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Find video protocols related to scientific articles indexed in Pubmed.
Evaluating a complex system-wide intervention using the difference in differences method: the Delivering Choice Programme.
BMJ Support Palliat Care
PUBLISHED: 02-25-2015
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We report the use of difference in differences (DiD) methodology to evaluate a complex, system-wide healthcare intervention. We use the worked example of evaluating the Marie Curie Delivering Choice Programme (DCP) for advanced illness in a large urban healthcare economy.
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?v?6 Expression in Myoepithelial Cells: A Novel Marker for Predicting DCIS Progression with Therapeutic Potential.
Cancer Res.
PUBLISHED: 10-15-2014
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The tumor microenvironment dynamically regulates the progression of cancer. In the breast, a unique component of the microenvironment is the myoepithelial cell. Normal myoepithelial cells act as "natural tumor suppressors"; however, more recent evidence suggests that these cells develop phenotypic changes, which may contribute to loss of tumor suppressor activity. We have shown that myoepithelial cells in a subset of preinvasive ductal carcinoma in situ (DCIS) upregulate expression of the integrin ?v?6, switching on tumor promoter activity through activation of TGF? and MMP9. This makes the tumor microenvironment more permissive to invasion, seen both in vitro and in vivo. In human tissue samples, increased myoepithelial ?v?6 expression correlated with increased risk of disease progression and recurrence. Current estimates suggest that as many as 50% of DCIS cases will never progress in the patient's lifetime, but there are no markers to predict the outcome of individual cases. The identification of ?v?6 in a subset of DCIS presents a unique way to stratify patients with DCIS into those who may or may not progress to more serious disease. As ?v?6 is not expressed on most normal adult tissues, this finding may also provide novel targets for therapy in this high-risk group. Cancer Res; 74(21); 5942-7. ©2014 AACR.
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Behavioural and psychiatric symptoms in people with dementia admitted to the acute hospital: prospective cohort study.
Br J Psychiatry
PUBLISHED: 07-24-2014
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Dementia is common in older people admitted to acute hospitals. There are concerns about the quality of care they receive. Behavioural and psychiatric symptoms of dementia (BPSD) seem to be particularly challenging for hospital staff. AIMS To define the prevalence of BPSD and explore their clinical associations.
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Diet and growth in infancy: relationship to socioeconomic background and to health and development in the Avon Longitudinal Study of Parents and Children.
Nutr. Rev.
PUBLISHED: 06-19-2014
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To assess the relationship between diet and growth in infancy and socioeconomic background, all publications from the Avon Longitudinal Study of Parents and Children (ALSPAC) covering breastfeeding, diet and growth in infancy, and the associations of these factors with socioeconomic background and later health and developmental outcomes were reviewed. Diet was assessed by parent-completed food records and parent-completed food frequency questionnaires covering infant feeding practices. Infancy growth was monitored through routine screening and by standardized measurements. Indicators of socioeconomic background were obtained by parent-completed questionnaires. Childhood outcomes were measured by standardized procedures. Rapid early weight gain was associated with later obesity. Longer breastfeeding duration was associated with lower body fat, but not lower body mass index, and with higher IQ in mid-childhood. Breastfed infants were better at regulating their energy intake than bottle-fed infants. In bottle-fed infants, energy intake at 4 months was associated with greater weight gain up to 5 years of age. Feeding cow's milk as a main drink in infancy was associated with anemia and high salt intake. Maternal education was a strong determinant of dietary differences: low education was associated with never breastfeeding and not following feeding guidelines. ALSPAC has provided unique insights into the relationship between diet and growth in infancy and later developmental outcomes.
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A protocol for an exploratory phase I mixed-methods study of enhanced integrated care for care home residents with advanced dementia: the Compassion Intervention.
BMJ Open
PUBLISHED: 06-19-2014
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In the UK approximately 700?000 people are living with, and a third of people aged over 65 will die with, dementia. People with dementia may receive poor quality care towards the end of life. We applied a realist approach and used mixed methods to develop a complex intervention to improve care for people with advanced dementia and their family carers. Consensus on intervention content was achieved using the RAND UCLA appropriateness method and mapped to sociological theories of process and impact. Core components are: (1) facilitation of integrated care, (2) education, training and support, (3) investment from commissioners and care providers. We present the protocol for an exploratory phase I study to implement components 1 and 2 in order to understand how the intervention operates in practice and to assess feasibility and acceptability.
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The experiences of close persons caring for people with chronic kidney disease stage 5 on conservative kidney management: Contested discourses of ageing.
Health (London)
PUBLISHED: 04-01-2014
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Chronic kidney disease stage 5 is a global health challenge in the context of population ageing across the world. The range of treatment options available to patients at all ages has increased and includes transplantation and dialysis. However, these options are often seen as inappropriate for older frailer patients who are now offered the option of conservative kidney management, which is presented as a non-invasive alternative to dialysis, involving symptom management and addressing psychosocial needs. In this study, we conducted qualitative interviews with 26 close persons caring for someone with chronic kidney disease stage 5 in the United Kingdom to investigate how conservative kidney management interacted with implicit ideas of ageing, in both the experience of conservative kidney management and the understanding of the prognosis and future care of the kidney disease. Our findings highlighted participant confusion about the nature of conservative kidney management, which stems from an initial lack of clarity about how conservative kidney management differed from conventional treatments for chronic kidney disease stage 5. In particular, some respondents were not aware of the implicit palliative nature of the intervention or indeed the inevitable end-of-life issues. Although these findings can be situated within the context of communication failure, we would further argue that they also bring to the surface tensions in the discourses surrounding ageing and old age, drawing on the use of a 'natural' and a 'normal' paradigm of ageing. In the context of chronic kidney disease stage 5, more patients are being dialysed at older ages, but conservative kidney management is being advanced as a better option than dialysis in terms of quality of life and experience. However, in doing so, conservative kidney management implicitly draws on a notion of older age that echoes natural ageing rather than advocate a more interventionist approach. The role of discourses of ageing in the provision of treatments for conservative kidney management has not previously been acknowledged, and this article addresses this gap.
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Adding value to rare tissue samples donated to biobanks: characterisation of breast tissue and primary cell cultures obtained from a female-to-male transgender patient.
Cell Tissue Bank
PUBLISHED: 03-29-2014
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Biobanks provide a window of opportunity to store and add value to material from rare cases allowing their future use in biomedical research. One such example is the opportunityto obtain good quality tissue from patients undergoing gender re-assignment. Following patient agreement to donate tissue samples to our biobank we catalogued the histological appearance, defined the expression of the hormone receptors ER?, PR, AR and the proliferation marker Ki67, and generated and characterised primary cell cultures in a female to male (FTM) transgender patient referred to our unit for surgery. Immunohistochemistry was performed for ER?, PR and AR and the proliferation marker Ki67. Hormone receptor expression was confined to epithelial cells lining the breast ducts. Ki67 immunoreactivity was sparse indicating little proliferation of luminal epithelium, consistent with normal mammary gland. Cultures of epithelial cells and fibroblasts were derived from surplus tissue. The latter lacked expression of epithelial markers and hormone receptors but exhibited expression of vimentin. Culture of the former on Matrigel saw an outgrowth of more rounded "epithelial-like" cells. Immunofluoresence characterisation showed a mixed phenotype with expression of vimentin and both myoepithelial and luminal epithelial markers. Sporadic weak ER? expression and moderate PR expression was seen. In summary, as well as routinely collecting tissue and blood samples, we have characterised and stored tissue and cells from a FTM transgender patient, adding value to this resource which,available from the Breast Cancer Campaign Tissue Bank for those interested in further studying the biology of FTM transgender tissue.
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Rigidity sensing and adaptation through regulation of integrin types.
Nat Mater
PUBLISHED: 03-27-2014
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Tissue rigidity regulates processes in development, cancer and wound healing. However, how cells detect rigidity, and thereby modulate their behaviour, remains unknown. Here, we show that sensing and adaptation to matrix rigidity in breast myoepithelial cells is determined by the bond dynamics of different integrin types. Cell binding to fibronectin through either ?5?1 integrins (constitutively expressed) or ?v?6 integrins (selectively expressed in cancer and development) adapts force generation, actin flow and integrin recruitment to rigidities associated with healthy or malignant tissue, respectively. In vitro experiments and theoretical modelling further demonstrate that this behaviour is explained by the different binding and unbinding rates of both integrin types to fibronectin. Moreover, rigidity sensing through differences in integrin bond dynamics applies both when integrins bind separately and when they compete for binding to fibronectin.
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Tumour-associated endothelial-FAK correlated with molecular sub-type and prognostic factors in invasive breast cancer.
BMC Cancer
PUBLISHED: 03-25-2014
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Breast cancer is a heterogeneous disease that can be classified into one of 4 main molecular sub-types: luminal A, luminal B, Her2 over-expressing and basal-like (BL). These tumour sub-types require different treatments and have different risks of disease progression. BL cancers can be considered a sub-group of Triple negative (TN) cancers since they lack estrogen (ER), progesterone (PR) and Her2 expression. No targeted treatment currently exists for TN/BL cancers. Thus it is important to identify potential therapeutic targets and describe their relationship with established prognostic factors. Focal adhesion kinase (FAK) is upregulated in several human cancers and also plays a functional role in tumour angiogenesis. However, the association between breast cancer sub-types and tumour endothelial-FAK expression is unknown.
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Narratives of continuity among older people with late stage chronic kidney disease who decline dialysis.
Soc Sci Med
PUBLISHED: 02-11-2014
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Chronic and life-threatening conditions are widely thought to shatter the lives of those affected. In this article, we examine the accounts of 19 older people diagnosed with late stage chronic kidney disease who declined dialysis. Accounts were collected through in-depth interview in the United Kingdom (March-November, 2010). Drawing on a phenomenological approach, we focus particularly on the embodied and lived experience of the condition and on how participants constructed treatment modalities and approached treatment choice. We look toward contemporary elaborations of the conceptual framework of biographical disruption to illustrate how participants managed to contain the intrusion of illness and maintain continuity in their lives. We argue that three interactive phenomena mitigated the potential for disruption and allowed participants to maintain continuity: (a) the framing of illness as "old age"; (b) the prior experience of serious illness; and (c) the choice of the treatment with the least potential for disruption. We conclude that a diagnosis of chronic illness in late life does not inevitably shatter lives or engender biographical disruption. Instead, people are able to construct continuity owing to complex narrative interpretations of diagnosis, sensation and treatment choices.
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Enhanced recovery in the resection of colorectal liver metastases.
J Surg Oncol
PUBLISHED: 02-11-2014
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There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM).
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Are diet and feeding behaviours associated with the onset of and recovery from slow weight gain in early infancy?
Br. J. Nutr.
PUBLISHED: 02-06-2014
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Infants with slow weight gain cause concern in parents and professionals, but it is difficult to be certain whether such infants are genetically small or whether their energy intake is insufficient. The aim of the present study was to assess the impact of diet and feeding behaviours on slow weight gain early in infancy. The sample was 11 499 term infants from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 507 cases of slow weight gain from birth to 8 weeks were identified and the remaining 10 992 infants were used as controls. It was found that infants who gained weight slowly between birth and 8 weeks were more likely to exhibit feeding problems such as weak sucking and slow feeding during this period. Feeding problems were substantially reduced during the recovery phase (8 weeks to 2 years) when these infants exhibited enhanced catch-up in weight. The proportion of mothers breast-feeding in the 4th week after birth was higher for slow weight gainers, but they were more likely to switch to formula at the start of recovery. During recovery, slow-weight gain infants had a slightly higher energy intake from formula and solids than controls. In conclusion, feeding problems seem to be the most important factors associated with the onset of early slow weight gain. Subsequently, a reduction of feeding problems and an increase in overall energy intake may contribute to their weight recovery. Health professionals should look for feeding problems in the first few weeks after birth and help mothers establish adequate feeding practices.
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A cost-utility analysis of a rehabilitation service for people living with and beyond cancer.
BMC Health Serv Res
PUBLISHED: 01-21-2014
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BackgroundWe conducted a wait-list control randomised trial of an outpatient rehabilitation service for people living with and beyond cancer, delivered in a hospice day care unit. We report the results of an economic evaluation undertaken using the trial data.MethodsForty-one participants were recruited into the study. A within-trial stochastic cost-utility analysis was undertaken using Monte-Carlo simulation. The outcome measure for the economic evaluation was quality adjusted life years (QALYs). Costs were measured from the perspective of the NHS and personal social services. Uncertainty in the observed data was captured through probabilistic sensitivity analysis. Scenario analysis was conducted to explore the effects of changing the way QALYs were estimated and adjusting for baseline difference in the population. We also explore assumptions about the length of treatment benefit being maintained.ResultsThe incremental cost-effectiveness ratio (ICER) for the base-case analysis was £14,231 per QALY. When QALYs were assumed to change linearly over time, this increased to £20,514 per QALY at three months. Adjusting the estimate of QALYs to account for differences in the population at baseline increased the ICER to £94,748 per QALY at three months. Increasing the assumed length of treatment benefit led to reduced ICERs in all scenarios.ConclusionsAlthough the intervention is likely to be cost-effective in some circumstances, there is considerable uncertainty surrounding the decision to implement the service. Further research, informed by a formal value of information analysis, would reduce this uncertainty.
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Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.
Cancer Res.
PUBLISHED: 01-02-2014
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Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
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Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.
Breast Cancer Res.
PUBLISHED: 08-08-2013
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Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
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A case of recurrent mesocolon myxoid liposarcoma and review of the literature.
Case Rep Oncol Med
PUBLISHED: 08-02-2013
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Background. Liposarcoma is the second most common soft tissue sarcoma affecting predominantly the retroperitoneal space and extremities. Mesenteric liposarcoma is uncommon and occurs in the small bowel mesentery. In this paper we report the case of a recurrent mesocolon myxoid liposarcoma manifesting 6 years from the initial right hemicolectomy for the primary tumour. Case Report. A 41-year-old female presented with a 4-day history of signs and symptoms indicative of small bowel obstruction, subsequently confirmed on plain abdominal X-ray. In 2006 she underwent a right hemicolectomy for a myxoid liposarcoma of the mesentery. The patient was initially managed conservatively; however she showed no signs of improvement and was taken to theatre for an exploratory laparotomy and division of adhesional bands. During this procedure an incidental finding of a dark purple, smooth pelvic mass was identified with similar macroscopic appearance to that of splenic tissue. Histological examination revealed a recurrent mesocolon myxoid liposarcoma. Conclusion. Mesocolon myxoid liposarcoma is a rare soft tissue neoplastic pathology and carries a high risk of recurrence. Therefore, a symptomatic patient with a previous history of primary liposarcoma excision should be treated with a high index of suspicion and a longer period of followup should be considered.
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A framework for understanding quality of life in individuals without capacity.
Qual Life Res
PUBLISHED: 08-01-2013
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The wide range of tools and methods developed for measuring and valuing health-related quality of life for use in economic evaluations are appropriate for use in most populations. However, for certain populations, specific tools may need to be developed to reflect the particular needs of that population. Patients without capacity-particularly patients with severe dementia-are such a population. At present, the tools available to economists for measuring and valuing quality of life in these patients lack validity. Here, we seek to understand the framework within which common instruments have been developed, critique these instruments with respect to patients with severely restricted capacity and to develop a new way of thinking about how to value health-related quality of life in such patients.
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The influence of early feeding practices on fruit and vegetable intake among preschool children in 4 European birth cohorts.
Am. J. Clin. Nutr.
PUBLISHED: 07-17-2013
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Fruit and vegetable intake in children remains below recommendations in many countries. The long-term effects of early parental feeding practices on fruit and vegetable intake are not clearly established.
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Prospective observational study of breast cancer treatment outcomes for UK women aged 18-40 years at diagnosis: the POSH study.
J. Natl. Cancer Inst.
PUBLISHED: 05-30-2013
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Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group.
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Using qualitative evidence on patients views to help understand variation in effectiveness of complex interventions: a qualitative comparative analysis.
Trials
PUBLISHED: 05-17-2013
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Complex healthcare interventions consist of multiple components which may vary in trials conducted in different populations and contexts. Pooling evidence from trials in a systematic review is challenging because it is unclear which components are needed for effectiveness. The potential is recognised for using recipients views to explore why some complex interventions are effective and others are not. Methods to maximise this potential are poorly developed.
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Spiritual beliefs near the end of life: a prospective cohort study of people with cancer receiving palliative care.
Psychooncology
PUBLISHED: 04-25-2013
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Despite growing research interest in spirituality and health, and recommendations on the importance of spiritual care in advanced cancer and palliative care, relationships between spiritual belief and psychological health near death remain unclear. We investigated (i) relationships between strength of spiritual beliefs and anxiety and depression, intake of psychotropic/analgesic medications and survival in patients with advanced disease; and (ii) whether the strength of spiritual belief changes as death approaches.
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Preferred place of death for children and young people with life-limiting and life-threatening conditions: a systematic review of the literature and recommendations for future inquiry and policy.
Palliat Med
PUBLISHED: 04-23-2013
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Home is often cited as preferred place of death in the United Kingdom and elsewhere. This position, however, usually relies on data concerning adults and not evidence about children. The latter data are scant, primarily retrospective and from parents.
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The stochastic silencing phenotype of Arabidopsis morc6 mutants reveals a role in efficient RNA-directed DNA methylation.
Plant J.
PUBLISHED: 03-27-2013
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The RNA-directed DNA methylation (RdDM) pathway is of central importance to the initiation and maintenance of transcriptional gene silencing in plants. DNA methylation is directed to target sequences by a mechanism that involves production of small RNAs by RNA polymerase IV and long non-coding RNAs by RNA polymerase V. DNA methylation then leads to recruitment of histone-modifying enzymes, followed by establishment of a silenced chromatin state. Recently MORC6, a member of the microrchidia (MORC) family of adenosine triphosphatases (ATPases), has been shown to be involved in transcriptional gene silencing. However, reports differ regarding whether MORC6 is involved in RdDM itself or acts downstream of DNA methylation to enable formation of higher-order chromatin structure. Here we demonstrate that MORC6 is required for efficient RdDM at some target loci, and, using a GFP reporter system, we found that morc6 mutants show a stochastic silencing phenotype. By using cell sorting to separate silenced and unsilenced cells, we show that release of silencing at this locus is associated with a loss of DNA methylation. Thus our data support a view that MORC6 influences RdDM and that it is not acting downstream of DNA methylation. For some loci, efficient initiation or maintenance of DNA methylation may depend on the ability to form higher-order chromatin structure.
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Mortality and medical care after bereavement: a general practice cohort study.
PLoS ONE
PUBLISHED: 01-25-2013
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Bereaved spouses or partners are thought to be at increased risk of morbidity and mortality. However, there are few large prospective studies and results are inconsistent. We estimated the relative mortality, prescription of psychotropic medication and use of primary medical care services in adults whose cohabitee died of cancer. To do this, we undertook a cohort study using The Health Improvement Network (THIN) UK primary care database. Participants were 1) people aged over 40, who were registered with general practices and had been exposed to the death of a cohabitee from cancer; and 2) a comparison cohort frequency matched on five year age bands and sex who were cohabiting with a living partner. The baseline was chosen as six months before the date of the cancer death for the exposed group and a random date for the unexposed group. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were estimated using random effects Poisson regression to account for clustering within general practices and adjusting for other key variables. 92,129 patients were studied for a median follow up of 4 years. Cohabitees of patients who died of cancer were less likely to die of any cause (IRR 0.71, CI 0.68-0.74) after adjustment for age, gender, number of non-psychotropic prescriptions 6 months before the cancer death/index date, use of psychotropic medication 6 months before the cancer death/index date, smoking, alcohol and area deprivation score. Exposed patients were more likely to receive a prescription for antidepressant or hypnotic medication and to attend their GP both before and after the death of the cohabitee. In conclusion, we did not confirm increased mortality in cohabitees of people dying from cancer.
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Availability of long-acting and permanent family-planning methods leads to increase in use in conflict-affected northern Uganda: evidence from cross-sectional baseline and endline cluster surveys.
Glob Public Health
PUBLISHED: 01-11-2013
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Humanitarian assistance standards require specific attention to address the reproductive health (RH) needs of conflict-affected populations. Despite these internationally recognised standards, access to RH services is still often compromised in war. We assessed the effectiveness of our programme in northern Uganda to provide family planning (FP) services through mobile outreach and public health centre strengthening. Baseline (n=905) and endline (n=873) cross-sectional surveys using a multistage cluster sampling design were conducted in the catchment areas of four public health centres in 2007 and 2010. Current use of any modern FP method increased from 7.1% to 22.6% (adjusted odds ratio [OR] 3.34 [95% confidence interval (CI) 2.27-4.92]); current use of long-acting and permanent methods increased from 1.2% to 9.8% (adjusted OR 9.45 [95%CI 3.99-22.39]). The proportion of women with unmet need for FP decreased from 52.1% to 35.7%. This study demonstrates that when comprehensive FP services are provided among conflict-affected populations, women will choose to use them. The combination of mobile teams and health systems strengthening can make a full range of methods quickly available while supporting the health system to continue to provide those services in challenging and resource-constrained settings.
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GATA3 mutations found in breast cancers may be associated with aberrant nuclear localization, reduced transactivation and cell invasiveness.
Horm Cancer
PUBLISHED: 01-02-2013
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Somatic and germline mutations in the dual zinc-finger transcription factor GATA3 are associated with breast cancers expressing the estrogen receptor (ER) and the autosomal dominant hypoparathyroidism-deafness-renal dysplasia syndrome, respectively. To elucidate the role of GATA3 in breast tumorigenesis, we investigated 40 breast cancers that expressed ER, for GATA3 mutations. Six different heterozygous GATA3 somatic mutations were identified in eight tumors, and these consisted of: a frameshifting deletion/insertion (944_945delGGinsAGC), an in-frame deletion of a key arginine residue (991_993delAGG), a seven-nucleotide frameshifting insertion (991_992insTGGAGGA), a frameshifting deletion (1196_1197delGA), and two frameshifting single nucleotide insertions (1224_1225insG found in three tumors and 1224_1225insA). Five of the eight mutations occurred in tumors that retained GATA3 immunostaining, indicating that absence of GATA3 immunostaining is an unreliable predictor of the presence of GATA3 mutations. Luciferase reporter assays, electrophoretic mobility shift assays, immunofluorescence, invasion and proliferation assays demonstrated that the GATA3 mutations resulted in loss (or reduction) of DNA binding, decrease in transactivational activity, and alterations in invasiveness but not proliferation. The 991_992insTGGAGGA (Arg330 frameshift) mutation led to a loss of nuclear localization, yet the 991_993delAGG (Arg330deletion) retained nuclear localization. Investigation of the putative nuclear localization signal (NLS) sites showed that the NLS of GATA3 does not conform to either a classical mono- or bi-partite signal, but contains multiple cooperative NLS elements residing around the N-terminal zinc-finger which comprises residues 264-288. Thus, approximately 20 % ER-positive breast cancers have somatic GATA3 mutations that lead to a loss of GATA3 transactivation activity and altered cell invasiveness.
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Functional Analysis of a Breast Cancer-Associated FGFR2 Single Nucleotide Polymorphism Using Zinc Finger Mediated Genome Editing.
PLoS ONE
PUBLISHED: 01-01-2013
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Genome wide association studies have identified single nucleotide polymorphisms (SNP) within fibroblast growth factor receptor 2 (FGFR2) as one of the highest ranking risk alleles in terms of development of breast cancer. The potential effect of these SNPs, in intron two, was postulated to be due to the differential binding of cis-regulatory elements, such as transcription factors, since all the SNPs in linkage disequilibrium were located in a regulatory DNA region. A Runx2 binding site was reported to be functional only in the minor, disease associated allele of rs2981578, resulting in increased expression of FGFR2 in cancers from patients homozygous for that allele. Moreover, the increased risk conferred by the minor FGFR2 allele associates most strongly in oestrogen receptor alpha positive (ER?) breast tumours, suggesting a potential interaction between ER? and FGFR signalling. Here, we have developed a human cell line model system to study the effect of the putative functional SNP, rs2981578, on cell behaviour. MCF7 cells, an ER? positive breast cancer cell line homozygous for the wild-type allele were edited using a Zinc Finger Nuclease approach. Unexpectedly, the acquisition of a single risk allele in MCF7 clones failed to affect proliferation or cell cycle progression. Binding of Runx2 to the risk allele was not observed. However FOXA1 binding, an important ER? partner, appeared decreased at the rs2981578 locus in the risk allele cells. Differences in allele specific expression (ASE) of FGFR2 were not observed in a panel of 72 ER? positive breast cancer samples. Thus, the apparent increased risk of developing ER? positive breast cancer seems not to be caused by rs2981578 alone. Rather, the observed increased risk of developing breast cancer might be the result of a coordinated effect of multiple SNPs forming a risk haplotype in the second intron of FGFR2.
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A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences.
Breast Cancer Res. Treat.
PUBLISHED: 10-03-2011
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Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ER?, ER?1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26-0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46-1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07-0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12-0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR-PRA-PRB and ER?1/2 clusters. A striking feature was the occurrence of ER? on distinct clusters between genders. In female breast cancer, ER? clustered with PR and its isoforms; in male breast cancer, ER? clustered with ER? isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.
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Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome.
Brain
PUBLISHED: 09-13-2011
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Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4(+)> CD8(+) T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4(+) T cells were studied regarding antigen specificity and function. CD4(+) T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4(+) Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-? and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4(+) T cells was confirmed and extended by examining brain-derived JC virus-specific CD4(+) T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4(+) T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcome.
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Using qualitative synthesis to explore heterogeneity of complex interventions.
BMC Med Res Methodol
PUBLISHED: 08-26-2011
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Including qualitative evidence on patients perspectives in systematic reviews of complex interventions may reveal reasons for variation in trial findings. This is particularly the case when the intervention is for a long-term disease, as management may rely heavily on the efforts of the patient. Inclusion though seldom happens, possibly because of methodological challenges, and when it does occur the different forms of evidence are often kept separate. To explore heterogeneity in trial findings, we tested a novel approach to integrate qualitative review evidence on patients perspectives with evidence from a Cochrane systematic review.
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Advance care planning for people with dementia: a review.
Int Psychogeriatr
PUBLISHED: 08-26-2011
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Few people with dementia have made advance plans for their health care. Advance care planning (ACP) is a process of discussion between an individual and their care providers that takes account of wishes and preferences for future care. We aimed to examine the facilitators and inhibitors to ACP in people with dementia. We also aimed to identify key themes in the literature and critically review the methodologies used.
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Study protocol: the behaviour and pain in dementia study (BePAID).
BMC Geriatr
PUBLISHED: 08-08-2011
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People with dementia admitted to the acute hospital often receive poor quality care particularly with regards to management of behavioural and psychiatric symptoms of dementia (BPSD) and of pain. There have been no UK studies on the prevalence and type of pain or BPSD in people with dementia in this setting, or on how these may impact on patients, carers, staff and costs of care.
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Interventions for supporting informal caregivers of patients in the terminal phase of a disease.
Cochrane Database Syst Rev
PUBLISHED: 06-17-2011
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Patients in the terminal phase of a disease may have complex needs. It is often family and friends who play a central role in providing support, despite health professional input and regardless of whether the patient is at home or elsewhere. Such informal caring may involve considerable physical, psychological, and economic stresses. A range of supportive programmes for caregivers is being developed including psychological support and practical assistance.
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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.
Anna Marie Mulligan, Fergus J Couch, Daniel Barrowdale, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Mark Robson, Mark Sherman, Amanda B Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M Sinilnikova, Ramunas Janavicius, Thomas Vo Hansen, Finn C Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz-Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benitez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E J Meijers-Heijboer, Juul Wijnen, Encarna B Gomez Garcia, Marcel R Nelen, C Marleen Kets, Caroline Seynaeve, Madeleine M A Tilanus-Linthorst, Rob B van der Luijt, Theo van Os, Matti Rookus, Debra Frost, J Louise Jones, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy E Side, Emma McCann, Alex Murray, Susan Peock, Andrew K Godwin, Rita K Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux-Moncoutier, Marion Fassy-Colcombet, Francois Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-Pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sévenet, Dominique Stoppa-Lyonnet, Claudine Isaacs, Trinidad Caldés, Miguel de la Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa B Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D'Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey N Weitzel, Henry T Lynch, Patricia A Ganz, Gail E Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S Pankratz, Noralane M Lindor, Csilla Szabó, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F Singer, Muy-Kheng Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Phuong L Mai, Mark H Greene, Evgeny Imyanitov, Frances P O'Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E Toland, Anne-Marie Gerdes, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan Chun Ding, Susan L Neuhausen, Mary Beattie, Paul D P Pharoah, Kirsten B Moysich, Katherine L Nathanson, Beth Y Karlan, Jenny Gross, Esther M John, Mary B Daly, Saundra M Buys, Melissa C Southey, John L Hopper, Mary Beth Terry, Wendy Chung, Alexander F Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F Easton, Irene L Andrulis, Antonis C Antoniou, .
Breast Cancer Res.
PUBLISHED: 04-27-2011
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Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
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Influence of the tumor microenvironment on angiogenesis.
Future Oncol
PUBLISHED: 03-23-2011
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It is becoming increasingly recognized that the host microenvironment is essential for regulating tumor cell behavior. The cellular stromal compartment can modulate angiogenesis either directly through enhanced secretion of pro-angiogenic factors or reduced secretion of antiangiogenic factors, or indirectly by modulating the surrounding extracellular matrix. Control of angiogenesis represents a critical step in cancer progression and is a potential therapeutic target. This article focuses on the role of the tumor microenvironment in the control of angiogenesis and how dissection of the molecular interactions may enhance prognostic and predictive power and facilitate therapeutic targeting.
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5-Benzamidoisoquinolin-1-ones and 5-(?-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2).
J. Med. Chem.
PUBLISHED: 03-18-2011
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PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH?CHCO(2)H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(?-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.
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Is maternal education level associated with diet in 10-year-old children?
Public Health Nutr
PUBLISHED: 03-18-2011
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To examine the associations between maternal education level and diet in 10-year-old children.
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Advance care planning discussions in advanced cancer: analysis of dialogues between patients and care planning mediators.
Palliat Support Care
PUBLISHED: 03-01-2011
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Advance care planning (ACP) provides patients with an opportunity to consider, discuss, and plan their future care with health professionals. Numerous policy documents recommend that ACP should be available to all with life-limiting illness.
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Advance care planning in advanced cancer: can it be achieved? An exploratory randomized patient preference trial of a care planning discussion.
Palliat Support Care
PUBLISHED: 03-01-2011
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Little is known about the effectiveness of advance care planning in the United Kingdom, although policy documents recommend that it should be available to all those with life-limiting illness.
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Clinical and functional significance of ?9?1 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion.
J. Pathol.
PUBLISHED: 02-21-2011
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Integrin ?9?1 is a receptor for ECM proteins, including Tenascin-C and the EDA domain of fibronectin, and has been shown to transduce TGF? signalling. This study has examined the expression pattern of ?9?1 in 141 frozen breast carcinoma samples and related expression to prognostic indices, molecular subtype and patient outcome. Effects of ?9?1 on tumour cell migration and invasion were assessed using blocking antibody and gene transduction approaches. Integrin ?9?1 localized to myoepithelial cells in normal ducts and acini, a pattern maintained in DCIS. A subset (17%) of invasive carcinomas exhibited tumour cell expression of ?9?1, which related significantly to the basal-like phenotype, as defined by either CK5/6 or CK14 expression. Tumour expression of ?9?1 showed a significant association with reduced overall patient survival (p < 0.0001; HR 5.94, 95%CI 3.26-10.82) and with reduced distant-metastasis-free survival (p < 0.0001; HR 6.37, CI 3.51-11.58). A series of breast cancer cell lines was screened for ?9?1 with the highly invasive basal-like GI-101 cell line expressing significant levels. Both migration and invasion of this line were reduced significantly in the presence of ?9-blocking antibody and following ?9-knockdown with siRNA. Conversely, migratory and invasive behaviour of ?9-negative MCF7 cells and ?9-low MDA MB468 cells was enhanced significantly by over-expression of ?9. Thus, ?9?1 acts as a novel marker of the basal-like breast cancer subtype and expression is associated with reduced survival, while its ability to promote breast cancer cell migration and invasion suggests that it contributes to the aggressive clinical behaviour of this tumour subtype.
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Laxatives or methylnaltrexone for the management of constipation in palliative care patients.
Cochrane Database Syst Rev
PUBLISHED: 01-21-2011
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Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review.
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Facial affect processing in patients receiving opioid treatment in palliative care: preferential processing of threat in pain catastrophizers.
J Pain Symptom Manage
PUBLISHED: 01-20-2011
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As a multidimensional phenomenon, pain is influenced by various psychological factors. One such factor is catastrophizing, which is associated with higher pain intensity and emotional distress in cancer and noncancer pain. One possibility is that catastrophizing represents a general cognitive style that preferentially supports the processing of negative affective stimuli. Such preferential processing of threat--toward negative facial expressions, for example--is seen in emotional disorders and is sensitive to pharmacological treatment. Whether pharmacological (analgesic) treatment might also influence the processing of threat in pain patients is currently unclear.
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Palliative assessment and advance care planning in severe dementia: an exploratory randomized controlled trial of a complex intervention.
Palliat Med
PUBLISHED: 01-12-2011
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Patients with advanced dementia often receive poor end-of-life care. We aimed to design and pilot a palliative care and advance care plan (ACP) intervention. Patients had undergone emergency hospital admission and had severe dementia. The intervention consisted of a palliative care patient assessment which informed an ACP discussion with the carer, who was offered the opportunity to write an ACP for the person with dementia. Carer-patient dyads were randomized to usual care or the intervention. Carer-related outcome measures included the Kessler Distress Scale, Decision Satisfaction Inventory, Client Satisfaction Questionnaire and the Euroqol-5D, measured at baseline, six weeks, six months and three months after bereavement. The Satisfaction with End of Life Care in Dementia Scale was completed if the patient died. The 32 patient participants were physically frail and in the advanced stages of dementia: 62% had pressure damage to the skin, all needed feeding assistance and 95% were in pain. Nearly 50% died during the six-month follow-up period. Carers were difficult to recruit during acute admission; 33 patients and carers entered the study (22 intervention arm; 11 control arm). Only seven carers made ACPs. The care planning discussion was well received, but few carers wrote an ACP, despite intensive support from an experienced nurse specialist. Advance care planning is, in theory, a necessary intervention for people with severe dementia; the reluctance of carers to write plans needs to be explored further.
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The role of acceptance in rehabilitation in life-threatening illness.
J Pain Symptom Manage
PUBLISHED: 01-06-2011
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Palliative care rehabilitation aims to maximize physical and psychological functioning, but negative thoughts can hinder patients from attempting this approach. Acceptance and commitment therapy (ACT), a modified form of cognitive behavioral therapy, encourages individuals to experience and manage negative emotions by focusing on changing individual behavior and so improve functioning. ACT has been used in many health-related behavioral interventions but not in palliative care rehabilitation.
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Family planning in conflict: results of cross-sectional baseline surveys in three African countries.
Confl Health
PUBLISHED: 01-01-2011
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Despite the serious consequences of conflict for reproductive health, populations affected by conflict and its aftermath face tremendous barriers to accessing reproductive health services, due to insecurity, inadequate numbers of trained personnel and lack of supplies. Family planning is often particularly neglected.
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Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor.
Org. Biomol. Chem.
PUBLISHED: 12-02-2010
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The considerable interest in substituted isoquinolin-1-ones related to 5-aminoisoquinolin-1-one (5-AIQ) as drugs points to a need for an efficient and straightforward synthesis of the 4,5-disubstituted bicycles. Bromination of 5-nitroisoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but neither this nor 5-amino-4-bromoisoquinolin-1-one would participate in Pd-catalysed couplings. Protection of the lactam as 1-methoxy- and 1-benzyloxy-4-bromo-5-nitroisoquinolines, however, permitted Stille, Suzuki and Buchwald-Hartwig couplings to take place in high yields, insensitive to electronic demands and severe steric bulk in the arylboronic acids. Lithiation of 4-bromo-1-methoxy-5-nitroisoquinoline and quench with iodomethane gave 1-methoxy-4-methyl-5-nitroisoquinoline in low yield. Demethylation of the 1-methoxy-4-substituted-5-nitroisoquinolines with hydrogen bromide gave 4-substituted-5-nitroisoquinolin-1-ones, whereas hydrogenolytic debenzylation was achieved with simultaneous reduction of the 5-nitro group. 5-Amino-4-(4-trifluoromethylphenyl)isoquinolin-1-one was identified as a new potent and selective inhibitor of poly(ADP-ribose)polymerase-2 (PARP-2).
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Palliative care in advanced heart failure: an international review of the perspectives of recipients and health professionals on care provision.
J. Card. Fail.
PUBLISHED: 09-27-2010
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People with advanced heart failure (HF) have demonstrable supportive and palliative care needs. Effective service configuration and delivery should be informed by the views of those with personal experience and knowledge and should be based on available evidence. This systematic literature review aimed to collate qualitative and quantitative evidence on: 1) patients perceived needs and experiences of care provision; and 2) the perspectives and understanding of health professionals on care delivery.
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Progression of Ductal Carcinoma in Situ from the Pathological Perspective.
Breast Care (Basel)
PUBLISHED: 08-23-2010
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Ductal carcinoma in situ (DCIS) now represents up to 20% of breast cancer cases, yet its behaviour is still poorly understood. Morphological classifications go some way to predicting prognosis, but more sophisticated approaches are required to better tailor therapy to the individual. A number of biological molecules have been identified that appear to relate to prognosis and, in model systems, promote progression to invasive disease. Some of these, such as COX-2, provide real therapeutic opportunities, whilst other marker combinations are showing promise in categorising women according to risk. Gene expression studies have led to an emerging molecular classification of invasive breast cancer, and it is now evident that at least some of these molecular subtypes can be identified at the pre-invasive stage. The difference in frequency of these subtypes between DCIS and invasive cancer may hold clues as to the biological mechanisms underpinning disease transition. It is increasingly clear that the host microenvironment can have a major impact on disease behaviour, and as well as acting as potential predictive factors, the altered microenvironment phenotype also offers novel therapeutic opportunities.
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Jekyll and Hyde: the role of the microenvironment on the progression of cancer.
J. Pathol.
PUBLISHED: 08-12-2010
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It is now recognized that the host microenvironment undergoes extensive change during the evolution and progression of cancer. This involves the generation of cancer-associated fibroblasts (CAFs), which, through release of growth factors and cytokines, lead to enhanced angiogenesis, increased tumour growth and invasion. It has also been demonstrated that CAFs may modulate the cancer stem cell (CSC) phenotype, which has therapeutic implications. The altered fibroblast phenotype also contributes to the development of an altered extracellular matrix (ECM), with synthesis of ECM isoforms rarely found in normal tissues, including tenascin-C isoforms and the fibronectin EDA isoform. There is also emerging evidence of how the tensile strength of the tumour-associated ECM may be modified and lead to altered signalling in tumour cells. The hypoxic environment of the tumour stimulates angiogenesis and also impacts on other aspects of cell signalling, including the c-met pathway and lysyl oxidase-mediated signalling, which can directly promote tumour cell invasion. The inflammatory infiltrate associated with many solid tumours also modulates tumour function, having both anti- and pro-tumour effects. All of these components of the microenvironment provide potential targets for therapeutic attack, with a number of molecules already in clinical trials. It is also becoming evident that characterizing the tumour microenvironment can provide important prognostic and predictive information about tumours, independent of the tumour cell phenotype.
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Golgi reassembly stacking protein 55 interacts with membrane-type (MT) 1-matrix metalloprotease (MMP) and furin and plays a role in the activation of the MT1-MMP zymogen.
FEBS J.
PUBLISHED: 07-01-2010
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Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a proteinase involved in the remodelling of extracellular matrix and the cleavage of a number of substrates. MT1-MMP is synthesized as a zymogen that requires intracellular post-translational cleavage to gain biological activity. Furin, a member of the pro-protein convertase family, has been implicated in the proteolytic removal of the MT1-MMP prodomain sequence. In the present study, we demonstrate a role for the peripheral Golgi matrix protein GRASP55 in the furin-dependent activation of MT1-MMP. MT1-MMP and furin were found to co-localize with Golgi reassembly stacking protein 55 (GRASP55). Further analysis revealed that GRASP55 associated with the cytoplasmic domain of both proteases and that the LLY(573) motif in the MT1-MMP intracellular domain was crucial for the interaction with GRASP55. Overexpression of GRASP55 was found to enhance the formation of a complex between MT1-MMP and furin. Finally, we report that disruption of the interaction between GRASP55 and furin led to a reduction in pro-MT1-MMP activation. Taken together, these data suggest that GRASP55 may function as an adaptor protein coupling MT1-MMP with furin, thus leading to the activation of the zymogen.
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Tetraspanin CD151 regulates growth of mammary epithelial cells in three-dimensional extracellular matrix: implication for mammary ductal carcinoma in situ.
Cancer Res.
PUBLISHED: 05-25-2010
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Tetraspanin CD151 is associated with laminin-binding integrins (i.e., alpha(3)beta(1), alpha(6)beta(1), and alpha(6)beta(4)) and regulates tumor cell migration and invasion. Here, we examined the role of CD151 in proliferation of mammary epithelial cells using in vitro and in vivo models. Depletion of CD151 suppressed growth of HB2 cells, a nontumorigenic breast epithelial cell line, in three-dimensional (3D) extracellular matrices (ECM) and in Matrigel-based xenografts. Whereas the presence of alpha(3)beta(1) (but not alpha(6) integrins) was necessary to support growth of HB2 cells in 3D ECM, the pro-proliferative activity of CD151 did not require direct interaction with integrins. Furthermore, depletion of CD151 potentiated formation of the internal lumen and partial restoration of polarity when HB2 cells were cultured in 3D ECM. This correlated with a decrease in phosphorylation levels of extracellular signal-regulated kinase 1/2 and cAkt in CD151-negative cells and increase in activation of caspase-3. Accordingly, the number of CD151-positive colonies with internal lumen was increased by approximately 5-fold when cells were cultured in the presence of MAP/ERK kinase (U0126) and phosphoinositide 3-kinase (LY29004) inhibitors. To establish the physiologic relevance of pro-proliferative and morphogenetic activities of CD151, we analyzed the expression of this tetraspanin in ductal carcinoma in situ (DCIS), which is characterized by neoplastic proliferation of mammary epithelial cells. Strong homogeneous membrane expression of CD151 was found to be associated with a high grade of DCIS (P = 0.004). Taken together, these results strongly suggest that CD151 complexes play a crucial role in the development of hyperproliferative diseases in the mammary gland.
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Breast cancer dormancy can be maintained by small numbers of micrometastases.
Cancer Res.
PUBLISHED: 05-25-2010
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Late relapse of breast cancer can occur more than 25 years after primary diagnosis. During the intervening years between initial treatment and relapse, occult cancers are maintained in an apparent state of dormancy that is poorly understood. In this study, we applied a probabilistic mathematical model to long-term follow-up studies of postresection patients to investigate the factors involved in mediating breast cancer dormancy. Our results suggest that long-term dormancy is maintained most often by just one growth-restricted dangerous micrometastasis. Analysis of the empirical data by Approximate Bayesian Computation indicated that patients in dormancy have between 1 and 5 micrometastases at 10 years postresection, when they escape growth restriction with a half-life of <69 years and are >0.4 mm in diameter. Before resection, primary tumors seed at most an average of 6 dangerous micrometastases that escape from growth restriction with a half-life of at least 12 years. Our findings suggest that effective preventive treatments will need to eliminate these small numbers of micrometastases, which may be preangiogenic and nonvascularized until they switch to growth due to one oncogenic mutation or tumor suppressor gene inactivation. In summary, breast cancer dormancy seems to be maintained by small numbers of sizeable micrometastases that escape from growth restriction with a half-life exceeding 12 years.
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A review of global mechanisms for tracking official development assistance for health in countries affected by armed conflict.
Health Policy
PUBLISHED: 03-30-2010
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Poverty is highly concentrated in countries affected by armed conflict which are the furthest from reaching the Millennium Development Goals. Tracking aid patterns for health is crucial for improving the effectiveness of external aid to countries affected by armed conflict which tend to depend heavily upon external assistance and also have particularly acute health needs.
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Association of invasion-promoting tenascin-C additional domains with breast cancers in young women.
Breast Cancer Res.
PUBLISHED: 03-23-2010
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Tenascin-C (TNC) is a large extracellular matrix glycoprotein that shows prominent stromal expression in many solid tumours. The profile of isoforms expressed differs between cancers and normal breast, with the two additional domains AD1 and AD2 considered to be tumour associated. The aim of the present study was to investigate expression of AD1 and AD2 in normal, benign and malignant breast tissue to determine their relationship with tumour characteristics and to perform in vitro functional assays to investigate the role of AD1 in tumour cell invasion and growth.
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Suppression of microRNA accumulation via RNA interference in Arabidopsis thaliana.
Plant Mol. Biol.
PUBLISHED: 03-08-2010
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MicroRNAs (miRNAs) are key regulatory molecules in plants. These small RNAs are processed in the nucleus from longer precursor transcripts that form distinct secondary structures. The miRNAs target specific messenger RNAs (mRNAs) and consequently down-regulate gene expression. The importance of these regulatory molecules is wide-ranging, however, few loss-of-function mutants have been identified in miRNA genes and understanding the biology of miRNA-target pairings has largely depended upon creating alterations in the sequences of the target genes. Here we demonstrate using Arabidopsis thaliana, that it is possible to use RNA interference (RNAi) to suppress accumulation of miRNAs. Significantly reduced accumulation of miR163 and miR171a was achieved using hairpin RNAi constructs that were designed to target both the primary miRNA transcripts and their promoters. The presence of DNA methylation in the targeted promoter regions suggests that inhibition of transcription of the miRNA precursors is responsible. Reduction of miRNA accumulation resulted in an increase in accumulation of the mRNA targets of these miRNAs. This demonstrates that knock-down of miRNA expression can be achieved, thereby providing a straightforward approach for disrupting miRNA-target pairings and studying miRNA functions.
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Influences on child fruit and vegetable intake: sociodemographic, parental and child factors in a longitudinal cohort study.
Public Health Nutr
PUBLISHED: 03-03-2010
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To examine the sociodemographic, parental and child factors that predict fruit and vegetable consumption in 7-year-old children.
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TobEA: an atlas of tobacco gene expression from seed to senescence.
BMC Genomics
PUBLISHED: 02-26-2010
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Transcriptomics has resulted in the development of large data sets and tools for the progression of functional genomics and systems biology in many model organisms. Currently there is no commercially available microarray to allow such expression studies in Nicotiana tabacum (tobacco).
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The Journal of Pathology 2008 Jeremy Jass Prize for Research Excellence in Pathology.
J. Pathol.
PUBLISHED: 10-24-2009
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The first Jass Prize for Research Excellence has been awarded to a group from Hannover in Germany. These authors discovered the epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer and characterized its biological and clinical relevance. This frequent epigenetic silencing was found to occur early in the development of breast cancer, and illustrates another mechanism by which tumour development is influenced by genes that operate without expression as proteins.
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Enteral tube feeding in older people with advanced dementia: findings from a Cochrane systematic review.
Int J Palliat Nurs
PUBLISHED: 09-24-2009
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Enteral tube feeding for people with advanced dementia who have difficulty swallowing and poor nutritional intake is common. Potential benefits or harms of this practice are unclear and the authors aimed to evaluate the outcomes of this intervention.
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Arabinan metabolism during seed development and germination in Arabidopsis.
Mol Plant
PUBLISHED: 07-17-2009
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Arabinans are found in the pectic network of many cell walls, where, along with galactan, they are present as side chains of Rhamnogalacturonan l. Whilst arabinans have been reported to be abundant polymers in the cell walls of seeds from a range of plant species, their proposed role as a storage reserve has not been thoroughly investigated. In the cell walls of Arabidopsis seeds, arabinose accounts for approximately 40% of the monosaccharide composition of non-cellulosic polysaccharides of embryos. Arabinose levels decline to approximately 15% during seedling establishment, indicating that cell wall arabinans may be mobilized during germination. Immunolocalization of arabinan in embryos, seeds, and seedlings reveals that arabinans accumulate in developing and mature embryos, but disappear during germination and seedling establishment. Experiments using 14C-arabinose show that it is readily incorporated and metabolized in growing seedlings, indicating an active catabolic pathway for this sugar. We found that depleting arabinans in seeds using a fungal arabinanase causes delayed seedling growth, lending support to the hypothesis that these polymers may help fuel early seedling growth.
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ELISPOT and functional T cell analyses using HLA mono-specific target cells.
J. Immunol. Methods
PUBLISHED: 07-03-2009
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Simple T cell assays specific for any chosen HLA class I or class II/peptide combination, are of enormous value in cancer immunotherapy, clinical trials, vaccine and infectious disease research. The reliable measurement of T cell activity can be difficult due to the presence of other alleles on target cells, particularly for the non-HLA-A2 alleles, and the varying baseline characteristics of the different APCs employed. In the absence of pulsing with HLA-A2 restricted peptides, T2 cells are functionally HLA class I and II negative. By coating these cells with recombinant HLA peptide complexes, HLA mono-specific cells are produced that present only a defined single epitope, and generate minimal background immune activation. In ELISPOT, intracellular cytokine staining (ICS) and killing assays using T cells specific for HLA-A2/peptide complexes, the HLA mono-specific cells gave comparable results, to those using standard peptide pulsed HLA-A2 positive T2 cells without significant background. Successful T cell assays for non-HLA-A2 T cells were also performed, with PBMCs recognizing HLA-A24 and HLA-DR15/peptide complexes. The data, obtained with ELISPOT, ICS and FACS-based killing assays, all demonstrate high specificity of T cell activity and low levels of background activity. HLA mono-specific cells are simple to prepare, and can be used with any stable recombinant HLA allele/peptide combination; providing a useful system for improved T cell functional analyses across all HLA allotypes. This represents a significant advance in the generation of reliable functional T cell data.
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Dementia in the acute hospital: prospective cohort study of prevalence and mortality.
Br J Psychiatry
PUBLISHED: 07-02-2009
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Increasing numbers of people will die with dementia, many in the acute hospital. It is often not perceived to be a life-limiting illness.
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Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility.
Nat. Cell Biol.
PUBLISHED: 06-15-2009
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Here we use intravital imaging to demonstrate a reversible transition to a motile state as breast cancer cells spread. Imaging primary tumours revealed heterogeneity in cell morphology and motility. Two distinct modes of motility were observed: collective and single-celled. By monitoring the localization of Smad2 and the activity of a TGFbeta-dependent reporter gene during breast cancer cell dissemination, we demonstrate that TGFbeta signalling is transiently and locally activated in motile single cells. TGFbeta1 switches cells from cohesive to single cell motility through a transcriptional program involving Smad4, EGFR, Nedd9, M-RIP, FARP and RhoC. Blockade of TGFbeta signalling prevented cells moving singly in vivo but did not inhibit cells moving collectively. Cells restricted to collective invasion were capable of lymphatic invasion but not blood-borne metastasis. Constitutive TGFbeta signalling promoted single cell motility and intravasation but reduced subsequent growth in the lungs. Thus, transient TGFbeta signalling is essential for blood-borne metastasis.
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Tracking official development assistance for reproductive health in conflict-affected countries.
PLoS Med.
PUBLISHED: 04-27-2009
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Reproductive health needs are particularly acute in countries affected by armed conflict. Reliable information on aid investment for reproductive health in these countries is essential for improving the efficiency and effectiveness of aid. The purpose of this study was to analyse official development assistance (ODA) for reproductive health activities in conflict-affected countries from 2003 to 2006.
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Enteral tube feeding for older people with advanced dementia.
Cochrane Database Syst Rev
PUBLISHED: 04-17-2009
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The use of enteral tube feeding for patients with advanced dementia who have poor nutritional intake is common. In one US survey 34% of 186,835 nursing home residents with advanced cognitive impairment were tube fed. Potential benefits or harms of this practice are unclear.
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Screening for distress and depression in cancer patients: is ultrashort depression screening a valid measure in the UK? A prospective validation study.
J Pain Symptom Manage
PUBLISHED: 04-02-2009
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This study sought to validate the two-question (2Q) depression screen as a screening tool for psychological distress and depression against four criterion measures (Hospital Anxiety and Depression Scale [HADS], General Health Questionnaire-12, Brief Symptom Inventory-18 [BSI-18], and the distress thermometer) for a UK cancer population. We used a prospective cross-sectional study design. A consecutive sample of 399 outpatients from four outpatient oncology clinics and a palliative care day center in North London were initially identified. Of these, 249 were eligible, of whom 171 consented to take part. Data were analyzed using receiver operating characteristic analysis to examine the sensitivity and specificity of the 2Q depression instrument against the cutoff scores already shown to demonstrate clinically significant symptoms ("caseness") in the criterion measures. Sensitivity and specificity, with 95% confidence intervals, were calculated in addition to positive and negative predictive values. The 2Q depression screen showed sensitivity of 68%-89% and specificity of 70%-84% when compared with our four criterion measures in screening for psychological distress; its best performance was against the HADS (89% sensitivity and 79% specificity). In screening for depression, the 2Q depression screen showed sensitivity of 84%-94% and specificity of 72%-73% when compared with our two criterion measures, its best performance being against the BSI depression subscale (94% sensitivity and 72% specificity). Our study demonstrated that the 2Q depression screen showed good psychometric properties, which further supports its usefulness as a simple instrument in screening for psychological distress in cancer patients in the UK.
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Diagnosis, incidence, and outcomes of suspected typhlitis in oncology patients--experience in a tertiary pediatric surgical center in the United Kingdom.
J. Pediatr. Surg.
PUBLISHED: 02-24-2009
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Typhlitis is clinically defined by the triad of neutropenia, abdominal pain, and fever. Radiologic evidence of colonic inflammation supports the diagnosis. We report a single United Kingdom tertiary center experience with management and outcome of typhlitis for 5 years.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.