assessed in each country (N = 3313). The prevalence rates were 15.6% to 41.8% for anxiety disorders, 12.1% to 47.6% for mood disorders, and 0.6% to 9.0% for substance use disorders. In multivariable analyses across countries, older age, female sex, having more potentially traumatic experiences during and after the war, and unemployment were associated with higher rates of mood and anxiety disorders. In addition, mood disorders were correlated with lower educational level and having more potentially traumatic experiences before the war. Male sex and not living with a partner were the only factors associated with higher rates of substance use disorders. Most of these associations did not significantly differ among countries. CONCLUSIONS: Several years after the end of the war, the prevalence rates of mental disorders among war-affected people vary across countries but are generally high. War experiences appear to be linked to anxiety and mood disorders but not substance use disorders. Long-term policies to meet the mental health needs of war-affected populations are required

Experience of human rights violations and subsequent mental disorders - A study following the war in the Balkans

War experiences are associated with substantially increased rates of mental disorders, particularly Post-Traumatic Stress Disorder (PTSD) and Major Depression (MD). There is limited evidence on what type of war experiences have particularly strong associations with subsequent mental disorders. Our objective was to investigate the association of violations of human rights, as indicated in the 4th Geneva Convention, and other stressful war experiences with rates of PTSD and MD and symptom levels of intrusion, avoidance and hyperarousal. In 2005/6, human rights violations and other war experiences, PTSD, post-traumatic stress symptoms and MD were assessed in war affected community samples in five Balkan countries (Bosnia-Herzegovina, Croatia, Kosovo, Macedonia, and Serbia) and refugees in three Western European countries (Germany, Italy, United Kingdom). The main outcome measures were the MINI International Neuropsychiatric Interview and the Impact of Event Scale-Revised. In total 3313 participants in the Balkans and 854 refugees were assessed. Participants reported on average 2.3 rights violations and 2.3 other stressful war experiences. 22.8% of the participants were diagnosed with current PTSD and also 22.8% had MD. Most war experiences significantly increased the risk for both PTSD and MD. When the number of rights violations and other stressful experiences were considered in one model, both were significantly associated with higher risks for PTSD and were significantly associated with higher levels of intrusion, avoidance and hyperarousal. However, only the number of violations, and not of other stressful experiences, significantly increased the risk for MD. We conclude that different types of war experiences are associated with increased prevalence rates of PTSD and MD more than 5 years later. As compared to other stressful experiences, the experience of human rights violations similarly increases the risk of PTSD, but appears more important for MD.Ex-Yugoslavia Germany Italy UK War experiences and violation of human rights Post-Traumatic Stress Disorder (PTSD) Major Depression War Human rights Balkans

Factors associated with mental disorders in long-settled war refugees: refugees from the former Yugoslavia in Germany, Italy and the UK.

BACKGROUND: Prevalence rates of mental disorders are frequently increased in long-settled war refugees. However, substantial variation in prevalence rates across studies and countries remain unexplained. AIMS: To test whether the same sociodemographic characteristics, war experiences and post-migration stressors are associated with mental disorders in similar refugee groups resettled in different countries. METHOD: Mental disorders were assessed in war-affected refugees from the former Yugoslavia in Germany, Italy and the UK. Sociodemographic, war-related and post-migration characteristics were tested for their association with different disorders. RESULTS: A total of 854 war refugees were assessed (≥ 255 per country). Prevalence rates of mental disorders varied substantially across countries. A lower level of education, more traumatic experiences during and after the war, more migration-related stress, a temporary residence permit and not feeling accepted were independently associated with higher rates of mood and anxiety disorders. Mood disorders were also associated with older age, female gender and being unemployed, and anxiety disorders with the absence of combat experience. Higher rates of post-traumatic stress disorder (PTSD) were associated with older age, a lower level of education, more traumatic experiences during and after the war, absence of combat experience, more migration-related stress, and a temporary residence permit. Only younger age, male gender and not living with a partner were associated with substance use disorders. The associations did not differ significantly across the countries. War-related factors explained more variance in rates of PTSD, and post-migration factors in the rates of mood, anxiety and substance use disorder. CONCLUSIONS: Sociodemographic characteristics, war experiences and post-migration stressors are independently associated with mental disorders in long-settled war refugees. The risk factors vary for different disorders, but are consistent across host countries for the same disorders

Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT

Sample characteristics.

<p>Sample characteristics.</p