Search

Background: Conveying information to parents is a core part of pediatric oncology nursing; however, most published interventions do not tailor information to individual parental needs. Objective: To evaluate the effect on parental illness-related stress of person-centered information provided to parents of children with cancer. Methods: A multicenter, unblinded randomized controlled trial with two parallel arms recruiting parents of children diagnosed within the past two months from two tertiary children's cancer centers in Sweden. Parents were randomized using sealed envelopes prepared and opened by an independent person. Parents in the intervention arm met four times with experienced nurses trained in the intervention, whereas controls received standard care. The effect of the intervention was measured five times regarding parents' illness-related stress. Secondary outcomes were psychosocial states, experiences with healthcare providers, and received information. Further, we collected process data on the intervention's content and fidelity. Results: Of the 32 parents included and analyzed in the study, 16 were randomized to the intervention, which addressed a broad variety of topics. The intervention increased parents' knowledge about the biophysiological and functional aspects of their child's illness, but it had no measurable effect on their distress. Discussion: Although fidelity to the intervention protocol was sufficient, the study was flawed by recruitment difficulties, primarily due to organizational factors, which may have prevented us from observing any possible effects on psychosocial distress. Having a person-centered perspective could be promising for future studies aimed at parents of children with cancer. (Registered at Clinicaltrials.gov, number NCT02332226.) [ABSTRACT FROM AUTHOR]

Acquiring information about one's child's cancer diagnosis is a complex and ever-changing process, and parents' needs change over time. As yet, we know little about what information parents require at different stages of their child's illness. This paper is part of a larger randomized control trial studying the parent-centered information given to mothers and fathers. The aim of this paper was to describe the topics addressed in person-centered meetings between nurses and parents of children with cancer and how those changed over time. Using qualitative content analysis, we analyzed nurses' written summaries of 56 meetings with 16 parents and then computed for each topic the percentage of parents who brought it up at any time during the intervention. The main categories were Child's disease and treatment (addressed by 100% of parents), Consequences of treatment (88%), Emotional management for the child (75%), Emotional management for the parent (100%), Social life of the child (63%), and Social life of the parent (100%). Different topics were addressed at different points in time, and fathers raised more concerns about the child's emotional management and the consequences of treatment than mothers. This paper suggests that parental information demands change over time and differ between fathers and mothers, implying that information should be person-centered. Registered at Clinicaltrials.gov (NCT02332226). [ABSTRACT FROM AUTHOR]

A child's diagnosis of type 1 diabetes can create major challenges for the family, and early education about the disease is crucial. The aim of this study was to identify and reach expert consensus about the priority of topics for the two initial weeks of education of families with a child diagnosed with type 1 diabetes. Specialist nurses (n = 15) working with children and adolescents with diabetes at Swedish pediatric clinics participated in a Delphi study. We sent these experts three rounds of a web survey and analyzed their answers using qualitative content analysis and descriptive statistics. The results show the experts' consensus on the most important educational topics for families of a child diagnosed with type 1 diabetes. The highest priority topics were actions for hypo-/hyperglycemia, blood-glucose monitoring, symptoms of hypo-/hyperglycemia and adjustment of insulin. The experts' top-ranked educational topics were in line with the International Society for Pediatric and Adolescent Diabetes guidelines for educating children with type 1 diabetes and also considered important by children and their families. The topics identified here can help nurses educate children with type 1 diabetes, contribute to further research into type 1 diabetes education, and inform the development of national guidelines. [ABSTRACT FROM AUTHOR]

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells. Author summary: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine (DA)-producing neurons and strongly compromised motor performance. Multiple observations suggest that DA neurons are particularly prone to acquire mitochondrial damage in adult life. This acquired mitochondrial dysfunction likely impairs DA neuron function and contributes to cell death. To study the consequences of adult-onset mitochondrial dysfunction in DA neurons, we generated a conditional activatable knockout mouse model lacking Mitofusin 2, a key regulator of mitochondrial homeostasis. This animal model allows the induction of mitochondrial dysfunction selectively in adult DA neurons and leads to motor defects and the typical pattern of neurodegeneration seen in PD. By studying gene expression in isolated DA neurons at early disease stages and by using in situ approaches on brain sections, we report an early onset of an inflammatory response. Inflammation is present already when the mutant DA neurons display the first signs of mitochondrial framgmentation and precedes the onset of respiratory chain dysfunction and neurodegeneration. The inflammatory response in DA neurons and activation of surrounding glia thus likely exacerbates or drives the neurodegenerative process in this animal model of adult-onset PD. [ABSTRACT FROM AUTHOR]

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients. [ABSTRACT FROM AUTHOR]

Interactions with staff are important aspects in patients' experiences of psychiatric inpatient care (PIC). This study aimed to evaluate patients' satisfaction with their interactions with PIC staff and whether sociodemographic factors, depression and anxiety symptoms were associated with their perceptions of these interactions. In this cross-sectional study, we collected data from 84 patients receiving inpatient care in three psychiatric settings in Sweden. The patients' perceptions of interactions with staff and self-reported degrees of depression and anxiety were evaluated through questionnaires. Overall, patients were satisfied with the patient–staff interaction. However, significantly higher scores were related to staffs' practical competence than to their compassion. Older patients reported significantly more satisfaction than younger patients with their most recent meeting with staff. Tailored nursing interventions may improve staff's compassionate capacity. Further research in larger samples is needed to improve our understanding of the factors associated with how patients perceive their interactions with staff. [ABSTRACT FROM AUTHOR]

A lack of meaningful activities for people with mental ill health admitted to psychiatric inpatient care has been related to feelings of boredom and 'doing nothing' and is not in line with recovery‐oriented care. Staff in psychiatric inpatient care report having limited time, ambiguous responsibilities, and insufficient support that counteracts their ideals of good nursing care and puts them at risk for high levels of stress and stress of conscience. Research highlights a need for interactions between patients and staff, but few nursing interventions with such a focus are described in the literature. This qualitative study aimed to illuminate staff experiences of introducing and participating in the nursing intervention Time Together, via qualitative content analysis of 17 individual semi‐structured interviews with nursing staff in psychiatric inpatient care. The results show that these staff members experienced Time Together as an arena for mental health nursing. They prepared for the introduction of the intervention by laying a framework for success. Although the actual implementation led to them feeling burdened, they found that Time Together fostered relationships between patients and staff. For successful implementation, mental health nurses need to advocate the intervention. As Time Together constitutes an arena for mental health nursing, play and conversations based on reciprocity and equality can contribute to patients' recovery. [ABSTRACT FROM AUTHOR]

This qualitative study aimed to illuminate patients' experiences of taking part in the nursing intervention Time Together. The data were drawn from 11 individual semi‐structured interviews with patients and analysed with qualitative content analysis using an inductive approach. The results show that patients taking part in Time Together felt confirmed and participated on equal terms; thus, they experienced being seen as humans among other humans. Time Together offered patients a break, and they felt strengthened, which contributed to their hopes for recovery. Furthermore, when Time Together was absent patients felt disconfirmed, which fostered feelings of distance from staff. The results support the effectiveness of the intervention, indicating that Time Together may be a tool to facilitate patients' personal recovery. However, the success of the intervention depends on staff compliance with the predetermined structure of the intervention in combination with engagement. [ABSTRACT FROM AUTHOR]

Historically, people with mental ill‐health have been isolated from society. Although mental health care has moved from closed to more open forms of care, in many societies care is still provided in locked wards, and people with mental ill‐health are sometimes secluded from their fellow patients, families, friends, and visitors. The aim of this study was to illuminate patients' experiences of isolation in psychiatric inpatient care. A systematic review of qualitative research was conducted, and the key findings were subjected to meta‐ethnographic synthesis. The findings were twofold: 'being admitted to prison' and 'having access to shelter'. The experience of isolated care as prison‐like symbolizes patients' longing for freedom and feeling restricted and limited by rules, stripped of rights, abandoned, controlled, powerless, and unsupported. In contrast, the experience of isolation as shelter symbolizes safety and the opportunity to regain control over one's own situation. A stigmatizing public view holds that people with mental ill‐health are dangerous and unpredictable and, therefore, unsafe to themselves and others. Being placed in isolation because these fears contribute to self‐stigma among patients. Promoting a sheltered experience in which isolation is used with respect for patients and the reasons are made explicit may encourage recovery. A shift in emphasis in ward culture from observation to engagement is needed to reduce blame, shift patient experiences from prison to shelter, and to support autonomy as a therapeutic intervention. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs. [ABSTRACT FROM AUTHOR]

The facilitation of quality time between patients and staff in psychiatric inpatient care is useful to promote recovery and reduce stress experienced by staff. However, interventions are reported to be complex to implement and are poorly described in the literature. This multisite study aimed to evaluate the feasibility and effects of the nursing intervention Time Together, using mixed methods. Data consisted of notes from participant observations and logs to evaluate feasibility, and questionnaires to evaluate effects. The primary outcome for patients was quality of interactions, and for staff, it was perceived stress. The secondary outcome for patients was anxiety and depression symptom levels, and for staff, it was stress of conscience. Data were analysed using visual analysis, percentage of nonoverlapping data, and qualitative content analysis. The results showed that Time Together was a feasible intervention, but measurements showed no effects on the two patient outcomes: quality of interactions and anxiety and depressive symptoms and, questionable effects on perceived stress and stress of conscience among staff. Shared responsibility, a friendly approach, and a predictable structure enabled Time Together, while a distant approach and an unpredictable structure hindered the intervention. In conclusion, the intervention proved to be feasible with potential to enable quality interactions between patients and staff using the enabling factors as supportive components. It also had some effects on perceived stress and stress of conscience among staff. Further evaluation is needed to build on the evidence for the intervention. [ABSTRACT FROM AUTHOR]

In this paper we present a case of a structured, facilitated group process with a climate action group engaged in a local Transition initiative. We explore how the interacting contexts between action researchers and the group acted as a constraint for the trajectory of the group process, by looking at the mismatches between the group’s and the researchers’ purposes and differences in expectations about methods of engagement. A methodological framework was used for evaluating the outcomes. The primary aim of this article was to investigate and point out dynamics that may be a hindrance to the effectiveness of a facilitated local climate initiative, with the view to inform facilitation practices and improve future action research processes. [ABSTRACT FROM AUTHOR]

The brain is composed of hundreds of different neuronal subtypes, which largely retain their identity throughout the lifespan of the organism. The mechanisms governing this stability are not fully understood, partly due to the diversity and limited size of clinically relevant neuronal populations, which constitute a technical challenge for analysis. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in small neuronal populations in vivo, we present a comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons, and embryonic neural progenitors. Furthermore, we utilize the map generated by our analysis to show that the transcriptional response of midbrain dopaminergic neurons following 6-OHDA or methamphetamine injection is characterized by increased expression of genes with promoters dually marked by H3K4me3/H3K27me3. Our study provides an in vivo genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare neuronal subtypes. [ABSTRACT FROM AUTHOR]

Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50–60% of the patients have no clinical benefit. Here, we searched for predictive biomarkers to ACT in melanoma. Whole exome- and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously progressed on other immunotherapies. We report that clinical benefit is associated with significantly higher predicted neoantigen load. High mutation and predicted neoantigen load are significantly associated with improved progression-free and overall survival. Further, clinical benefit is associated with the expression of immune activation signatures including a high MHC-I antigen processing and presentation score. These results improve our understanding of mechanisms behind clinical benefit of ACT in melanoma. [ABSTRACT FROM AUTHOR]

Introduction Despite the long-known significance of the nurse-patient relationship, research in psychiatric inpatient care still reports unfulfilled expectations of, and difficulties in, interactions and relationships between patients and staff. Interventions that create structures to allow quality interactions between patients and staff are needed to solve these problems. The aim of this project is to test effects of the nursing intervention Time Together and to evaluate the intervention process. Methods and analysis This is a multisite study with a single-system experimental design using frequent measures. The primary outcomes are quality interactions for patients and perceived stress for staff. Secondary outcomes are levels of symptoms of anxiety and depression for patients and stress of conscience for staff. A process evaluation is performed to describe contextual factors and experiences. Data are collected using questionnaires, participant observations and semistructured interviews. For analysis of quantitative data, both visual and statistical methods will be used. Qualitative data will be analysed using qualitative content analysis. Ethics and dissemination Ethical approval was granted by the Ethical Review Board in the region (Dnr 2016/339- 31). The findings will contribute to the development of nursing interventions in general, but more specifically to the development of the intervention. This is relevant both nationally and internationally as similar interventions are needed but sparse. The findings will be disseminated through conference presentations and peer-reviewed publications. Trial registration number NCT02981563 [ABSTRACT FROM AUTHOR]

Introduction Fatigue is a major symptom of rheumatoid arthritis (RA), the most common chronic inflammatory joint disease. The present study explored patients' experiences of RA fatigue to elucidate unique elements and management strategies. Methods This single site study recruited tumour necrosis factor-α inhibitor (TNFi)-treated RA patients with a moderate/good response in disease activity and persistent moderate/greater fatigue on a five-point verbal rating scale. This qualitative descriptive design used semi-structured questions, individual interviews and content analysis of narrative data. Results Ten patients were interviewed (six women), with age and disease duration ranges of 44-75 and 6-36 years, respectively. Perceptions of the RA fatigue experience generated four categories (experiencing a distinct, yet seldom discussed RA symptom; seeking an explanation for fatigue; being in an incapacitating state; and trying to manage) and eight subcategories. Fatigue was newly identified as a distinct part of the entity of RA. While patients proposed many plausible root causes, the only rational explanation for the nature of this fatigue was that it was integral to their RA. Singularly, fatigue contributed considerably to RA-imposed lifestyle restrictions. Patients had learnt to accommodate and self-manage fatigue in the absence of professional input. Novel management strategies proposed included patients talking about the nature of RA fatigue with others and the need for staff to alert patients to this distinct symptom of RA. Conclusion Fatigue, branded as a distinct symptom of RA, exerted an identifiable impact on patients. Fatigue is potentially amenable to modification; talking about fatigue was proposed as a novel management strategy. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Accessible summary What is known on the subject? Psychiatric inpatient care has been described by both ward staff and patients as being demanding and disorganized, lacking opportunities for quality interactions in everyday life through joint activities., Qualitative research on interprofessional teams' perspectives on everyday life processes in psychiatric inpatient care is lacking., What this paper adds to existing knowledge? Staff have ideals about care and collaboration, but the obstacles they face in everyday life, such as a poor environment, power asymmetry, lacking structure and the demands of managing chaos, mean that they appear to resign and shift focus from the patients' best interests to self-survival., Different professions in general describe the same obstacles in everyday life on the wards but there are also profession-specific perspectives on distancing and feelings of abandonment. To our knowledge, these findings have not been reported in the international evidence., What are the implications for practice? Given these findings we suggest interventions such as Protected Engagement Time as well as reflective dialogues within interprofessional teams., This would help staff to resume their caring role in everyday life in psychiatric inpatient care and put their ideals into practice., Abstract Introduction Patients and ward staff describe psychiatric inpatient care as demanding, characterized by unpredictable events, yet research on interprofessional teams perspectives of everyday life processes in psychiatric inpatient care lacks. Aim This study aims to explore everyday life processes in psychiatric inpatient care, as reported by staff in interprofessional teams. Method A grounded theory design was used and 36 participants were interviewed. Results The analysis resulted in a process-oriented core category From ideals to resignation. Related to this core category were three further categories: Knowing where to go, Walking a path of obstacles and Shifting focus from the patient's best interests to self-survival. The staff had ideals about care and collaboration, but a poor environment, power asymmetry, lacking structure and demands of managing chaos meant that they appeared to resign from putting their ideals into practice. Discussion Different professions in general describe the same obstacles in everyday life on the wards but there are also profession-specific perspectives on distancing and feelings of abandonment. To our knowledge similar findings have not been reported in the international evidence. Implications In order to support interprofessional teams to work according to their ideals, interventions such as Protected Engagement Time and reflective dialogues within the teams are suggested. [ABSTRACT FROM AUTHOR]

Background: Immigrants experience significant challenges when in contact with healthcare and report less satisfaction with maternity care compared to native Swedes. Research that gives voice to pregnant immigrant women and their partners following a prenatal diagnosis of a fetal anomaly is scarce. Thus, the aim of this study was to explore experiences and preferences of care following a prenatal diagnosis of congenital heart defect among Swedish immigrants.Methods: Pregnant immigrants and their partners were consecutively recruited following a prenatal diagnosis of a congenital heart defect in the fetus. Nine respondents were interviewed in five interviews, four with the aid of a professional interpreter. The material was analyzed using manifest qualitative content analysis.Results: The analysis resulted in five categories: 1) "Trustworthy information", 2) "Language barriers", 3) "Psychosocial situation", 4) "Peer support", and 5) "Religious positions".Conclusion: The potential need for interpreter services, visual information, psychosocial support, coordination with welfare officers, and respect for religious positions about termination of pregnancy are all important aspects for health professionals to consider when consulting immigrants faced with a prenatal diagnosis of fetal anomaly in the fetus. Peer support within this context needs to be further explored in future studies. [ABSTRACT FROM AUTHOR]

Background: DNA methylation at CpG dinucleotides is modified in tumorigenesis with potential impact on transcriptional activity. Methods: We used the Illumina 450 K platform to evaluate DNA methylation patterns of 50 metastatic melanoma tumors, with matched gene expression data. Results: We identified three different methylation groups and validated the groups in independent data from The Cancer Genome Atlas. One group displayed hypermethylation of a developmental promoter set, genome-wide demethylation, increased proliferation and activity of the SWI/SNF complex. A second group had a methylation pattern resembling stromal and leukocyte cells, over-expressed an immune signature and had improved survival rates in metastatic tumors (p < 0.05). A third group had intermediate methylation levels and expressed both proliferative and immune signatures. The methylation groups corresponded to some degree with previously identified gene expression phenotypes. Conclusions: Melanoma consists of divergent methylation groups that are distinguished by promoter methylation, proliferation and content of immunological cells. [ABSTRACT FROM AUTHOR]

Background: The neural transcription factor SOX11 is present at specific stages during embryo development with a very restricted expression in adult tissue, indicating precise regulation of transcription. SOX11 is strongly up-regulated in some malignancies and have a functional role in tumorgenesis. With the aim to explore differences in epigenetic regulation of SOX11 expression in normal versus neoplastic cells, we investigated methylation and histone modifications related to the SOX11 promoter and the possibility to induce re-expression using histone deacetylase (HDAC) or EZH2 inhibitors. Methods: The epigenetic regulation of SOX11 was investigated in distinct non-malignant cell populations (n = 7) and neoplastic cell-lines (n = 42) of different cellular origins. DNA methylation was assessed using bisulfite sequencing, methylation-specific melting curve analysis, MethyLight and pyrosequencing. The presence of H3K27me3 was assessed using ChIP-qPCR. The HDAC inhibitors Vorinostat and trichostatin A were used to induce SOX11 in cell lines with no endogenous expression. Results: The SOX11 promoter shows a low degree of methylation and strong enrichment of H3K27me3 in non-malignant differentiated cells, independent of cellular origin. Cancers of the B-cell lineage are strongly marked by de novo methylation at the SOX11 promoter in SOX11 non-expressing cells, while solid cancer entities display a more varying degree of SOX11 promoter methylation. The silencing mark H3K27me3 was generally present at the SOX11 promoter in non-expressing cells, and an increased enrichment was observed in cancer cells with a low degree of SOX11 methylation compared to cells with dense methylation. Finally, we demonstrate that the HDAC inhibitors (vorinostat and trichostatin A) induce SOX11 expression in cancer cells with low levels of SOX11 methylation. Conclusions: We show that SOX11 is strongly marked by repressive histone marks in non-malignant cells. In contrast, SOX11 regulation in neoplastic tissues is more complex involving both DNA methylation and histone modifications. The possibility to re-express SOX11 in non-methylated tissue is of clinical relevance, and was successfully achieved in cell lines with low levels of SOX11 methylation. In breast cancer patients, methylation of the SOX11 promoter was shown to correlate with estrogen receptor status, suggesting that SOX11 may be functionally re-expressed during treatment with HDAC inhibitors in specific patient subgroups. [ABSTRACT FROM AUTHOR]

Background: Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors. Methods: We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs. Results: We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis. Conclusions: Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC. [ABSTRACT FROM AUTHOR]

Hypoxia, or low oxygen tension, is a major regulator of tumor development and aggressiveness. However, how cancer cells adapt to hypoxia and communicate with their surrounding microenvironment during tumor development remain important questions. Here, we show that secreted vesicles with exosome characteristics mediate hypoxia-dependent intercellular signaling of the highly malignant brain tumor glioblastoma multiforme (GBM). In vitro hypoxia experiments with glioma cells and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins (e.g., matrix metalloproteinases, IL-8, PDGFs, caveolin 1, and lysyl oxidase), several of which were associated with poor glioma patient prognosis. We show that exosomes derived from GBM cells grown at hypoxic compared with normoxic conditions are potent inducers of angiogenesis ex vivo and in vitro through phenotypic modulation of endothelial cells. Interestingly, endothelial cells were programmed by GBM cell-derived hypoxic exosomes to secrete several potent growth factors and cytokines and to stimulate pericyte PI3K/AKT signaling activation and migration. Moreover, exosomes derived from hypoxic compared with normoxic conditions showed increased autocrine, promigratory activation of GBM cells. These findings were correlated with significantly enhanced induction by hypoxic compared with normoxic exosomes of tumor vascularization, pericyte vessel coverage, GBM cell proliferation, as well as decreased tumor hypoxia in a mouse xenograft model. We conclude that the proteome and mRNA profiles of exosome vesicles closely reflect the oxygenation status of donor glioma cells and patient tumors, and that the exosomal pathway constitutes a potentially targetable driver of hypoxia-dependent intercellular signaling during tumor development. [ABSTRACT FROM AUTHOR]

Abstract: Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2−/Ki67low, ER+/HER2−/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer. [Copyright &y& Elsevier]

Amplification of chromosomal region 11q13, containing the cell cycle regulatory gene CCND1, is frequently found in breast cancer and other malignancies. It is associated with the favourable oestrogen receptor (ER)-positive breast tumour phenotype, but also with poor prognosis and treatment failure. 11q13 spans almost 14 Mb and contains more than 200 genes and is affected by various patterns of copy number gains, suggesting complex mechanisms and selective pressure during tumour progression. In this study, we used 32 k tiling BAC array CGH to analyse 94 CCND1-amplified breast tumours from sporadic, hereditary, and familial breast cancers to fine map chromosome 11q13. A set containing 281 CCND1-non-amplified breast tumours was used for comparisons. We used gene expression data to further validate the functional effect of gene amplification. We identified six core regions covering 11q13.1-q14.1 that were amplified in different combinations. The major core contained CCND1, whereas two cores were found proximal of CCND1 and three distal. The majority of the CCND1-amplified tumours were ER-positive and classified as luminal B. Furthermore, we found that CCND1 amplification is associated with a more aggressive phenotype within histological grade 2 tumours and luminal A subtype tumours. Amplification was equally prevalent in familial and sporadic tumours, but strikingly rare in BRCA1- and BRCA2-mutated tumours. We conclude that 11q13 includes many potential target genes in addition to CCND1. [ABSTRACT FROM AUTHOR]

Male breast cancer (MBC) is extremely rare and poorly characterized on the molecular level. Using high-resolution genomic data, we aimed to characterize MBC by genomic imbalances and to compare it with female breast cancer (FBC), and further to investigate whether the genomic profiles hold any prognostic information. Fifty-six fresh frozen MBC tumors were analyzed using high-resolution tiling BAC arrays. Significant regions in common between cases were assessed using Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. A publicly available genomic data set of 359 FBC tumors was used for reference purposes. The data revealed a broad pattern of aberrations, confirming that MBC is a heterogeneous tumor type. Genomic gains were more common in MBC than in FBC and often involved whole chromosome arms, while losses of genomic material were less frequent. The most common aberrations were similar between the genders, but high-level amplifications were more common in FBC. We identified two genomic subgroups among MBCs; male-complex and male-simple. The male-complex subgroup displayed striking similarities with the previously reported luminal-complex FBC subgroup, while the male-simple subgroup seems to represent a new subgroup of breast cancer occurring only in men. There are many similarities between FBC and MBC with respect to genomic imbalances, but there are also distinct differences as revealed by high-resolution genomic profiling. MBC can be divided into two comprehensive genomic subgroups, which may be of prognostic value. The male-simple subgroup appears notably different from any genomic subgroup so far defined in FBC. [ABSTRACT FROM AUTHOR]

Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44high/CD24low ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basallike breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer. [ABSTRACT FROM AUTHOR]

Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo), allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1) rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2) identification of co-expressed genes for creation of potential metagenes, 3) association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881- sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform. [ABSTRACT FROM AUTHOR]

Information has been described as a critical part of the care for parents of children with cancer, but not much is known about how caregivers makes decisions about informing parents. This study aims to illuminate professional caregivers’ perceptions of providing information to parents of children with cancer. Twenty caregivers at a Swedish pediatric oncology ward participated in four focus group interviews. The interviews were transcribed verbatim and subjected to qualitative content analysis. Two themes were found: Matching the amount of information to the parents’ needs concerned situations where the amount of information provided according to the caregivers’ assessment is deemed too small, appropriate, or too large. Navigating through a vague structure dealt with a disrupted setting, unclear responsibilities within the team, difficult timing, unintelligible information, and underused tools for communication. Implications for intervention development are discussed. [ABSTRACT FROM PUBLISHER]

SENN B., KIRSCH M., SANZ C.C., KARLOU C., TULUS K., DE LEEUW J., RINGNÉR A., GOOSSENS G.A. & CLEARY V. (2011) European Journal of Cancer Care, 1-4 [ABSTRACT FROM AUTHOR]

Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma. Genome-wide expression profiling revealed correlations between specific T-UCR expression levels and important clinicogenetic parameters such as MYCN amplification status. A functional genomics approach based on the integration of multi-level transcriptome data was adapted to gain insights into T-UCR functions. Assignments of T-UCRs to cellular processes such as TP53 response, differentiation and proliferation were verified using various cellular model systems. For the first time, our results define a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis. [ABSTRACT FROM AUTHOR]

Background: The use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures. Results: We develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 105 gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes. Conclusions: The presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes. [ABSTRACT FROM AUTHOR]

The childhood cancer neuroblastoma arises in the developing sympathetic nervous system and is a genotypically and phenotypically heterogeneous disease. Prognostic markers of poor survival probability include amplification of the MYCN oncogene and an undifferentiated morphology. Whereas these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. In this study, we analyze two large neuroblastoma microarray datasets using a priori-defined gene expression signatures. We show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predicts relapse and death from disease. This was evident not only for high-risk patients but was also robust in identifying groups of poor prognosis patients who were otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma. [ABSTRACT FROM AUTHOR]

Background: Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods: 32 K tiling microarray-based comparative genomic hybridization (aCGH) was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results: Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 x 10-5) unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29) displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion: Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and underscores the importance of evaluating the clonality of multiple tumors for optimal patient management. In summary, our findings demonstrate the importance of evaluating the properties of both tumors in order to determine the most optimal patient management. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The purpose was to explore negative and positive consequences of cancer during adolescence experienced two years after diagnosis. METHODS: Two years after diagnosis 38 persons, 15–21 years old, were asked two questions over the telephone: What, if anything, is bad for you due to the cancer disease? and What, if anything, is good for you due to the cancer disease? The answers were analysed by content analysis. RESULTS: Four categories of negative experiences were identified: a problematic body; unpleasant thoughts and feelings; outside the circle of friends; and difficulties with schoolwork. Six categories of positive experiences were identified: a more positive view of life; good self-esteem; knowledge and experience with regard to disease and hospital care; good relations; broader perspectives; and material gains. CONCLUSIONS: Two years after diagnosis those struck by cancer during adolescence experience not only a number of negative, but also positive, consequences of the cancer disease and its treatment. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3–q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2–q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.Oncogene (2007) 26, 4738–4748; doi:10.1038/sj.onc.1210252; published online 29 January 2007 [ABSTRACT FROM AUTHOR]

Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (BC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-PI3K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve. [ABSTRACT FROM AUTHOR]

Using high-throughput technologies, abundances and other features of genes and proteins have been measured on a genome-wide scale in Saccharomyces cerevisiae. In contrast, secondary structure in 5'-untranslated regions (UTRs) of mRNA has only been investigated for a limited number of genes. Here, the aim is to study genome-wide regulatory effects of mRNA 5'-UTR folding free energies. We performed computations of secondary structures in 5'-UTRs and their folding free energies for all verified genes in S. cerevisiae. We found significant correlations between folding free energies of 5'-UTRs and various transcript features measured in genome-wide studies of yeast. In particular, mRNAs with weakly folded 5'-UTRs have higher translation rates, higher abundances of the corresponding proteins, longer half-lives, and higher numbers of transcripts, and are upregulated after heat shock. Furthermore, 5'-UTRs have significantly higher folding free energies than other genomic regions and randomized sequences. We also found a positive correlation between transcript half-life and ribosome occupancy that is more pronounced for short-lived transcripts, which supports a picture of competition between translation and degradation. Among the genes with strongly folded 5'-UTRs, there is a huge overrepresentation of uncharacterized open reading frames. Based on our analysis, we conclude that (i) there is a widespread bias for 5'-UTRs to be weakly folded, (ii) folding free energies of 5'-UTRs are correlated with mRNA translation and turnover on a genomic scale, and (iii) transcripts with strongly folded 5'-UTRs are often rare and hard to find experimentally. [ABSTRACT FROM AUTHOR]